Acrylamide-substituted indane compounds and their therapeutic uses

Abstract

The present invention relates to indane compounds of formula (I), their preparation and therapeutic use. [Case 1] TIFF2023535482000049.tif3299

Description

[Technical Field]

[0001] The present disclosure relates to indane compounds, their preparation, and their therapeutic uses.

[0002] The compounds described herein are inhibitors of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription. [Background technology]

[0003] TEAD proteins and the HIPPO-YAP1 / TAZ signaling cascade Transcriptional enhanced associate domain (TEAD) proteins are transcription factors consisting of four family members (TEAD1-4) that function in regulating gene expression in response to the HIPPO pathway. TEAD proteins preferentially associate with the transcription coactivator yes associated protein 1 (YAP1) or transcriptional coactivator with a PDZ-binding motif (TAZ, also known as VWVTR1). YAP1-TEAD or TAZ-TEAD binds to DNA and initiates transcription of several different genes involved in cell proliferation, survival, migration, stemness, and differentiation (reviewed in (Non-Patent Document 1)). YAP1 / TAZ-TEAD activity is tightly regulated by the HIPPO pathway.

[0004] The Hippo pathway was first discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling pathway that regulates many biological processes, including cell proliferation and lifespan determination, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of kinases including MST1 / 2 and LATS1 / 2, their associated adaptor proteins SAV1 and MOB1, and a cascade of upstream regulators such as NF2, SCRIBBLE, CRUMBS, and multiple G protein-coupled receptors. The Hippo pathway is tightly regulated by both intrinsic and extrinsic signals, such as mechanical forces, cell-cell contact, polarity, energy status, stress, and many diffusible hormonal factors (reviewed in (Non-Patent Document 2)). When Hippo pathway kinases are activated (i.e., when Hippo is "on"), the cytosolic YAP1 and TAZ proteins are phosphorylated and therefore remain inactive by cytoplasmic sequestration and / or degradation by the proteasome. When Hippo pathway kinases are inactivated (i.e., Hippo is in an "off" state), cytosolic YAP1 and TAZ are no longer phosphorylated and are therefore free to translocate to the cell nucleus, where they associate with TEAD transcription factors, bind to DNA, and regulate gene expression. Decreased levels of pYAP1 / YAP1, as well as increased gene expression regulated by YAP1 / TAZ-TEAD activity and increased promoter activity in TEAD-regulated genes, are common indicators of YAP1 activation (reviewed in (Non-Patent Document 3)).

[0005] The Hippo-YAP1 / TAZ / TEAD pathway and human cancer In recent years, studies have demonstrated that deregulation of Hippo-YAP1 / TAZ-TEAD activity contributes to tumor progression and resistance to treatment in many different cancer indications and settings. In mice, systematic genetic studies have clearly demonstrated that knocking out components of the Hippo pathway (YAP1 inhibitors) or overexpressing YAP1 activators, such as YAP1, TAZ, and TEAD, activates YAP1 and leads to YAP1-TEAD-dependent tumor development and progression (see Non-Patent Documents 4, 5, 6, and 7). In humans, genetic alterations in the pathway occur most frequently in NF2 (neurofibromin), an upstream regulator of the core Hippo pathway that has been associated with hereditary cancer syndromes and classified as a tumor suppressor gene. Hundreds of somatic mutations in NF2 have been reported, primarily in meningiomas, mesotheliomas, and peripheral nerve sheath tumors, but also in other cancer types (reviewed in Non-Patent Document 8). Genetic alterations directly within the core Hippo pathway, more common than NF2, are less commonly observed in patients and are found to occur at high rates only in certain indications, such as malignant mesothelioma. Malignant mesothelioma is a lethal serous cancer almost exclusively associated with asbestos exposure. Malignant mesothelioma is a therapeutic indication that exhibits a high rate of alterations in the HIPPO signaling pathway and a high dependency on YAP1 activation and YAP1-TEAD activity (reviewed in (Non-Patent Document 9)). Increased YAP1 or YAP1-TEAD activity is not limited to genetic alterations in the HIPPO pathway but can also be the result of upregulation by multiple interconnected signals. Well-described examples of numerous pathways that play a key role in tumorigenesis involving the HIPPO-YAP1 / TAZ / TEAD1 cascade include the RTK-RAS-RAF-MEK-ERK, WNT, TGF-beta, and AMPK pathways (reviewed in (Non-Patent Document 10)).Thus, the number of tumor types that depend, at least in part, on YAP1-TEAD activation is enormous, ranging from breast, ovarian, uterine, and prostate cancers to lung, gastric, colorectal, bladder, pancreatic, and liver cancers, as well as sarcomas, esophageal, head and neck cancers, uveal melanoma, and gliomas (reviewed in (Non-Patent Document 11)). Recent studies have revealed an interplay between the HIPPO-YAP / TAZ / TEAD pathway and the human immune response (reviewed in (Non-Patent Document 12)).

[0006] YAP1 activation has been observed in the context of therapy resistance and is recognized as a major mechanism of resistance and survival to anticancer therapy. In esophageal cancer, YAP1 is a positive regulator of EGFR (epidermal growth factor receptor), and YAP1 induction is associated with resistance to 5-FU and docetaxel. In the context of targeted therapy, YAP1 in BRAF-mutant tumors functions as a parallel survival donor to promote resistance to RAF and MEK inhibitor treatment in melanoma. Similarly, YAP1 activation is a mechanism of survival against EGFR and MEK inhibitor treatment in the context of EGFR-mutant lung cancer, and multiple studies have identified YAP1 activation as one of the major bypass mechanisms for KRAS inhibition. In the context of hormone-dependent tumors, TAZ inhibition has been shown to restore sensitivity to tamoxifen in breast cancer. In prostate cancer cells, resistance to androgen deprivation treatment has been associated with increased YAP nuclear localization and activity (reviewed in (Non-Patent Document 13) (Non-Patent Document 14)).

[0007] Thus, the HIPPO-YAP / TAZ / TEAD pathway is a critical player in cancer development and tumor maintenance, and targeting this pathway is key to cancer therapy both in the first-line setting and in addressing drug resistance in multiple cancer indications. [Prior art documents] [Non-patent literature]

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 1 atent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document atent Document 13

Non-Patent Document 14

Summary of the Invention

Problems to be Solved by the Invention

[0009] Therefore, there is a need for inhibitors of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription. [Means for solving the problem]

[0010] As used herein, compounds of formula (I) [ka] [In the formula, R1 is - oxygen atoms, and - -N(H)- or -N(R8)- radicals, where R8 is a (C1-C4) alkyl group, in particular a methyl group; is selected from R2 is a phenyl group which is unsubstituted or substituted by one or more R groups, a benzyl group which is unsubstituted or substituted by one or more R5 groups, - (C4-C8)cycloalkyl groups, in particular cyclohexyl or cyclopentyl groups, more particularly cyclohexyl groups, wherein the (C4-C8)cycloalkyl groups are unsubstituted or substituted by one or more R5 groups, heteroaryl groups, in particular pyridinyl groups, wherein the heteroaryl groups are unsubstituted or substituted by one or more R5 groups; - (C1-C6) alkyl groups, in particular (C1-C4) alkyl groups, wherein the (C1-C6) alkyl groups are substituted with one or more fluorine atoms, is selected from R4 is halogen atoms, in particular fluorine or chlorine atoms, - unsubstituted or (C1-C4) alkyl groups substituted by one or more fluorine atoms, in particular methyl or trifluoromethyl groups, - unsubstituted or (C1-C4)alkoxy groups substituted by one or more fluorine atoms, in particular methoxy or trifluoromethoxy groups, - C(O)-O-(C1-C4) alkyl groups, in particular C(O)-O-methyl groups; - (C3-C6) cycloalkyl groups, in particular cyclopropyl groups; - (C1-C4) alkylthio groups, in particular methylthio groups; - Pentafluorosulfanyl group is selected from R5 is halogen atoms, in particular fluorine atoms, and - unsubstituted or (C1-C4) alkyl groups substituted by one or more fluorine atoms, in particular trifluoromethyl groups, is selected from R3 is - hydrogen atoms, and - (C1-C4) alkyl groups, especially methyl groups is selected from R6 is selected from hydrogen atoms and halogen atoms, in particular fluorine atoms; R7 is independent, halogen atoms, in particular fluorine atoms, - (C1-C4) alkyl groups, in particular methyl groups; - a hydroxy group, - (C1-C4) alkoxy groups, especially methoxy groups is selected from n is 0, 1, or 2] or a pharmaceutically acceptable salt thereof is disclosed.

[0011] In certain embodiments, a compound of formula (I') [ka] [In the formula, R1 is - oxygen atoms, and - -N(H)- group is selected from R2 is a phenyl group which is unsubstituted or substituted by one or more R groups, a benzyl group which is unsubstituted or substituted by one or more R5 groups, -(C4-C8)cycloalkyl groups, in particular cyclohexyl groups, wherein the (C4-C8)cycloalkyl group is unsubstituted or substituted with one or more R5 groups; heteroaryl groups, in particular pyridinyl groups, where the heteroaryl groups are unsubstituted or substituted with one or more R5 groups, and - (C1-C4) alkyl groups substituted with one or more fluorine atoms; is selected from R4 is halogen atoms, in particular fluorine atoms, - unsubstituted or (C1-C4) alkyl groups substituted by one or more fluorine atoms, in particular methyl or trifluoromethyl groups, - (C1-C4)alkoxy groups, unsubstituted or substituted by one or more fluorine atoms, in particular methoxy or trifluoromethoxy groups, and - C(O)-O-(C1-C3) alkyl groups, especially C(O)-O-methyl groups is selected from R5 is halogen atoms, in particular fluorine atoms, and - unsubstituted or (C1-C4) alkyl groups substituted with one or more fluorine atoms, in particular trifluoromethyl groups; is selected from R3 is - hydrogen atoms, and - (C1-C4) alkyl groups, especially methyl groups or a pharmaceutically acceptable salt thereof.

[0012] The compounds of formula (I), and in particular the compounds of formula (I'), may contain one or more asymmetric carbon atoms and therefore may exist in the form of enantiomers or diastereoisomers and mixtures thereof.

[0013] Compounds of formula (I), and in particular compounds of formula (I'), may also exist in tautomeric forms.

[0014] The compounds of formula (I), and in particular the compounds of formula (I'), can exist in the form of bases or addition salts with acids or bases, in particular pharmaceutically acceptable salts.

[0015] Pharmaceutically acceptable salts of the compounds of formula (I), and in particular of formula (I'), form part of the invention. DETAILED DESCRIPTION OF THE INVENTION

[0016] As used herein, certain terms have the following definitions: - Halogen atoms: fluorine, chlorine, bromine, or iodine atoms; - alkyl group: a linear or branched saturated aliphatic group. Examples include methyl, ethyl, propyl, isopropyl, etc.; - cycloalkyl groups: cyclic alkyl groups including spiro groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexanyl, etc.; - alkenyl groups: linear or branched monounsaturated or polyunsaturated aliphatic groups, for example containing one or two ethylenic unsaturations; - alkoxy group: the group -O-alkyl, in which the alkyl group is as defined above. Alkoxy groups include methoxy, ethoxy, isopropoxy, etc.; - heteroaryl group: a cyclic aromatic group containing 4 to 9 carbon atoms and containing 1 or 2 heteroatoms, such as oxygen or nitrogen, more particularly nitrogen. Examples of heteroaryl groups include pyridinyl groups; - alkylcarboxy group: C(O)-O-alkyl group, wherein the alkyl group is as defined above. For example, a (C1-C3) alkylcarboxy group is a C(O)-O-(C1-C3) alkyl group. Examples of alkylcarboxy groups include methylcarboxy, ethylcarboxy, etc.; - alkylthio group: an -S-alkyl group, wherein the alkyl group is as defined above. Examples of alkylthio groups include the methylthio group; - Benzyl group: -CH2-phenyl group;

[0017] Among the compounds of formula (I), mention may be made of compounds in which R6 is a hydrogen atom.

[0018] Among the compounds of formula (I), mention may be made of compounds in which n is 0.

[0019] Among the compounds of formula (I), mention may be made of compounds in which R1 is an oxygen atom or an —N(H)— group.

[0020] In one embodiment, the compounds of formula (I) are compounds of a first group in which the indane is substituted at the 1-position with a -R1-R2 group according to IUPAC numbering, i.e., compounds of formula (Ia) below: [ka] or a pharmaceutically acceptable salt thereof.

[0021] In particular, the compounds of formula (I') belong to a subgroup of compounds in which the indane is substituted in the 1-position according to the IUPAC numbering with a -R1-R2 group, i.e. compounds of formula (I'a) below: [ka] or a pharmaceutically acceptable salt thereof.

[0022] In another embodiment, the compounds of formula (I) are compounds of a second group in which the indane is substituted at the 3-position according to the IUPAC numbering with a -R1-R2 group, i.e., compounds of formula (Ib) below: [ka] or a pharmaceutically acceptable salt thereof.

[0023] In particular, the compounds of formula (I') belong to a subgroup of compounds in which the indane is substituted in the 3-position according to the IUPAC numbering with a -R1-R2 group, namely compounds of formula (I'b) below: [ka] or a pharmaceutically acceptable salt thereof.

[0024] In another embodiment, the compounds of formula (I) are compounds of a third group in which the indane is substituted at the 2-position with a -R1-R2 group according to the IUPAC numbering, namely compounds of formula (Ic) below: [ka] or a pharmaceutically acceptable salt thereof.

[0025] In particular, the compounds of formula (I') belong to the group of compounds in which the indane is substituted in the 2-position according to the IUPAC numbering with a -R1-R2 group, i.e. compounds of formula (I'c) below: [ka] or a pharmaceutically acceptable salt thereof.

[0026] In another embodiment, the compounds of formula (I), and in particular the compounds of formula (I'), comprise a fourth group consisting of compounds in which R3 is a hydrogen atom.

[0027] In another embodiment, compounds of formula (I), and in particular compounds of formula (I'), are R1 is an oxygen atom and R2 is a phenyl group which is unsubstituted or substituted by one or more R groups, - (C4-C8)cycloalkyl groups, in particular cyclohexyl or cyclopentyl groups, where the cycloalkyl groups are unsubstituted or substituted by one or more R5 groups, and - (C1-C5) alkyl groups, in particular (C1-C4) alkyl groups, in which the alkyl groups are substituted by one or more fluorine atoms, in particular CF3-substituted (C1-C4) alkyl groups, in particular (C2-C3) alkyl groups, or R1 is -N(H)- and R2 is selected from: - a phenyl group that is unsubstituted or substituted by one or more R4 groups, and heteroaryl groups, in particular pyridinyl groups, where the heteroaryl group is unsubstituted or substituted by one or more R5 groups; Selected from A fifth group of compounds is included.

[0028] Among the compounds of the fifth group, R2 is a phenyl group which is unsubstituted or substituted by one or more R groups, - (C4-C8)cycloalkyl groups, in particular cyclohexyl or cyclopentyl groups, where the cycloalkyl groups are substituted with one or more R5 groups, with the proviso that R1 is an oxygen atom; and - (C1-C5) alkyl groups, in particular (C1-C4) alkyl groups, which are substituted by one or more fluorine atoms, in particular CF3-substituted (C1-C4) alkyl groups, in particular (C2-C3) alkyl groups, in which R1 is an oxygen atom; Mention may be made of compounds of formula (I), and in particular of formula (I'), selected from:

[0029] In one embodiment, among the above group of compounds, mention may be made of compounds of formula (I), in particular compounds of formula (I'), in which R2 is a phenyl group that is unsubstituted or substituted with one or more R4 groups.

[0030] In another embodiment, mention may be made of compounds of formula (I), and in particular of formula (I'), in which R2 is a phenyl group substituted with one or more R4 groups.

[0031] In another embodiment, R1 is an oxygen atom, R2 is a (C4-C8)cycloalkyl group, in particular a cyclohexyl group or a cyclopentyl group, wherein the cycloalkyl group is substituted with one or more R5 groups; Mention may be made of compounds of formula (I) and in particular of formula (I').

[0032] In another embodiment, R1 is an oxygen atom, R2 is a (C1-C4) alkyl group, particularly a (C2-C3) alkyl group, substituted with CF3; Mention may be made of compounds of formula (I) and in particular of formula (I').

[0033] In yet another embodiment, R1 is a -N(H)- group, R2 is a pyridinyl group substituted with one or more R5 groups; Mention may be made of compounds of formula (I) and in particular of formula (I').

[0034] Among the compounds of the above group, R4 is halogen atoms, in particular fluorine or chlorine atoms, in particular fluorine atoms, and - (C1-C4) alkyl groups, unsubstituted or substituted by one or more fluorine atoms, in particular methyl or trifluoromethyl groups; Mention may be made of compounds of formula (I), and in particular of formula (I'), selected from:

[0035] In one embodiment, in the compounds of formula (I), and particularly in the compounds of formula (I'), R4 is selected from a fluorine atom, a methyl group, and a trifluoromethyl group.

[0036] In another embodiment, in the compounds of formula (I), and particularly in the compounds of formula (I'), R4 is selected from a fluorine atom and a trifluoromethyl group.

[0037] In another embodiment, in compounds of formula (I), and particularly in compounds of formula (I'), the R4 groups are located meta and / or para to the R2 phenyl group.

[0038] Among the above group of compounds, mention may be made of the compounds of formula (I) and in particular of formula (I') in which R5 is chosen from a fluorine atom and a trifluoromethyl group.

[0039] In one embodiment, in compounds of formula (I), and particularly in compounds of formula (I'), the R5 group is in the para position to the R2 group.

[0040] In another embodiment, in compounds of formula (I), and particularly in compounds of formula (I'), the R5 group is meta to the R2 group.

[0041] In another embodiment, compounds of formula (I), and in particular compounds of formula (I'), are R1 is -N(H)-; R2 is a benzyl group unsubstituted or substituted by one or more R5 groups, in particular a trifluoromethyl group; A sixth group is comprised of compounds of formula (I), particularly compounds of formula (I').

[0042] Among the sixth group of compounds, mention may be made of compounds of formula (I), and in particular of formula (I'), in which the R5 group is in the meta or para position to the R2 benzyl group.

[0043] In the compounds of formula (I), n is 1 and R7 is - fluorine atoms, - (C1-C4) alkyl groups, in particular methyl groups; - a hydroxy group, - (C1-C4) alkoxy groups, especially methoxy groups The compound may be selected from:

[0044] Among the compounds of formula (I), mention may be made of compounds in which n is 2 and R7 are both (C1-C4) alkyl groups, in particular methyl groups, where the alkyl groups, in particular methyl groups, are more particularly borne by the same carbon atom.

[0045] In another embodiment, the compound of formula (I) is R1 is selected from an oxygen atom, an —N(H)— group, and an —N(CH3)— group; R2, a phenyl group which is unsubstituted or substituted by one or more R groups, - a benzyl group which is unsubstituted or substituted by one or more trifluoromethyl groups, provided that R1 is -N(H)-; a cyclohexyl or cyclopentyl group, in particular a cyclohexyl group, wherein the cyclohexyl or cyclopentyl group is substituted by one or more R groups, - a pyridinyl group substituted with one or more R5 groups, and - (C2-C5) alkyl groups substituted with one or more fluorine atoms, in particular (C1-C4) alkyl groups substituted with CF3; is selected from R4 is selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, a C(O)—O-methyl group, a cyclopropyl group, a methylthio group, and a pentafluorosulfanyl group; R5 is selected from a fluorine atom and a trifluoromethyl group; R3 is selected from a hydrogen atom and a methyl group; R6 is selected from a hydrogen atom and a fluorine atom; R7 is independent, - fluorine atoms, - methyl group, - a hydroxy group, - methoxy group, is selected from n is 0, 1 or 2; A seventh group consists of compounds of formula (I): or a pharmaceutically acceptable salt thereof.

[0046] In another embodiment, the compound of formula (I') is R1 is selected from an oxygen atom and an —N(H)— group; R2, a phenyl group which is unsubstituted or substituted by one or more R groups, - a benzyl group which is unsubstituted or substituted by one or more trifluoromethyl groups, provided that R1 is -N(H)-; a cyclohexyl group substituted with one or more R5 groups, - a pyridinyl group substituted with one or more R5 groups, and - (C3-C4) alkyl groups substituted with one or more fluorine atoms, in particular (C2-C3) alkyl groups substituted with CF3; is selected from R4 is selected from a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, and a C(O)—O-methyl group; R5 is selected from a fluorine atom and a trifluoromethyl group; R3 is selected from a hydrogen atom and a methyl group; A seventh group consists of compounds of formula (I'), or a pharmaceutically acceptable salt thereof:

[0047] In another embodiment, the compound of formula (I), in particular formula (I'), is the following compound: N-(2-((4,4,4-trifluorobutyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-((3-fluoropropyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-(((cis)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-(((trans)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((3-methoxyphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; Methyl-3-((5-acrylamido-2,3-dihydro-1H-inden-1-yl)amino)benzoate; An eighth group comprises compounds of formula (I), particularly compounds of formula (I'), excluding: and pharmaceutically acceptable salts thereof.

[0048] All these subgroups, taken alone or in combination, are part of the present description.

[0049] Among the compounds of formula (I) that are the subject of the present invention, in particular the following compounds: (No. 1) N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 2) (R)—N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 3) (S)—N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 4) N-methyl-N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 5) N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 6) (S)—N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 7) (R)—N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 8) N-(1-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 9) N-(1-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 10) N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 11) N-(3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 12) N-(3-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 13) N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 14) N-(3-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 15) N-(3-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 16) N-(1-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 17) N-(1-((3-methoxyphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 18) N-(1-(m-tolylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 19) N-(1-((6-fluoropyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 20) N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 21) N-(1-((5-fluoropyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 22) Methyl-3-((5-acrylamido-2,3-dihydro-1H-inden-1-yl)amino)benzoate; (No. 23) N-(3-(benzylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 24) N-(1-((3-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 25) N-(1-((4-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 26) N-(2-(((cis)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 27) N-(2-(((trans)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 28) N-(2-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 29) N-(2-((4,4,4-trifluorobutyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 30) N-(2-((3-fluoropropyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 31) N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 32) N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 33) N-(3-(4,4,4-trifluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 34) N-(3-(4-fluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 35) N-(3-((4,4-difluorocyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 36) N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 37) N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 38) N-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 39) N-(3-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 40) N-(3-(3,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 41) N-(3-(3-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 42) N-(3-(4-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 43) N-(3-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 44) N-(3-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 45) N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 46) N-(1-(3-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 47) Methyl 3-[6-(prop-2-enoylamino)-2,3-dihydro-1H-inden-1-yl]oxybenzoate; (No. 48) (S)—N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; No. 49) (R)—N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 50) (R)—N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 51) (S)—N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 52) N-[2-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 53) N-(3-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 54) N-(1-((3-(pentafluoro-16-sulfanyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 55) (R)—N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 56) (S)—N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 57) N-[(1S)-1-[[4-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 58) N-[(1R)-1-[[4-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 59) N-(1-((4-(trifluoromethyl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide 2,2,2-trifluoroacetate; (No. 60) N-(1-((6-(trifluoromethyl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 61) N-(1-((5-(trifluoromethyl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 62) N-(1-(methyl(3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 63) N-(1-(methyl(phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 64) N-(1-(methyl(4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 65) N-(3,3-dimethyl-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; No. 66. N-(3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 67) N-[7-fluoro-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 68) N-[4-fluoro-1-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 69) N-methyl-N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 70) N-(3-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 71) N-(3-((3-(trifluoromethyl)cyclopentyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 72) N-(3-((5,5,5-trifluoropentyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 73) N-(3-(4,4-difluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 74) N-(3-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 75) N-(3-(3,3,3-trifluoropropoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 76) N-methyl-N-(1-((4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 77) N-(3-(4-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 78) N-(3-(3-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 79) N-(3-(m-tolyloxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 80) N-(3-(3-(methylthio)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 81) N-(3-(3-cyclopropylphenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 82) N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 83) N-methyl-N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 84) (S)—N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 85) (R)—N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 86) (S)—N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 87) (R)—N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 88) N-[3-[[5-(trifluoromethyl)pyridin-2-yl]oxy]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 89) N-methyl-N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 90) N-[2-fluoro-3-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 91) N-(2-fluoro-3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 92) N-[2-fluoro-3-[4-(trifluoromethyl)phenoxy]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 93) N-methyl-N-(2-methyl-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 94) N-[(cis)-3-methoxy-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 95) N-[(trans)-2-hydroxy-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; (No. 96) N-[rac-(2R,3R)-2-hydroxy-3-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; or a pharmaceutically acceptable salt thereof.

[0050] Among the compounds of formula (I') that are the subject of the present invention, in particular the following compounds: (No. 1) N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 2) (R)—N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 3) (S)—N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 4) N-methyl-N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 5) N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 6) (S)—N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 7) (R)—N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 8) N-(1-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 9) N-(1-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 10) N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 11) N-(3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 12) N-(3-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 13) N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 14) N-(3-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 15) N-(3-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 16) N-(1-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 17) N-(1-((3-methoxyphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 18) N-(1-(m-tolylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 19) N-(1-((6-fluoropyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 20) N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 21) N-(1-((5-fluoropyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 22) Methyl-3-((5-acrylamido-2,3-dihydro-1H-inden-1-yl)amino)benzoate; (No. 23) N-(3-(benzylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 24) N-(1-((3-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 25) N-(1-((4-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 26) N-(2-(((cis)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 27) N-(2-(((trans)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 28) N-(2-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 29) N-(2-((4,4,4-trifluorobutyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 30) N-(2-((3-fluoropropyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 31) N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 32) N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 33) N-(3-(4,4,4-trifluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 34) N-(3-(4-fluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 35) N-(3-((4,4-difluorocyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 36) N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 37) N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 38) N-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 39) N-(3-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 40) N-(3-(3,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 41) N-(3-(3-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 42) N-(3-(4-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 43) N-(3-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 44) N-(3-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 45) N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 46) N-(1-(3-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (No. 47) Methyl 3-[6-(prop-2-enoylamino)-2,3-dihydro-1H-inden-1-yl]oxybenzoate; or a pharmaceutically acceptable salt thereof.

[0051] Among the compounds listed above, the following compounds in particular: (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (18), (19), (20), (21), (31), (32), (33), (35), and (36) , (37), (38), (39), (40), (41), (42), (43), (44), (45), (48), (49), (50), (53), (54), (55), (56), (57), (58), (59), (60), (61), (62), (63), (64), (66), (67), (68), (69 ), (71), (72), (76), (77), (78), (80), (81), (82), (83), (84), (85), (86), (87), (88), (90), (91), (92), (93), (94), and (95), especially (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (18), (19), (20), (21), (31), (32), (33), (35), (36), (37), (38), (39), (40), (41), (42), (43), (44), and (45).

[0052] Among the compounds listed above, the following compounds in particular are preferred: (1), (2), (3), (5), (6), (7), (10), (11), (12), (13), (14), (15), (16), (31), (32), (36), (37), (38), (39), (40), (41), (42), (45), (44), (45), (48), (50), (53), (55), (56), (59), (62), ( 67), (77), (78), (82), (85), (87), (88), (90), and (92), in particular (1), (2), (3), (5), (6), (7), (10), (11), (12), (13), (14), (15), (16), (31), (32), (36), (37), (38), (39), (40), (41), (42), (45), (44), and (45).

[0053] Compounds of formula (I) can be prepared according to the following process: Unless otherwise stated, R1 to R7 are as defined above.

[0054] In the schemes that follow, starting compounds and reagents, where their preparation is not described, are commercially available, described in the literature, or can be prepared according to methods otherwise described therein or known to those skilled in the art.

[0055] Scheme 1: Preparation of compounds of formula (I) where R1 is a -N(H)- group - General Process No. 1 [ka]

[0056] Step 1 consists of an acylation procedure of the amine group using the corresponding acid chloride, acid anhydride, or acid in the presence of a coupling agent.

[0057] Step 2 represents the alkylation of the nitrogen, which is achieved using an aliphatic halogenoalkane derivative in the presence of a base.

[0058] Step 3 is a reductive amination of the ketone group using an amine in the presence of a reducing agent.

[0059] When R3 is a hydrogen atom, step 2 is not carried out.

[0060] Scheme 2: Preparation of compounds of formula (I) where R1 is a -N(H)- group and R3 = H - General process no. 2 [ka]

[0061] PG represents a protecting group such as a tert-butyloxycarbonyl group (Boc group).

[0062] Scheme 2 represents an alternative to Scheme 1.

[0063] Step 1 consists of an acylation procedure of the amino group using the corresponding acid chloride, acid anhydride, or acid in the presence of a coupling agent.

[0064] Step 2 represents a deprotection step in which the protecting group is removed using conventional methods, such as acidic treatment in the case of a Boc group or basic treatment in the case of an Fmoc group.

[0065] Step 3 is a reductive amination of an amine with a ketone or aldehyde in the presence of a reducing agent. Alternatives to reductive amination can be organometallic couplings such as the Buchwald-Hartwig reaction or the Chan-Lam cross-coupling reaction, using, for example, aryl halides in the presence of a palladium catalyst or arylboronic acids in the presence of a copper salt.

[0066] Scheme 3: Preparation of compounds of formula (I) where R1 is an oxygen atom - General process no. 3 [ka]

[0067] Step 1 consists of an acylation procedure of the amine group using the corresponding acid chloride, acid anhydride, or acid in the presence of a coupling agent.

[0068] Step 2 represents the alkylation of the nitrogen of the amide functionality, which is achieved using an aliphatic halogenoalkane derivative in the presence of a base.

[0069] Step 3 is the reduction of the ketone in the presence of a reducing agent.

[0070] Step 4 is an alkylation reaction using an alcohol in the presence of a phosphine and an oxidizing agent such as DEAD / DIAD / DMEAD / DCAD / ADDP, such as the Mitsunobu reaction, or an alcohol in the presence of a strong Lewis acid such as boron trifluoride diethyl etherate. An alternative reaction is an organometallic coupling such as the Chan-Lam cross-coupling reaction using an arylboronic acid in the presence of a copper salt.

[0071] When R3 is a hydrogen atom, step 2 is not carried out.

[0072] All compounds described below can be synthesized according to Schemes 1-3. [Example]

[0073] The following examples describe the preparation of certain compounds of formula (I). The examples are not limiting and serve merely to illustrate the invention.

[0074] The following abbreviations and empirical formulas are used: AcOEt ethyl acetate AcOH acetic acid ADDP 1,1-(azodicarbonyl)dipiperidine DCAD Di-(4-chlorobenzyl)azodicarboxylate DCM dichloromethane DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropylethylamine DMEAD Di-2-methoxyethyl azodicarboxylate DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EA Ethylamine ee enantiomeric excess Et3N Triethylamine EtOAc ethyl acetate EtOH ethanol FA formic acid LCMS Liquid Chromatography Mass Spectrometry m-CPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeOH Methanol OR optical rotation RT room temperature STAB Sodium triacetoxyborohydride TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Tr retention time ℃ Celsius ml milliliter mmol millimolar minutes minutes μmol micromol μl microliter h time

[0075] The following schemes show typical procedures for the synthesis of the compounds of Examples 1-4, following the general process shown in Scheme 1:

[0076] [ka]

[0077] Example 1: N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (151 mg, 751 μmol) was dissolved in AcOEt (8 ml). 3-(Trifluoromethyl)aniline (85 μl, 0.68 mol) and TFA (101 μl, 1.37 mmol) were added. STAB (174 mg, 0.82 mol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 3 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 85 / 15) to give 113 mg of N-(1-((3-(trifluoromethyl)-phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 48%).

[0078] Examples 2 and 3: Enantiomers 1 and 2 of N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide Chiral separation of N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide was achieved as follows: 100 mg of N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide was dissolved in 10 ml of EtOH / heptane 50 / 50 and purified by reverse-phase chiral chromatography (Chiralcel OD-H 5 μm column, 250 × 30 mm, eluent heptane / EtOH 75 / 25). Fractions for each enantiomer were combined, evaporated, and then lyophilized.

[0079] The first enantiomer, designated "Enantiomer 1," was isolated as a white amorphous solid (41 mg, 41%) in 99% ee. OR=+38°, c=2.4mg / ml DMSO, room temperature

[0080] The second enantiomer, designated "Enantiomer 2," was isolated as a white amorphous solid (42 mg, 42%) in 99% ee. OR=-38°, c=2,4mg / ml DMSO, room temperature

[0081] Example 4: N-methyl-N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide Synthesis of N-methyl-N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide: To a solution of N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (300 mg, 1.49 mmol) in 10 ml of anhydrous DMF at 0° C., NaH (60% in mineral oil) (60 mg, 1.49 mmol) was added. The temperature was raised to room temperature, stirred at room temperature for 10 minutes, and cooled again to 0° C., after which iodomethane (100 μl, 1.49 mol) was slowly added. The reaction mixture was raised to room temperature and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and ice-cold water was added, followed by extraction with AcOEt. The combined organic layer was then washed with water and saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give 80 mg of N-methyl-N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 25%).

[0082] Synthesis of N-methyl-N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide: N-methyl-N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (51 mg, 236 μmol) was dissolved in AcOEt (3 ml). 3-Trifluoromethylaniline (27 μl, 215 μmol) and TFA (65 μl, 860 μmol) were added. STAB (110 mg, 516 μmol) was added to the mixture in one portion. The reaction mixture was stirred at 40° C. for 1 hour. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 80 / 20) to give 21 mg of N-methyl-N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 25%).

[0083] The following examples were accomplished by using the appropriate N-(oxoindanyi-5-yl)prop-2-enamide as the starting material and by using the appropriate amine in the final reductive amination in step 3 of scheme 1.

[0084] Example 5: N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (800 mg, 3.98 mmol) was dissolved in 1,2-dichloroethane (50 ml). 4-Fluoroaniline (1.7 ml, 17.9 mmol) and acetic acid (683 μl, 11.9 mmol) were added. STAB (3.8 g, 17.9 mmol) was added in several portions to the mixture. The reaction mixture was stirred at room temperature for 48 hours and at 40° C. for 12 hours. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give 369 mg of N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 31%).

[0085] Examples 6 and 7: Enantiomers 1 and 2 of N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide Chiral separation of N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide was achieved as follows: 90 mg of N-[1-(4-fluoroanilino)indan-5-yl]prop-2-enamide was dissolved in 8 ml of 85 / 15 heptane / EtOH and purified by reversed-phase chiral chromatography (Chiralcel OD-H 5 μm column, 250 × 30 mm, eluent: 85 / 15 heptane / EtOH). Fractions for each enantiomer were combined, evaporated, and then lyophilized.

[0086] The first enantiomer, designated "Enantiomer 1," was isolated as a white amorphous solid (32 mg, 36% yield) with 99.6% ee.

[0087] The second enantiomer, designated "Enantiomer 2," was isolated as a white amorphous solid (33 mg, 37% yield) with 99.5% ee.

[0088] Example 8: N-(1-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (360 mg, 1.79 mmol) was dissolved in 1,2-dichloroethane (25 mL). 3-Fluoroaniline (776 μL, 7.9 mmol) and acetic acid (100 μL, 1.79 mmol) were added. STAB (2.2 g, 10 mmol) was added in portions to the mixture. The reaction mixture was stirred at room temperature for 30 hours and at 40°C for 30 hours. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. 200 mg of the crude compound was dissolved in 4 mL of MeCN / water 50 / 50 and purified by reverse-phase chromatography (C18, eluent HO (0.1% FA) / MeCN, gradient 20 / 80 to 0 / 100). The fractions were combined, evaporated, and then lyophilized to isolate 59.2 mg of N-(1-((3-fluorophenyl)-amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white lyophilizate (9.4% yield).

[0089] Example 9: N-(1-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (80 g, 397 μmol) was dissolved in AcOEt (4 ml). 3,5-Difluoroaniline (48 mg, 361 μmol) and TFA (54 μl, 721 μmol) were added. STAB (92 mg, 433 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 2 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 80 / 20) to give 7.2 mg of N-(1-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 6%).

[0090] Example 10: N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (79 mg, 392 μmol) was dissolved in AcOEt (4 ml). 4-(Trifluoromethyl)aniline (45 μl, 356 μmol) and TFA (53 μl, 713 μmol) were added. STAB (91 mg, 428 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 2 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, cyclohexane / AcOEt 100 / 0 to 90 / 10) to give 20.6 mg of N-(1-((4-(trifluoromethyl)-phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 17%).

[0091] Example 11: N-(3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (450 mg, 2.24 mmol) was dissolved in 1,2-dichloroethane (25 ml). 3-(Trifluoromethyl)aniline (940 μL, 6.7 mmol) and acetic acid (128 μL, 2.24 mmol) were added. STAB (4.3 g, 20.1 mmol) was added in several portions to the mixture. The reaction mixture was stirred at room temperature for 120 hours and at 40° C. for 14 hours. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 80 / 20) to give 31 mg of N-(3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless oil (yield 4%).

[0092] Example 12: N-(3-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (80.1 mg, 398 μmol) was dissolved in AcOEt (4 ml). 4-(Trifluoromethyl)aniline (46 μl, 322 μmol) and TFA (108 μl, 1.45 mmol) were added. STAB (92 mg, 434 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 24 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 75 / 25) to give 29 mg of N-(3-((4-(trifluoromethyl)phenyl)-amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a yellow foam (yield 23%).

[0093] Example 13: N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (80 mg, 397 μmol) was dissolved in AcOEt (4 ml). 3,4-Difluoroaniline (48 mg, 361 μmol) and TFA (54 μl, 721 μmol) were added. STAB (92 mg, 433 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 2 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 80 / 20) to give 39.4 mg of N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 34%).

[0094] Example 14: N-(3-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (56 mg, 277 μmol) was dissolved in AcOEt (3 mL). 3-Fluoroaniline (28 mg, 252 μmol) and TFA (37 μL, 504 μmol) were added. STAB (64 mg, 302 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 4 hours. 1N aqueous NaOH was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, cyclohexane / AcOEt 100 / 0 to 90 / 10) to give 23.7 mg of N-(3-((3-fluorophenyl)-amino)-2,3-dihydro-1H)-inden-5-yl)acrylamide as a colorless oil (32% yield).

[0095] Example 15: N-(3-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (56 mg, 277 μmol) was dissolved in AcOEt (3 mL). 4-Fluoroaniline (28 mg, 252 μmol) and TFA (37 μL, 504 μmol) were added. STAB (64 mg, 302 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 4 h. 1N aqueous NaOH was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, cyclohexane / AcOEt 100 / 0 to 90 / 10) to give 40.2 mg of N-(3-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (54% yield).

[0096] Example 16: Synthesis of N-(1-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (80 mg, 397 μmol) was dissolved in AcOEt (4 ml). 3,4-Difluoroaniline (48 mg, 361 μmol) and TFA (54 μl, 721 μmol) were added. STAB (92 mg, 433 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 2 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 90 / 10 to 85 / 15) to give 45.6 mg of N-(1-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 39%).

[0097] Example 17: N-(1-((3-methoxyphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (80 mg, 398 μmol) was dissolved in AcOEt (4 mL). m-Anisidine (42 μL, 362 μmol) and TFA (54 μL, 725 μmol) were added. STAB (92 mg, 435 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 3 h. 1N aqueous NaOH was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 80 / 20) to afford 45 mg of N-(1-((3-methoxyphenyl)amino)-2,3-dihydro-1H)-inden-5-yl)acrylamide as a white foam (39% yield).

[0098] Example 18: N-(1-(m-tolylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (81 mg, 400 μmol) was dissolved in AcOEt (4 mL). m-Toluidine (39 μL, 364 μmol) and TFA (54 μL, 728 μmol) were added. STAB (93 mg, 437 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 3 h. 1N aqueous NaOH was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 85 / 15) to afford 59.6 mg of N-(1-(m-tolylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (56% yield).

[0099] Example 19: N-(1-((6-fluoropyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (400 mg, 2 mmol) was dissolved in 1,2-dichloroethane (25 ml). 6-Fluoropyridin-3-amine (2 g, 17.9 mmol) and acetic acid (114 μl, 2 mmol) were added. STAB (3.8 g, 17.9 mmol) was added in portions to the mixture. The reaction mixture was stirred at room temperature for 72 hours and at 40° C. for 6 hours. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give 12 mg of N-(1-((6-fluoropyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 2%).

[0100] Example 20: N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (80 mg, 400 μmol) was dissolved in AcOEt (4 ml). 5-Amino-2-(trifluoromethyl)pyridine (62 mg, 363 μmol) and TFA (54 μl, 727 μmol) were added. STAB (93 mg, 436 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 3 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 75 / 25) to give 54.5 mg of N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino))-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless oil (yield 41%).

[0101] Example 21: N-(1-((5-fluoropyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (70 mg, 348 μmol) was dissolved in AcOEt (4 ml). 2-Amino-5-fluoropyridine (80 mg, 696 μmol) and TFA (104 μl, 1.39 mmol) were added. STAB (177 mg, 834 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 30 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 50 / 50) to give 10 mg of N-(1-((5-fluoropyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 9.6%).

[0102] Example 22: Methyl-3-((5-acrylamido-2,3-dihydro-1H-inden-1-yl)-amino)benzoate N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (80 mg, 400 μmol) was dissolved in AcOEt (4 mL). Methyl 3-aminobenzoate (56 mg, 363 μmol) and TFA (54 μL, 726 μmol) were added. STAB (92 mg, 436 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature for 3 h. 1N aqueous NaOH was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 30 / 70) to give 66 mg of methyl 3-((5-acrylamido-2,3-dihydro-1H-inden-1-yl)amino)benzoate as a white solid (49% yield).

[0103] Example 23: N-(3-(benzylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 994 μmol) was dissolved in THF (8 mL). Benzylamine (330 μL, 3 mmol) and acetic acid (60 mg, 994 μmol) were added. STAB (948 mg, 4.5 mmol) was added in portions to the mixture. The reaction mixture was stirred at room temperature for 24 h. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, cyclohexane / AcOEt 100 / 0 to 90 / 10) to afford 41 mg of N-(3-(benzylamino)-2,3-dihydro-1H-inden-5-yl)-acrylamide as a colorless oil (14% yield).

[0104] Example 24: N-(1-((3-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (160 mg, 795 μmol) was dissolved in 1,2-dichloroethane (15 ml). 3-(Trifluoromethyl)benzylamine (233 μL, 1.6 mmol) and acetic acid (46 μL, 795 μmol) were added. STAB (472 mg, 2.2 mmol) was added to the mixture in several portions. The reaction mixture was stirred at room temperature for 24 hours. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give 50 mg of N-(1-((3-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless oil (yield 17%).

[0105] Example 25: N-(1-((4-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 994 μmol) was dissolved in 1,2-dichloroethane (20 ml). 4-(trifluoromethyl)benzylamine (161 μl, 1.1 mmol) and acetic acid (58 μl, 0.9 mmol) were added. STAB (608 mg, 2.8 mmol) was added in portions to the mixture. The reaction mixture was stirred at room temperature for 72 hours. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give 73 mg of N-(1-((4-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless oil (yield 20%).

[0106] Examples 26-29 according to General Scheme 2 are described below.

[0107] In Examples 26-29, commercially available tert-butyl N-(5-aminoindan-2-yl)-carbamate was used as previously described to give the corresponding tert-butyl N-[5-(prop-2-enoylamino)indan-2-yl]-carbamate, which was deprotected as known to those skilled in the art to give N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide.

[0108] [ka]

[0109] Synthesis of tert-butyl N-[5-(prop-2-enoylamino)indan-2-yl]carbamate tert-Butyl N-(5-aminoindan-2-yl)carbamate (400 mg, 1.6 mmol) was dissolved in THF (8 mL). Triethylamine (258 μL, 1.8 mol) was added. After the reaction mixture was cooled to 0°C, acryloyl chloride (146 μL, 1.8 mmol) was slowly added and stirred at room temperature for 2 h. The reaction mixture was diluted with AcOEt. Saturated aqueous NaHCO3 was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 60 / 40) to give 370 mg of tert-butyl N-[5-(prop-2-enoylamino)indan-2-yl]carbamate as a white solid (76% yield).

[0110] Synthesis of N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide A suspension of tert-butyl N-[5-(prop-2-enoylamino)indan-2-yl]carbamate (100 mg, 331 μmol) in DCM (6 ml) was cooled to 0° C., and then TFA (640 μl, 8.3 mmol) was slowly added and stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM. 1N aqueous NaOH solution was added, followed by extraction with DCM. The combined organic layers were then dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was used in the next step without purification.

[0111] Example 26: N-(2-(((cis)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide and Example 27: N-(2-(((trans)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide (90 mg, 445 μmol) was dissolved in DCM (4 ml). Powdered molecular sieves 4 Å, 4-(trifluoromethyl)cyclohexan-1-one (74 mg, 445 μmol), and acetic acid (26 μl, 445 μmol) were added. The reaction mixture was cooled to 0 °C. STAB (142 mg, 668 μmol) was added in one portion to the mixture and stirred overnight. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 50 / 50) to isolate 43.3 mg of N-(2-(((cis)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 27%). Further increasing the gradient of cyclohexane / AcOEt from 50 / 50 to 0 / 100 gave 29.6 mg of N-(2-(((trans)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 19%).

[0112] Example 28: N-(2-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide (92 mg, 455 μmol) was dissolved in 1,2-dichloroethane (3 ml). Powdered molecular sieves 4 Å, 4,4-difluorocyclohexanone (64 mg, 455 μmol), and acetic acid (30 μl, 455 μmol) were added. The reaction mixture was cooled to 0°C, and STAB (150 mg, 682 μmol) was added to the mixture in one portion. The reaction mixture was stirred at room temperature overnight. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 45 / 55) to give 63.4 mg of N-(2-((4,4-difluoro-cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 43%).

[0113] Example 29: N-(2-((4,4,4-trifluorobutyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide (104 mg, 514 μmol) was dissolved in DCM (5 ml). 4,4,4-Trifluorobutyraldehyde (68 mg, 514 μmol) and acetic acid (30 μl, 514 μmol) were added. The reaction mixture was cooled to 0°C. STAB (327 mg, 1.54 mmol) was added in one portion to the mixture and stirred overnight. 1N aqueous NaOH was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient DCM / MeOH 98 / 2 to 95 / 5) to give 49.9 mg of N-(2-((4,4,4-trifluorobutyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 32%).

[0114] Example 30 below illustrates the alkylation procedure for the previously described N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide by using a primary halogenoalkane derivative.

[0115] [ka]

[0116] Example 30: N-(2-((3-fluoropropyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide (108 mg, 532 μmol) was dissolved in acetonitrile (2 ml). Potassium carbonate (149 mg, 1.06 mmol) and 1-bromo-3-fluoropropane (33 μl, 355 μmol) were added dropwise to the mixture. The 10 ml microwave tube was sealed, and the reaction mixture was stirred in a sand bath at 80 °C for 3 h. The solvent was evaporated. Water was added, followed by extraction with DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient DCM / MeOH 98 / 2 to 95 / 5) to give 20.2 mg of N-(2-((3-fluoropropyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (22% yield).

[0117] Examples 31 and 32 below demonstrate the use of the previously described N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide under Chan-Lam reaction conditions to enable aryl carbon-heteroatom bond formation via oxidative coupling of boronic acids with NH-containing compounds in the presence of copper(II) salts in air.

[0118] [ka]

[0119] Example 31: N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide (134 mg, 663 μmol) was dissolved in DCM (20 ml). Powdered molecular sieves (4 Å), 3-fluorophenylboronic acid (195 mg, 1.33 mmol), triethylamine (464 μl, 3.31 mmol), and copper(II) acetate (250 mg, 1.33 mmol) were added and stirred at room temperature under an oxygen atmosphere for 24 hours. The reaction mixture was then filtered through Celite, and the filter pad was washed with DCM. Water was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 80 / 20) to give 24.6 mg of N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 12%).

[0120] Example 32: N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(2-amino-2,3-dihydro-1H-inden-5-yl)acrylamide (67 mg, 331 μmol) was dissolved in DCM (10 ml). Powdered molecular sieves 4 Å, 3-(trifluoromethyl)phenylboronic acid (132 mg, 663 μmol), triethylamine (70 μl, 497 μmol), and copper(II) acetate (94 mg, 497 μmol) were added and stirred at room temperature under an oxygen atmosphere for 24 hours. The reaction mixture was then filtered through Celite, and the Celite pad was washed with DCM. Water was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 50 / 50) to give 10.5 mg of N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 9.2%).

[0121] Examples 33-36 below illustrate Scheme 1 by illustrating R1=O using an alkylation reaction with an alcohol in the presence of a strong Lewis acid such as boron trifluoride diethyl etherate.

[0122] [ka]

[0123] Example 33: N-(3-(4,4,4-trifluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 0.5 mmol) was solubilized in DCM (15 mL) containing 4,4,4-trifluoro-1-butanol (0.2 mL, 1.8 mmol). After cooling to -25 °C, boron trifluoride diethyl etherate (0.2 mL, 0.7 mmol) was added and the mixture was stirred at room temperature overnight. 15 mL of 1 M aqueous NaHCO3 was added, and the organic layer was separated, dried over Na2SO4, and concentrated in vacuo. The residual crude product was purified by column chromatography (silica gel, eluent: DCM / MeOH 100 / 0 to 97 / 3) to give 70 mg of N-(3-(4,4,4-trifluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as an amorphous solid (45% yield).

[0124] Example 34: N-(3-(4-fluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 0.5 mmol) was solubilized in DCM (15 mL) containing 4-fluoro-1-butanol (0.16 mL, 1.5 mmol). After cooling to 25 °C, boron trifluoride diethyl etherate (0.08 mL, 0.66 mmol) was added and the mixture was stirred at -25 °C for 2 h and then at room temperature overnight. 15 mL of 1 M aqueous NaHCO was added, and the organic layer was separated, dried over NaSO, and concentrated in vacuo. The residual crude product was purified by column chromatography (silica gel, eluent: DCM / MeOH 100 / 0 to 97 / 3) to give 140 mg of N-(3-(4-fluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as an amorphous solid (76% yield).

[0125] Example 35: N-(3-((4,4-difluorocyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 0.5 mmol) was solubilized in DCM (15 mL) containing 4,4-difluorocyclohexan-1-ol (200 mg, 1.5 mmol). After cooling to -25 °C, boron trifluoride diethyl etherate (0.1 mL, 0.7 mmol) was added and the mixture was stirred at -25 °C for 2 h and at room temperature overnight. 15 mL of 1 M aqueous NaHCO was added, and the organic layer was separated, dried over NaSO, and concentrated in vacuo. The residual crude product was purified by column chromatography (silica gel, eluent: DCM / MeOH 100 / 0 to 97 / 3) to give 60 mg of N-(3-((4,4-difluorocyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as an amorphous solid (38% yield).

[0126] Example 36: N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 0.5 mmol) was solubilized in DCM (15 ml) containing 4-trifluoromethylcyclohexanol (253 mg, 1.5 mmol) and cooled to -25 °C. Boron trifluoride diethyl etherate (0.08 ml, 0.66 mmol) was added and the mixture was stirred at -25 °C for 2 hours and at room temperature overnight. 15 ml of 1 M aqueous NaHCO was added, and the organic layer was separated, dried over NaSO, and concentrated in vacuo. The residual crude product was purified by column chromatography (silica gel, eluent DCM / MeOH 100 / 0 to 97 / 3) to give 41 mg of N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl))oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as an amorphous solid (yield 23%).

[0127] Example 37 below illustrates Scheme 1 by illustrating R=O using the Mitsunobu procedure for ether bond formation. The indanone intermediate was reduced to the corresponding secondary alcohol, which was then further derivatized with a phenol derivative.

[0128] Example 37: N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide [ka]

[0129] Synthesis of N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide 6-Aminoindan-1-one (3 g, 20.4 mmol) was dissolved in THF (60 mL) and triethylamine (3 mL, 22.4 mmol) was added. The reaction mixture was cooled to 0 °C, and acryloyl chloride (1.8 mL, 22.4 mmol) was slowly added and stirred at room temperature for 2 h. The reaction mixture was diluted with AcOEt. Saturated aqueous NaHCO3 was added, followed by extraction with AcOEt. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 40 / 60) to give a yellow solid. This solid was washed with diethyl ether to give 3 g of N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide as a yellow solid (73% yield).

[0130] Synthesis of N-(3-hydroxyindan-5-yl)prop-2-enamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (900 mg, 4.5 mmol) was dissolved in methanol (36 ml). After the reaction mixture was cooled to 0 °C, sodium borohydride (186 mg, 5 mmol) was added and stirred at room temperature for 1 h. The solvent was evaporated. Water was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 50 / 50) to give 809 mg of N-(3-hydroxyindan-5-yl)prop-2-enamide as a white solid (89% yield).

[0131] Synthesis of N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxyindan-5-yl)prop-2-enamide (215 mg, 1 mmol) was dissolved in THF (12 mL). 4-(Trifluoromethyl)phenol (206 mg, 1.3 mmol) and triphenylphosphane (332 mg, 1.3 mmol) were added. The reaction mixture was cooled to 0°C, and then DIAD (250 μL, 1.3 mmol) was added slowly. The mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the crude product was pre-purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 90 / 10) followed by a second column chromatography using a less polar gradient (silica gel, gradient DCM / AcOEt 100 / 0 to 99 / 1) to give 140 mg of N-(3-(4-(trifluoromethyl)-phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 38%).

[0132] The following examples were accomplished as described above.

[0133] Example 38: N-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (180 mg, 886 μmol) was dissolved in THF (10 mL). Phenol (94 μL, 1.1 mmol) and triphenylphosphane (284 mg, 1.1 mmol) were added. After the reaction mixture was cooled to 0°C, DIAD (213 μL, 1.1 mmol) was added slowly at room temperature for 4 h. The solvent was purified by reverse-phase chromatography (Column CSH 250 mm x 5 mm, eluent HO (0.1% FA) / MeCN (0.1% FA), gradient 74 / 26 to 5 / 95) to give 23 mg of N-(3-phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 9.3%).

[0134] Example 39: N-(3-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (300 mg, 1.5 mmol) was dissolved in THF (14 mL). 3-(Trifluoromethyl)phenol (218 μL, 1.8 mmol) and triphenylphosphane (474 ​​mg, 1.8 mmol) were added. After the reaction mixture was cooled to 0°C, DIAD (356 μL, 1.8 mmol) was slowly added and stirred at room temperature for 4 hours. The solvent was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 70 / 30) and a second column chromatography (silica gel, gradient cyclohexane / DCM 100 / 0 to 35 / 65) to give 34.2 mg of N-(3-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (6.7% yield).

[0135] Example 40: N-(3-(3,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 984 μmol) was dissolved in THF (12 mL). 3,4-Difluorophenol (157 mg, 1.2 mmol) and triphenylphosphane (310 mg, 1.2 mmol) were added. After the reaction mixture was cooled to 0°C, DIAD (233 μL, 1.2 mmol) was slowly added and stirred at room temperature for 4 hours. The solvent was evaporated, and the crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 85 / 15) and then by column chromatography (silica gel, gradient DCM / AcOEt 100 / 0 to 99 / 1) to give 33 mg of N-(3-(3,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (10% yield).

[0136] Example 41: N-(3-(3-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (150 mg, 738 μmol) was dissolved in THF (8 mL). 3-Fluorophenol (80 μL, 886 μmol) and triphenylphosphane (232 mg, 886 μmol) were added. The reaction mixture was cooled to 0°C, and then DIAD (174 μL, 886 μmol) was slowly added. The mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 85 / 15) to give 250 mg, which was solubilized in 10 ml of MeCN / HO 50 / 50 and further purified by reverse-phase chromatography (column CSH 250 mm × 5 mm 5 μm, eluent HO (0.1% FA) / MeCN (0.1% FA), gradient 66 / 34 to 56 / 54) to give 51 mg of N-(3-(3-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white lyophilizate (yield 23%).

[0137] Example 42: N-(3-(4-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (150 mg, 738 μmol) was dissolved in THF (8 mL), and 4-fluorophenol (99 mg, 886 μmol) and triphenylphosphane (237 mg, 886 μmol) were added. After cooling the reaction mixture to 0°C, DIAD (176 μL, 886 μmol) was slowly added and stirred at room temperature for 24 hours. The solvent was evaporated. 955 mg of the crude product was dissolved in 18 mL (6 mL MeCN / 12 mL MeOH) and purified by reverse-phase chromatography (HO (0.1% FA) / MeCN, gradient 63 / 37 to 0 / 100). The fractions were combined, evaporated, and then lyophilized. 29.6 mg of N-(3-(4-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide was isolated as a white lyophilizate (14% yield).

[0138] Example 43: N-(3-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (150 mg, 738 μmol) was dissolved in THF (8 ml). 3,5-Difluorophenol (115 mg, 886 μmol) and triphenylphosphane (237 mg, 886 μmol) were added. After the reaction mixture was cooled to 0°C, DIAD (176 μl, 886 μmol) was slowly added and stirred at room temperature for 24 hours. The solvent was evaporated. 1.1 g of the crude product was dissolved in 7 ml of MeOH and purified by reverse-phase chromatography (HO (0.1% FA) / MeCN, gradient 68 / 32 to 0 / 100). The fractions were combined, evaporated, and then lyophilized. 12 mg of N-(3-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide was isolated as a white lyophilizate (5.2% yield).

[0139] Example 44: N-(3-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (150 mg, 738 μmol) was dissolved in THF (8 ml). 2,4-Difluorophenol (86 μl, 886 μmol) and triphenylphosphane (237 mg, 886 μmol) were added. After the reaction mixture was cooled to 0°C, DIAD (176 μl, 886 μmol) was slowly added and stirred at room temperature for 24 hours. The solvent was evaporated. 1 g of the crude product was dissolved in 12 ml of MeOH and purified by reverse-phase chromatography (HO (0.1% FA) / MeCN, gradient 67 / 33 to 0 / 100). The fractions were combined, evaporated, and then lyophilized. 41.7 mg of N-(3-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide was isolated as a yellow lyophilizate (18% yield).

[0140] Example 45: N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (60 mg, 295 μmol) was dissolved in THF (5 mL). 3-(Trifluoromethyl)phenol (44 μL, 354 μmol) and triphenylphosphane (95 mg, 354 μmol) were added. After the reaction mixture was cooled to 0°C, DIAD (71 μL, 354 μmol) was slowly added and stirred at room temperature for 24 hours. The solvent was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 90 / 10) and then by column chromatography (silica gel, gradient DCM / AcOEt 100 / 0 to 99 / 1) to give 19 mg of N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (18% yield).

[0141] Example 46: N-(1-(3-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (250 mg, 1.23 mmol) was dissolved in DCM (14 mL). 3-(Trifluoromethoxy)phenol (191 μL, 1.5 mmol) and triphenylphosphane (395 mg, 1.5 mmol) were added. After the reaction mixture was cooled to 0°C, DIAD (293 μL, 1.5 mmol) was slowly added and stirred at room temperature for 3 hours. The solvent was evaporated, and the crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 85 / 15) followed by column chromatography (silica gel, gradient DCM / AcOEt 100 / 0 to 99 / 1). 170 mg of N-(1-(3-(trifluoromethoxy)-phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide was obtained as a white solid (38% yield).

[0142] Example 47: Methyl 3-[6-(prop-2-enoylamino)-2,3-dihydro-1H-inden-1-yl]oxybenzoate N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (500 mg, 2.4 mmol) was dissolved in THF (12 ml). Methyl 3-hydroxybenzoate (458 mg, 3 mmol) and triphenylphosphane (790 mg, 3 mmol) were added. The reaction mixture was cooled to 0°C, and then DIAD (595 mg, 3 mmol) was slowly added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) and further purified by reversed-phase chromatography (C18 5 μm OBD 50 × 250 mm, eluent HO (0.1% FA) / MeCN, gradient 67 / 33 to 0 / 100) to give 106 mg of methyl 3-[6-(prop-2-enoylamino)-indan-1-yl]oxybenzoate as a white foam (yield 13%).

[0143] Examples 48 and 49: Enantiomers 1 and 2 of N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide Chiral separation of N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide (Example 31) was achieved as follows: 570 mg of N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide was dissolved in 50 ml of heptane / EtOH 80 / 20 and purified by reversed-phase chiral chromatography (Chiralcel OD-1 20 μm column, 350 × 76 mm, eluent heptane / EtOH 80 / 20). The fractions of each enantiomer were combined and evaporated.

[0144] The first enantiomer, designated "Enantiomer 1," was isolated as a white amorphous solid (254 mg, 45% yield) with 99.5% ee.

[0145] The second enantiomer, designated "Enantiomer 2," was isolated as a white amorphous solid (237 mg, 42% yield) with 99.5% ee.

[0146] Examples 50 and 51: Enantiomers 1 and 2 of N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide Chiral separation of N-(2-((3-trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide (Example 32) was achieved as follows: 360 mg of N-(2-((3-trifluoromethylphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide was dissolved in 50 ml of heptane / EtOH 85 / 15 and purified by reversed-phase chiral chromatography (Chiralcel OD-1 20 μm column, 350 × 76 mm, eluent heptane / EtOH 85 / 15, 400 ml / min). The fractions for each enantiomer were combined, evaporated, and then lyophilized.

[0147] The first enantiomer, designated "Enantiomer 1," was isolated as a white amorphous solid (157 mg, 44% yield) with 99.5% ee.

[0148] The second enantiomer, designated "Enantiomer 2," was isolated as a white amorphous solid (156 mg, 43% yield) with 99.5% ee.

[0149] Example 52: N-[2-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide To a solution of N-(2-aminoindan-5-yl)acrylamide (TFA salt) (105 mg, 331 μmol) and powdered molecular sieves (4 Å) in DCM (5 ml), 4-(trifluoromethyl)-phenylboronic acid (126 mg, 661 μmol), triethylamine (500 μl, 3.307 mmol), and copper(II) acetate (120 mg, 661 μmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 h. After filtration through Dicalite, water and a few drops of aqueous NH3 (33%) were added, followed by extraction with DCM. The combined organic layers were then washed with water and brine, filtered through a hydrophobic cartridge, and concentrated under reduced pressure. The crude product was purified by column chromatography (S i O2, cyclohexane / AcOEt 90 / 10 to 50 / 50) and a second column chromatography (Si Purification by HCl, DCM / AcOEt 100 / 0 to 90 / 1) gave 26 mg of N-[2-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide as a white solid (yield 23%).

[0150] Example 53: N-(3-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (81 mg, 405 μmol) was dissolved in AcOEt (4 ml) and 3,5-difluoroaniline (47 mg, 368 μmol), and TFA (54 μl, 736 μmol) was added. STAB (94 mg, 442 μmol) was added to the mixture in one portion. The reaction mixture was stirred overnight at 25 °C. 1N aqueous NaOH solution (10 ml) was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by two subsequent identical column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 50 / 5) to give 60 mg of a white foam, which was further purified by reverse-phase chromatography (column WATERS Xselect CSH Prep C18 5 μm OBD, 50 × 250 mm, mobile phase A: HO + 0.1% FA / B: MeCN, gradient 63 / 37 to 8 / 92) to give, after lyophilization, 16 mg of N-(3-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 15%).

[0151] Example 54: N-(1-((3-(pentafluoro-16-sulfanyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (725 mg, 3.57 mmol) was dissolved in AcOEt (20 mL) containing powdered molecular sieves (4 Å), and 3-(pentafluoro-16-sulfanyl)aniline (740 mg, 3.21 mmol) was added, followed by TFA (495 μL, 6.40 mmol). STAB (2.5 g, 7.8 mmol) was added to the mixture in two portions. The reaction mixture was stirred at 60 °C overnight. After filtration through dicalite, the pH was adjusted to pH 8 by adding 1 N aqueous NaOH, followed by extraction with DCM, drying over Na SO , filtering, and concentrating under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 40) to give, after trituration in diisopropyl ether, 460 mg of N-(1-((3-(pentafluoro-16-sulfanyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 35%).

[0152] Examples 55 and 56: Enantiomers 1 and 2 of N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide Chiral separation of N-(1-((4-trifluoromethylphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide (Example 10) was achieved as follows: 400 mg of N-(1-((4-trifluoromethylphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide was dissolved in 100 ml of 80 / 20 heptane / EtOH and purified by reverse-phase chiral chromatography (Chiralpak AY 20 μm, 230 × 100 mm, eluent: 80 / 20 to 50 / 50 heptane / EtOH, 400 ml / min). Fractions for each enantiomer were combined, evaporated, and then lyophilized.

[0153] The first enantiomer, designated "Enantiomer 1," was isolated as a white amorphous solid (191 mg, 48% yield) with 99.5% ee.

[0154] The second enantiomer, designated "Enantiomer 2," was isolated as a white amorphous solid (183 mg, 46% yield) with 99.5% ee.

[0155] Examples 57 and 58: Enantiomers 1 and 2 of N-1-[[4-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide Chiral separation of N-1-[[4-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide (Example 59 below) was achieved as follows: 236 mg of N-1-[[4-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide was dissolved in two 100 ml portions of 80 / 20 heptane / EtOH. Purification was performed by reverse-phase chiral chromatography (Chiralpak AY 20 μm, 230 × 100 mm, eluent: 80 / 20 to 50 / 50 heptane / EtOH, 400 ml / min). Fractions of each enantiomer were combined, evaporated, and then lyophilized.

[0156] The first enantiomer, designated "Enantiomer 1," was isolated as a white amorphous solid (100 mg, 42% yield) in 99% ee.

[0157] The second enantiomer, designated "Enantiomer 2," was isolated as a white amorphous solid (101 mg, 46% yield) in 99% ee.

[0158] Example 59: N-[1-[[4-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide TFA salt To a suspension of N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (1.12 g, 5.29 mmol), molecular sieves (4 Å), and 4-(trifluoromethyl)pyridin-2-amine (0.8 g, 4.79 mmol) in AcOEt (30 ml) was added TFA (750 μl, 9.37 mmol). After stirring at room temperature for 10 minutes, STAB (2.52 g, 11.54 mmol) was slowly added to the mixture (in portions). The reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was filtered through dicalite, diluted with 1N aqueous NaOH, and subsequently extracted with AcOEt. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 60 / 40) followed by reverse phase chromatography (C18, gradient MeCN / HO+0.1% TFA) to give, after crystallization in diisopropyl ether, 70 mg of N-[1-[[4-(trifluoromethyl)-2-pyridyl]-amino]-2,3-dihydro-1H-inden-5-yl]acrylamide TFA salt as a white solid (yield 3.1%).

[0159] Example 60: N-[1-[[6-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide To a suspension of N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (1.1 g, 4.7 mmol), molecular sieves (4 Å), and 6-(trifluoromethyl)pyridin-2-amine (0.8 g, 4.69 mmol) in AcOEt (30 ml) was added TFA (750 μl, 9.37 mmol). After stirring at room temperature for 10 minutes, STAB (2.52 g, 11.54 mmol) was slowly added to the mixture (in portions). The reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was filtered through dicalite, and the filtrate was added with 1N aqueous NaOH solution, followed by extraction with AcOEt. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified twice by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give, after crystallization in a mixture of diisopropyl ether / heptane 1 / 1, 133 mg of N-[1-[[6-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide as a white solid (yield 8%).

[0160] Example 61: N-[1-[[5-(trifluoromethyl)pyridin-3-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide To a suspension of N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (1.1 g, 4.7 mmol), molecular sieves (4 Å), and 5-(trifluoromethyl)pyridin-3-amine (0.8 g, 4.69 mmol) in AcOEt (30 ml) was added TFA (720 μl, 9.31 mmol). After stirring at room temperature for 10 minutes, STAB (2.52 g, 11.54 mmol) was slowly added to the mixture (in portions). The reaction mixture was refluxed overnight. After cooling, the reaction mixture was filtered through dicalite, and the filtrate was added with 1N aqueous NaOH solution, followed by extraction with AcOEt. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified twice by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 60 / 40) followed by reverse phase chromatography (C18, gradient MeCN / HO+0.1% FA) to give, after crystallization in a mixture of diisopropyl ether / heptane 1 / 1, 72 mg of N-[1-[[5-(trifluoromethyl)pyridin-3-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide as a white solid (yield 4.4%).

[0161] Example 62: N-(1-(methyl(3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (250 mg, 1.24 mmol) was dissolved in AcOEt (8 ml), and N-methyl-3-(trifluoromethyl)aniline (162 μl, 1.24 mmol) and TFA (283 μl, 3.73 mmol) were added. STAB (474 ​​mg, 2.24 mmol) was added to the mixture in one portion. The reaction mixture was stirred at 35° C. for 3 hours. 1N aqueous NaOH solution (20 ml) was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 200 mg of N-(1-(methyl(3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 45%).

[0162] Example 63: N-(1-(methyl(phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 497 μmol) was dissolved in AcOEt (4 ml). N-methylaniline (51 μl, 452 μmol) and TFA (69 μl, 904 μmol) were added. STAB (120 mg, 543 μmol) was added to the mixture in one portion. The reaction mixture was stirred at 35° C. for 3 hours. 1N aqueous NaOH solution (10 ml) was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 60 mg of N-(1-(methyl(phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 45%).

[0163] Example 64: N-(1-(methyl(4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (250 mg, 1.26 mmol) was dissolved in AcOEt (8 ml). N-methyl-4-(trifluoromethyl)aniline (162 μl, 1.14 mmol) and TFA (260 μl, 3.43 mmol) were added. STAB (435 mg, 2.06 mmol) was added to the mixture in one portion. The reaction mixture was stirred at 35° C. for 3 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 158 mg of N-(1-(methyl(4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 38%).

[0164] Example 65: N-(3,3-dimethyl-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3,3-Dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (93 mg, 406 μmol) was dissolved in AcOEt (4 ml). 3-(Trifluoromethyl)aniline (47 μl, 367 μmol) and TFA (90 μl, 1.11 mmol) were added. STAB (120 mg, 553 μmol) was added in portions to the mixture. The reaction mixture was stirred at room temperature for 4 hours. 1N aqueous NaOH solution (10 ml) was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 26 mg of N-(3,3-dimethyl-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a yellow gum (yield 19%).

[0165] Example 66: N-(3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3,3-Dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (71 mg, 308 μmol) was dissolved in AcOEt (4 ml). 4-(Trifluoromethyl)aniline (108 μl, 923 μmol) and TFA (130 μl, 1.8 mmol) were added. STAB (220 mg, 1.11 mmol) was added to the mixture in several portions. The reaction mixture was stirred at 40° C. for 5 hours. 1N NaOH aqueous solution (10 ml) was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 53 mg of N-(3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 51%).

[0166] Example 67: N-[7-fluoro-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide N-(7-Fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (280 mg, 1.2773 mmol) was dissolved in AcOEt (12 ml), and 3-(trifluoromethyl)aniline (160 μL, 1.2773 mmol) and TFA (160 μL, 2.5546 mmol) were added. STAB (324.86 mg, 1.5328 mmol) was added to the mixture in one portion. The reaction mixture was stirred at 40°C for 2 hours. Since not all solids were solubilized, additional TFA (100 μL, 1 equiv.) was added, and stirring at 40°C was continued for 5 hours. 1N aqueous NaOH solution (20 ml) was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 182 mg of N-[7-fluoro-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide as a white foam (yield 39%).

[0167] Example 68: N-[4-fluoro-1-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide N-(4-Fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (130 mg, 0.93 mmol) was dissolved in AcOEt (6 ml), and 4-(trifluoromethyl)aniline (74 μl, 0.93 mmol) and TFA (273 μl, 3.53 mmol) were added. STAB (453 mg, 2.136 mmol) was added in portions to the mixture. The reaction mixture was stirred at 40° C. for 6 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 58 mg of N-[4-fluoro-1-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide as a white foam (yield 27%).

[0168] Example 69: N-methyl-N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(1((4-trifluoromethyl)phenyl)amino-2,3-dihydro-1H-inden-5-yl)acrylamide (30 mg, 87 μmol) was dissolved in MeCN (1 ml). Cesium carbonate (56 mg, 173 μmol) was added, followed by iodomethane (27 μl, 433 μmol). The reaction mixture was stirred at 80 °C for 2 h. Water was added, followed by extraction with AcOEt. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 40 / 60) to give 10 mg of N-methyl-N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless oil (32% yield).

[0169] Example 70: N-(3-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-amino-2,3-dihydro-1H-inden-5-yl)acrylamide (30 mg, 148 μmol) was dissolved in DCM (3 ml) containing 4,4-difluorocyclohexan-1-one (22 mg, 163 μmol), AcOH (9 μl, 163 μmol), and powdered molecular sieves (4 Å). STAB (50 mg, 223 μmol) was then added, and the reaction mixture was stirred at room temperature for 24 h. After filtration through dicalite, 1N aqueous NaOH (5 ml) was added, followed by extraction with DCM. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 10 mg of N-(3-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 20%).

[0170] Example 71: N-(3-((3-(trifluoromethyl)cyclopentyl)oxy)-2,3-dihydro-1H-inden-5-yl)-acrylamide To a solution of N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 1.0 mmol) and 3-(trifluoromethyl)cyclopentan-1-ol (455 mg, 3.00 mmol) in DCM (15 ml) was added boron trifluoride diethyl etherate (0.2 ml, 1.40 mmol) at 0 °C, and the mixture was stirred at 0 °C for 2 h. 1N aqueous NaHCO was added, and the organic phase was separated, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S iThe crude product was purified by SFC (column IA: 250 mm × 30 mm; mobile phase: [A: CO, B: MeOH / 0.1% DEA]) to give 100 mg of a colorless resin, N-(3-((3-(trifluoromethyl))(cyclopentyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide (30% yield).

[0171] Example 72: N-(3-((5,5,5-trifluoropentyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 0.5 mmol) and 5,5,5-trifluoropentan-1-ol (420 mg, 3 mmol) in DCM (15 ml) at 0 °C, boron trifluoride diethyl etherate (0.2 ml, 1.4 mmol) was added. The mixture was stirred at 0 °C for 2 h. 1N aqueous NaHCO3 was added, and the organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S i Purification by 02, DCM / AcOEt, 100 / 0 to 99 / 1) gave 170 mg of N-(3-((5,5,5-trifluoropentyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (yield 53%).

[0172] Example 73: N-(3-(4,4-difluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (134 mg, 0.64 mmol) and 4,4-difluorobutan-1-ol (230 mg, 1.98 mmol) in DCM (15 ml) at 0 °C, boron trifluoride diethyl etherate (0.127 ml, 0.99 mmol) was added. The mixture was stirred at 0 °C for 2 h. 1N aqueous NaHCO3 was added, and the organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S i Purification by 02, DCM / MeOH, 100 / 0 to 99 / 1) gave 65 mg of N-(3-(4,4-difluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (33% yield).

[0173] Example 74: N-(3-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (130 mg, 0.64 mmol) and 2,2,2-trifluoroethanol (0.142 mL, 1.92 mmol) in DCM (15 mL) at 0°C, boron trifluoride diethyl etherate (0.123 mL, 0.96 mmol) was added. The mixture was stirred at 0°C for 2 hours. 1N aqueous NaHCO3 was added, and the organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S i Purification by 02, DCM / MeOH, 100 / 0 to 99 / 1) gave 30 mg of N-(3-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (16% yield).

[0174] Example 75: N-(3-(3,3,3-trifluoropropoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 0.5 mmol) and 4-fluoro-1-butanol (0.160 mL, 1.9 mmol) in DCM (15 mL) at 0°C, boron trifluoride diethyl etherate (0.080 mL, 1.5 mmol) was added. The mixture was stirred at 0°C for 5 hours. 1N aqueous NaHCO3 was added, and the organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S i Purification by 02, DCM / MeOH, 100 / 0 to 99 / 1) gave 70 mg of N-(3-(2,2,2-trifluoropropoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white powder (47% yield).

[0175] Example 76: N-methyl-N-(1-((4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of N-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-N-methylacrylamide (53 mg, 0.24 mmol) and 4-(trifluoromethyl)cyclohexanol (0.10 mL, 0.73 mmol) in DCM (5 mL) at 0°C, boron trifluoride diethyl etherate (0.04 mL, 0.34 mmol) was added. The mixture was stirred at 0°C for 2 hours. 1N aqueous NaHCO3 was added, and the organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (S i Purification by HCl, DCM / MeOH (100 / 0 to 99 / 1) gave 39 mg of an isomeric mixture (74 / 26) of N-methyl-N-(1-((4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless gum (47% yield).

[0176] Example 77: N-(3-(4-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (217 mg, 1.07 mmol) was dissolved in DCM (15 ml) under N2. 4-Chlorophenol (168 mg, 1.28 mmol) and triphenylphosphane (343 mg, 1.28 mmol) were added. After the reaction mixture was cooled to 0 °C, DIAD (255 μl, 1.28 mmol) solubilized in DCM (5 ml) was slowly added and stirred at 0 °C for 20 min, then at room temperature overnight. The solvent was evaporated and the crude product was purified by column chromatography (S i Purification by HO, gradient DCM / AcOEt 100 / 0 to 98 / 2) and reverse-phase chromatography (column: Phenomenex Gemini-NX C18 75 × 30 mm 3 μm; mobile phase: [A: HO (0.225% FA) B: MeCN]; gradient B%: 50% to 80%, 7 min) gave 17 mg of N-(3-(4-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 5%).

[0177] Example 78: N-(3-(3-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (214 mg, 1.05 mmol) was dissolved in DCM (15 ml) under N2. 3-Chlorophenol (130 μl, 1.26 mmol) and triphenylphosphane (343 mg, 1.28 mmol) were added. After the reaction mixture was cooled to 0 °C, DIAD (251 μl, 1.28 mmol) solubilized in DCM (5 ml) was slowly added and stirred at 0 °C for 20 min, then at room temperature overnight. The solvent was evaporated and the crude product was purified by column chromatography (S iPurification by HO, gradient DCM / AcOEt 100 / 0 to 98 / 2) and reverse-phase chromatography (column: Phenomenex Gemini-NX C18 75 × 30 mm 3 μm; mobile phase: [A: HO (0.225% FA) B: MeCN]; gradient B%: 50% to 80%, 7 min) gave 34 mg of N-(3-(3-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a gum (10% yield).

[0178] Example 79: N-(3-(m-tolyloxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 0.98 mmol) was dissolved in 10 mL of anhydrous THF under nitrogen, and m-cresol (130 mg, 130 μL, 1.18 mmol) and triphenylphosphane (316 mg, 1.18 mmol) were added. The reaction mixture was cooled to 0°C, and then DIAD (230 μL, 1.2 mmol) solubilized in THF (5 mL) was slowly added. The mixture was stirred at 0°C for 20 minutes and then at room temperature overnight. The solvent was evaporated, and the crude product was purified by column chromatography (S i Purification by HO, gradient DCM / AcOEt 100 / 0 to 98 / 2) and reverse-phase chromatography (column: Phenomenex Gemini-NX C18 75 × 30 mm 3 μm; mobile phase: [A: HO (0.225% FA) B: MeCN]; gradient B%: 50% to 80%, 7 min) gave 20 mg of N-(3-(m-tolyloxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white foam (yield 7%).

[0179] Example 80: N-(3-(3-(methylthio)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 0.984 mmol) was dissolved in THF (10 mL) under N2. 3-(Methylsulfanyl)phenol (174 mg, 1.24 mmol) and triphenylphosphane (316 mg, 1.2 mmol) were added. The reaction mixture was cooled to 0 °C, and then DIAD (240 μL, 1.18 mmol) solubilized in THF (5 mL) was slowly added. The mixture was stirred at 0 °C for 20 minutes and then at room temperature overnight. The solvent was evaporated and the crude product was purified by reverse-phase chromatography (column: Phenomenex Gemini-NX C18 75 × 30 mm 3 μm; mobile phase: [A: HO (0.225% FA) B: MeCN]; gradient B%: 50% to 80%, 7 min) to give 24 mg of N-(3-(3-(methylthio)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a gum (yield 8%).

[0180] Example 81: N-(3-(3-cyclopropylphenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (207 mg, 1.02 mmol) was dissolved in THF (10 mL) under a nitrogen atmosphere. 3-Cyclopropylphenol (172 mg, 1.22 mmol) and triphenylphosphane (327 mg, 1.22 mmol) were added. The reaction mixture was cooled to 0°C, and then DIAD (0.24 mL, 1.2 mmol) solubilized in THF (5 mL) was slowly added. The mixture was stirred at 0°C for 20 minutes, then at room temperature for 24 hours. The solvent was evaporated and the crude product was purified by column chromatography (silica gel, gradient DCM / MeOH 100 / 0 to 97 / 3) and further purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75 × 30 mm 3 μm; mobile phase: [A: HO (0.225% FA) B: MeCN]; gradient B%: 50% to 80%, 7 min) to give 9 mg of N-(3-(3-cyclopropylphenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a gum (yield 3%).

[0181] Example 82: N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (200 mg, 0.984 μmol) was dissolved in THF (10 mL) under a nitrogen atmosphere. 3-(Trifluoromethyl)phenol (168 mg, 0.984 μmol) and triphenylphosphane (316 mg, 1.18 mmol) were added. After the reaction mixture was cooled to 0°C, DIAD (0.24 mL, 1.2 mmol) solubilized in THF (5 mL) was slowly added and stirred at 0°C for 20 minutes, then at room temperature for 24 hours. The solvent was evaporated, and the crude product was purified by column chromatography (silica gel, gradient DCM / MeOH 100 / 0 to 98 / 2) to give 80 mg of N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (23% yield).

[0182] Example 83: N-methyl-N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 288 μmol, see Example 82) in 3 ml of anhydrous DMF at 0° C., NaH (60% in mineral oil, 14 mg, 345 μmol) was added. The temperature was allowed to rise to room temperature, and the reaction mixture was stirred at room temperature for 10 minutes. After cooling to 0° C. again, iodomethane (30 μl, 432 μmol) was slowly added. The reaction mixture was allowed to rise to room temperature and stirred at room temperature for 3 hours. The reaction mixture was cooled to 0° C., and ice-cold water was added, followed by extraction with AcOEt. The combined organic layers were then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give 50 mg of N-methyl-N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a yellow gum (yield 48%).

[0183] Examples 84 and 85: Enantiomers 1 and 2 of N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide Chiral separation of N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide (Example 45) was achieved as follows: 300 mg of N-(2-((3-trifluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide was dissolved in 50 ml of EtOH and purified by reverse-phase chiral chromatography (Chiralcel OD-I 20 μm column, 350 × 76 mm, eluent heptane / EtOH 90 / 10, 400 ml / min). Fractions for each enantiomer were combined, evaporated, and then lyophilized.

[0184] The first enantiomer, designated "Enantiomer 1," was isolated as a white amorphous solid (132 mg, 44% yield) with 99.5% ee.

[0185] The second enantiomer, designated "Enantiomer 2," was isolated as a white amorphous solid (126 mg, 42% yield) with 99.5% ee.

[0186] Examples 86 and 87: Enantiomers 1 and 2 of N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (600 mg, 2.95 mmol) was dissolved in THF (30 ml) under N2. 4-(Trifluoromethyl)phenol (605 mg, 3.54 mmol) and triphenylphosphane (948 mg, 3.54 mmol) were added. After the reaction mixture was cooled to 0 °C, DIAD (704 μl, 3.54 mmol) solubilized in DCM (5 ml) was slowly added and stirred at 0 °C for 20 min, then at room temperature for 4 h. The solvent was evaporated and the crude product was purified by column chromatography (S i The resulting mixture was purified by CO2, gradient DCM / AcOEt 100 / 0 to 98 / 2 to give 290 mg of a mixture of two isomers, which were separated by chiral SFC chromatography (column IB-N5 30 × 250 mm, mobile phase A: CO2, B: MeOH (0.1% diethylamine), A / B 80 / 20) and lyophilized to give 120 mg of enantiomer 1, N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white amorphous solid (11% yield) and 95 mg of enantiomer 2, N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a white amorphous solid (9% yield).

[0187] Example 88: N-[3-[[5-(trifluoromethyl)pyridin-2-yl]oxy]-2,3-dihydro-1H-inden-5-yl]acrylamide N-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)acrylamide (202 mg, 1.00 mmol) was dissolved in THF (10 ml) under N2. 2-Hydroxy-5-(trifluoromethyl)pyridine (201 mg, 1.20 mmol) and triphenylphosphane (313 mg, 1.20 mmol) were added. After the reaction mixture was cooled to 0 °C, DIAD (235 μL, 1.20 mmol) solubilized in THF (5 ml) was slowly added and stirred at 0 °C for 20 minutes, then at room temperature overnight. The solvent was evaporated and the crude product was purified by column chromatography (S i Purification by HCl (0.05 ml, gradient DCM / AcOEt 100 / 0 to 97 / 3) gave 130 mg of N-[3-[[5-(trifluoromethyl)-pyridin-2-yl]oxy]-2,3-dihydro-1H-inden-5-yl]acrylamide as a white solid (38% yield).

[0188] Example 89: N-methyl-N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)-acrylamide To a solution of N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide (100 mg, 288 μmol, Example 45) in 3 ml of anhydrous DMF at 0° C., NaH (60% in mineral oil) (14 mg, 345 μmol) was added. The temperature was allowed to rise to room temperature, stirred at room temperature for 10 minutes, and cooled again to 0° C., after which iodomethane (30 μl, 432 μmol) was slowly added. The reaction mixture was allowed to rise to room temperature and stirred at room temperature for 3 hours. The reaction mixture was cooled to 0° C., and ice-cold water was added, followed by extraction with AcOEt. The combined organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 70 / 30) to give 83 mg of N-methyl-N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless gum (yield 80%).

[0189] Example 90: N-[2-fluoro-3-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide N-(2-Fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (37 mg, 169 μmol, synthesis described in Example 91) was dissolved in AcOEt (3 ml). 4-(Trifluoromethyl)aniline (42 μl, 338 μmol) and TFA (38 μl, 506 μmol) were added. STAB (112 mg, 506 μmol) was added to the mixture in several portions. The reaction mixture was stirred at 35° C. for 6 hours. 1N aqueous NaOH solution was added, followed by extraction with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 19 mg of N-[2-fluoro-3-[4-(trifluoromethyl)-anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide as a white solid (yield 31%).

[0190] Example 91: N-(2-fluoro-3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide [ka]

[0191] Step 1: Synthesis of 6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one: 6-Bromo-indanone (2 g, 9.5 mmol) was dissolved in anhydrous MeOH (80 ml). Selectfluor (4 g, 11 mmol) was added. The reaction mixture was stirred at 50 °C for 7 h. The solvent was evaporated under reduced pressure. DCM was added, and the insoluble material was filtered. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / DCM 100 / 0 to 92 / 8) to give 220 mg of 6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one as a white solid (10% yield).

[0192] Step 2: Synthesis of tert-butyl (2-fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)carbamate: A microwave tube equipped with a magnetic stir bar was charged with 6-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one (100 mg, 437 μmol), tert-butyl carbamate (63 mg, 524 μmol), and cesium carbonate (203 mg, 611 μmol). Anhydrous 1,4-dioxane (2 ml) was added, and the mixture was flushed with nitrogen. JohnPhos (14 mg, 44 μmol) and palladium(II) acetate (5 mg, 22 μmol) were added. The microwave tube was then sealed, and the reaction mixture was stirred in a sand bath at 90 °C for 2 h. After cooling to room temperature, the reaction mixture was poured into water and extracted several times with AcOEt. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient DCM / AcOEt 100 / 0 to 0 / 100) to give 50 mg of tert-butyl (2-fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)carbamate as a brown oil (yield 43%).

[0193] Step 3: Synthesis of 6-amino-2-fluoro-2,3-dihydro-1H-inden-1-one: A solution of tert-butyl (2-fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)carbamate (50 mg, 189 μmol) in DCM (3 ml) was cooled to 0° C., and then TFA (365 μl, 4.71 mmol) was slowly added and stirred at room temperature for 1 h. The reaction mixture was diluted with DCM. 1N aqueous NaOH was added, followed by extraction with DCM several times. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude product, 6-amino-2-fluoro-2,3-dihydro-1H-inden-1-one, was used in the next step without further purification.

[0194] Step 4: Synthesis of N-(2-fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide: 6-Amino-2-fluoro-2,3-dihydro-1H-inden-1-one (31 mg, 188 μmol) was dissolved in THF (1.5 mL). Triethylamine (34 μL, 244 μmol) was added. After cooling the reaction mixture to 0°C, acryloyl chloride (21 μL, 244 μmol) was slowly added and stirred at room temperature for 1 h. The reaction mixture was diluted with AcOEt. Saturated aqueous NaHCO3 was added, followed by several extractions with AcOEt. The combined organic layers were then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 75 / 25) to give 20 mg of N-(2-fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide as a white solid (49% yield).

[0195] Step 5: Synthesis of N-(2-fluoro-3-((3-trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide: N-(2-Fluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (20 mg, 91 μmol) was dissolved in AcOEt (1.5 ml). 3-Trifluoromethylaniline (11 μl, 91 μmol) and TFA (21 μl, 274 μmol) were added. STAB (35 mg, 164 μmol) was added to the mixture in one portion. The reaction mixture was stirred at 40° C. for 4 hours. 1N aqueous NaOH solution was added and extracted several times with AcOEt. The combined organic layer was then washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 95 / 5 to 85 / 15) to give 9 mg of N-(2-fluoro-3-((3-trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a colorless oil (yield 27%).

[0196] Example 92: N-[2-fluoro-3-[4-(trifluoromethyl)phenoxy]-2,3-dihydro-1H-inden-5-yl]acrylamide N-(2-Fluoro-3-hydroxy-indan-5-yl)acrylamide (40 mg, 181 μmol) was dissolved in THF (3 ml) under N2. 4-(Trifluoromethyl)phenol (37 mg, 217 μmol) and triphenylphosphane (60 mg, 217 μmol) were added. After the reaction mixture was cooled to 0 °C, DIAD (45 μl, 217 μmol) solubilized in THF (5 ml) was slowly added and stirred at 0 °C for 20 min, then at room temperature overnight. The solvent was evaporated and the crude product was purified by column chromatography (S i 02, gradient cyclohexane / AcOEt, 100 / 0 to 50 / 50) to give 50 mg of N-[2-fluoro-3-[4-(trifluoromethyl)phenoxy]indan-5-yl]acrylamide as a mixture, which was purified by a second column chromatography (S iFurther purification by HCl (gradient DCM / AcOEt, 100 / 0 to 90 / 10) gave 9 mg of N-[2-fluoro-3-[4-(trifluoromethyl)-phenoxy]indan-5-yl]acrylamide as a white solid (yield 13%).

[0197] Example 93: N-methyl-N-(2-methyl-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide [ka]

[0198] To a solution of N-(1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (700 mg, 3.48 mmol) in 17 ml of anhydrous DMF at 0° C., NaH (60% in mineral oil) (167 mg, 4.17 mmol) was added. The temperature was allowed to rise to room temperature, stirred at room temperature for 10 minutes, and cooled again to 0° C., after which iodomethane (432 μl, 6.96 mmol) was slowly added. The reaction mixture was allowed to rise to room temperature and stirred at room temperature for 3 hours, 32 μl of iodomethane was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0° C., ice-cold water was added, followed by extraction with AcOEt. The combined organic layer was then washed with water and saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to give 110 mg of N-methyl-N-(2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide as a gum (yield 15%).

[0199] N-methyl-N-(2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)acrylamide (45 mg, 196 μmol) was dissolved in AcOEt (1 ml). 3-(Trifluoromethyl)aniline (29 μl, 236 μmol) and TFA (30 μl, 393 μmol) were added. STAB (50 mg, 236 μmol) was added to the mixture in one portion. The reaction mixture was stirred at 35° C. for 3 hours. 1N aqueous NaOH solution (20 ml) was added, followed by extraction with AcOEt. The combined organic layer was then washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 90 / 10 to 40 / 60) to give 6 mg of N-methyl-N-(2-methyl-1-((3-(trifluoromethyl)phenyl))amino)-2,3-dihydro-1H-inden-5-yl)acrylamide as a gum (yield 8%).

[0200] Example 94: N-[(cis)-3-methoxy-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide [ka]

[0201] Step 1: Trimethyl-[(6-nitro-3H-inden-1-yl)oxy]silane To a solution of 6-nitroindan-1-one (3 g, 16.9 mmol, 1 equiv.) and TEA (3.43 g, 33.9 mmol, 4.71 ml, 2 equiv.) in DCM (60 ml), trimethylsilyl trifluoromethanesulfonate (5.65 g, 25.4 mmol, 4.59 ml, 1.5 equiv.) was added at 0° C., and the mixture was stirred at 0° C. for 0.5 h. The reaction mixture was concentrated under vacuum at 30° C. to give a residue which was purified by column chromatography (S iPurification by 02, petroleum ether / AcOEt gradient 200 / 1 to 10 / 1) gave trimethyl-[(6-nitro-3H-inden-1-yl)oxy]silane (1.4 g, 5.61 mmol, 33% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.19 (d, J = 2.0 Hz, 1H, Ar), 8.13 (dd, J = 2.0, 8.0 Hz, 1H, Ar), 7.50 (d, J = 8.0 Hz, 1H, Ar), 5.59 (t, J = 2.4 Hz, 1H, CH), 3.39 (d, J = 2.4 Hz, 2H, CH2), 0.35 (s, 9H, CH3).

[0202] Step 2: 6-nitroinden-1-one To a mixture of Pd(OAc)2 (3.69 g, 16.44 mmol, 1 equiv.) in MeCN (80 ml) was added trimethyl-[(6-nitro-3H-inden-1-yl)oxy]silane (4.1 g, 16.44 mmol, 1 equiv.) in DCM (40 ml) under N2. The reaction bottle was wrapped in aluminum foil. The mixture was stirred at 20 °C for 4 h. TLC showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (S i Purification by HCl, petroleum ether / AcOEt=100 / 1 to 5 / 1) gave 6-nitroinden-1-one (2.2 g, 10.68 mmol, yield 64.93%, purity 85%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.34 (dd, J = 2.0, 7.9 Hz, 1H, Ar), 8.26 (s, 1H, Ar), 7.73 (d, J = 6.0 Hz, 1H, CHCH), 7.30 (d, J = 7.9 Hz, Ar), 6.24 (d, J = 6.0 Hz, 1H, CHCH).

[0203] Step 3: 6-nitro-3-[3-(trifluoromethyl)anilino]indan-1-one A mixture of 6-nitroinden-1-one (2.2 g, 12.56 mmol, 1 eq.) and 3-(trifluoromethyl)aniline (4.05 g, 25.12 mmol, 3.14 ml, 2 eq.) in THF (7 ml) was stirred at 20° C. for 12 hours. TLC showed the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (S i Purification by HCl, petroleum ether / AcOEt (100 / 1 to 5 / 1) gave 6-nitro-3-[3-(trifluoromethyl)anilino]indan-1-one (2.4 g, 6.28 mmol, 50.00% yield, 88% purity) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.62 (d, J = 2.0 Hz, 1H, Ar), 8.54 (dd, J = 2.0, 8.4 Hz, 1H, Ar), 7.91 (d, J = 8.4 Hz, 1H, Ar), 7.37 (t, J = 8.0 Hz, 1H, Ar), 7.10 (d, J = 7.6 Hz, 1H, Ar), 6.95 (s, 1H, ArH), 6.87 (d, J = 8.0 Hz, 1H, Ar), 5.36 (dt, J = 3.6, 8.0 Hz, 1H, CH), 4.26 (d, J = 8.8 Hz, 1H, ArNH), 3.41 (dd, J = 7.2, 19.2 Hz, 1H, CH2), 2.71 (dd, J = 3.6, 19.2 Hz, 1H, CH2). ES-MS m / z 337.3 [M+H]

[0204] Step 4: 6-nitro-3-[3-(trifluoromethyl)anilino]indan-1-ol To a solution of 6-nitro-3-[3-(trifluoromethyl)anilino]indan-1-one (1 g, 2.97 mmol, 1 equiv.) in MeOH (15 ml) was added NaBH (225 mg, 5.95 mmol, 2 equiv.) portionwise at 0° C. The mixture was stirred at 20° C. for 2 h. TLC showed the reaction was complete. The reaction mixture was quenched by adding 1N HCl (10 ml) at 0° C., then diluted with water (15 ml), extracted with EtOAc (30 ml×2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i Purification by HCl, petroleum ether / AcOEt=100 / 1 to 3 / 1) gave 6-nitro-3-[3-(trifluoromethyl)anilino]-indan-1-ol (990 mg, 2.49 mmol, 83.65% yield, 85% purity) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.33 (d, J = 1.6 Hz, 1H, Ar), 8.18 (dd, J = 2.0, 8.4 Hz, 1H, Ar), 7.53 (d, J = 8.6 Hz, 1H, Ar), 7.34 (t, J = 8.0 Hz, 1H, Ar), 7.06 (br d, J = 8.0 Hz, 1H, Ar), 6.98 (s, 1H, Ar), 6.93 - 6.87 (m, 1H, Ar), 5.29 (t, J = 6.8 Hz, 1H, CH), 4.99 (t, J = 7.2 Hz, 1H, CH), 3.18 (td, J = 6.8, 13.2 Hz, 1H, CH2), 1.99 - 1.87 (m, 1H, CH2). ES-MS m / z 339.3 [M+H] + , Retention time: 2.347 min.

[0205] Step 5: 3-M Ethoxy-5-nitro-N-[3-(trifluoromethyl)phenyl]indan-1-amine A mixture of 6-nitro-3-[3-(trifluoromethyl)anilino]indan-1-ol (990 mg, 2.93 mmol, 1 equiv.), MeI (830.78 mg, 5.85 mmol, 364.38 μl, 2 equiv.), and AgO (3.39 g, 14.63 mmol, 5 equiv.) in DCM (10 ml) was stirred at 20° C. for 12 h. TLC showed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (S i Purification by HCl, petroleum ether / AcOEt=100 / 1 to 5 / 1) gave 3-methoxy-5-nitro-N-[3-(trifluoromethyl)phenyl]indan-1-amine (690 mg, 1.84 mmol, 62.91% yield, 94% purity) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 8.32 (d, J = 2.0 Hz, 1H, Ar), 8.20 (dd, J = 2.0, 8.4 Hz, 1H, Ar), 7.56 (d, J = 8.4 Hz, 1H, Ar), 7.33 (t, J = 8.0 Hz, 1H, 7.05 (d, J = 7.6 Hz, 1H, Ar), 6.98 (s, 1H, Ar), 6.90 (br d, J = 8.0 Hz, 1H, Ar), 5.02 (t, J = 6.8 Hz, 1H, CH), 4.82 (t, J = 6.0 Hz, 1H, CH), 3.52 (s, 3H, CH3), 3.04 (td, J = 6.8, 13.4 Hz, 1H, CH2), 2.05 - 1.97 (m, 1H, CH2). ES-MS m / z 353.4 [M+H] + , Retention time: 1.014 min.

[0206] Step 6: 3-Methoxy-N1-[3-(trifluoromethyl)phenyl]indan-1,5-diamine To a solution of 3-methoxy-5-nitro-N-[3-(trifluoromethyl)phenyl]indan-1-amine (690 mg, 1.96 mmol, 1 equiv.) in AcOEt (6 ml) was added Lindlar's catalyst (600 mg) under N2 atmosphere. The suspension was degassed and purged with H2 three times. The mixture was stirred under H2 (15 Psi) at 20 °C for 4 h. TLC showed that the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (S i The mixture was purified by HCl (petroleum ether / AcOEt = 100 / 1 to 3 / 1) to give 3-methoxy-N1-[3-(trifluoromethyl)phenyl]indan-1,5-diamine (350 mg, 977.28 μmol, yield 49.90%, purity 90%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 7.27 (t, J = 7.6 Hz, 1H, Ar), 6.96 (s, 1H, ArNH), 6.94 (br d, J = 8.0 Hz, 2H, Ar), 6.80 (d, J = 7.6 Hz, 1H, Ar), 6.59 (d, J = 2.0 Hz, 1H, Ar), 6.52 (dd, J = 2.0, 8.0 Hz, 1H, Ar), 6.35 (d, J = 8.4 Hz, 1H, Ar), 5.06 (s, 2H, ArNH2), 4.73 (q, J = 7.2 Hz, 1H, CH), 4.64 (t, J = 6.8 Hz, 1H, CH), 3.34 - 3.33 (m, 3H, CH3), 2.94 - 2.87 (m, 1H, CH2), 1.64 - 1.46 (m, 1H, CH2).

[0207] Step 7: N-[(cis)-3-methoxy-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide To a solution of 3-methoxy-N1-[3-(trifluoromethyl)phenyl]indan-1,5-diamine (400 mg, 1.24 mmol, 1 equiv) in DCM (4 ml) was added a solution of acryloyl chloride (124 mg, 1.37 mmol, 111.31 μl, 1.1 equiv) in DCM (1.5 ml) at 0° C. The mixture was then stirred at 0° C. for 0.5 h. LCMS showed that the reaction was complete. The reaction mixture was poured into HO (10 ml) and extracted with EA (3×10 ml). The combined organic layers were washed with brine (20 ml), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.225% FA)-MeCN]; B%: 45% to 75%, 7 min) to give N-[(cis)-3-methoxy-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide (235 mg, 623.76 μmol, yield 50.26%, purity 99.9%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.19 (s, 1H, CONH), 7.84 (s, 1H, Ar), 7.52 (dd, J = 1.6, 8.4 Hz, 1H, Ar), 7.33 - 7.27 (m, 1H, Ar), 7.23 (d, J = 8.0 Hz, 1H, Ar), 7.00 (s, 1H, ArNH), 7.00 - 6.95 (m, 1H, Ar), 6.84 (d, J = 7.6 Hz, 1H, Ar), 6.51 (d, J = 8.4 Hz, 1H, Ar), 6.48 - 6.38 (m, 1H, CH2CH), 6.31 - 6.21 (m, 1H, CHCH2), 5.75 (dd, J = 2.0, 10.0 Hz, 1H, CHCH2), 4.89 (q, J = 7.6 Hz, 1H, CH), 4.77 (t, J = 6.8 Hz, 1H, CH), 3.39 (s, 3H, CH3), 3.01 (td, J = 6.8, 12.4 Hz, 1H, CH2), 1.63 (td, J = 7.6, 12.4 Hz, 1H, CH2).

[0208] Example 95: N-[(trans)-2-hydroxy-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide [ka]

[0209] Step 1: 5-nitro-2,3-dihydro-1H-inden-2-ol To a solution of 5-nitroindan-2-one (13 g, 73.38 mmol, 1 equiv.) in MeOH (550 ml) was added NaBH (5.55 g, 146.76 mmol, 2 equiv.) portionwise at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC showed the reaction was complete. The mixture was poured into ice-cold HCl solution (100 ml, 1 M). The aqueous phase was extracted with AcOEt (500 ml × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give 5-nitroindan-2-ol (7.4 g, 41.32 mmol, 56.27% yield) as a black solid. 1 H NMR (400 MHz, CDCl3) δ = 8.07 - 8.04 (m, 2H, Ar), 7.36 (d, J = 8.4 Hz, 1H, Ar), 4.82-4.78 (m, 1H, CH), 3.46 (s, 1H, OH), 3.31-3.23 (m, 2H, CH2), 3.03 - 2.98 (m, 2H, CH2)

[0210] Step 2: 5-nitro-1H-indene; 6-nitro-1H-indene A mixture of 5-nitroindan-2-ol (2 g, 11.16 mmol, 1 equiv.) and H2SO4 (9 M, 80.00 ml, 64.50 equiv.) was stirred at 130 °C for 2 h. TLC showed that starting material remained and two new spots were detected. The mixture was extracted with AcOEt (50 ml × 3). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i The mixture was purified by HClO2, petroleum ether / AcOEt=1 / 0 to 50 / 1) to give a mixture of 5-nitro-1H-indene and 6-nitro-1H-indene (750 mg, 4.65 mmol, 41.69% yield) as a white solid.

[0211] Step 3: (1aR,6aS)-4-nitro-6,6a-dihydro-1aH-indeno[1,2-b]oxirene and (1aS,6aR)-3-nitro-6,6a-dihydro-1aH-indeno[1,2-b]oxirene To a solution of 5-nitro-1H-indene and 6-nitro-1H-indene (1.80 g, 11.17 mmol, 1 equiv.) in DCM (40 ml) was added m-CPBA (4.82 g, 22.34 mmol, 80% purity, 2 equiv.). The mixture was stirred at 25 °C for 16 h. TLC showed the reaction was complete. The mixture was diluted with DCM (150 ml) and washed with saturated Na2SO3 solution (3 x 50 ml) and saturated NaHCO3 solution (80 ml). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a mixture of cis-4-nitro-6,6a-dihydro-1aH-indeno[1,2-b]oxirene and cis-3-nitro-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (2 g, 10.73 mmol, 96% yield, 95% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 8.36 (d, J = 2.0 Hz, 1H, Ar), 8.18 (dd, J = 2.0, 8.0 Hz, 1H, Ar), 8.13 - 8.11 (m, 2H, Ar), 7.65 (d, J = 8.0 Hz, 1H, Ar), 7.39 (d, J = 8.0 Hz, 1H, Ar), 4.37-4.33 (m, 2H ,CHCH), 4.26-4.22 (m, 2H, CHCH), 3.33 (d, J = 18.4 Hz, 2H, CH2), 3.12 - 3.05 (m, 2H, CH2).

[0212] Step 4: trans-5-nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol and trans-6-nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol [ka] To a solution of 3-(trifluoromethyl)aniline (1.48 g, 9.19 mmol, 1.15 ml, 1 equiv.) in pentan-1-ol (80 ml), cis-4-nitro-6,6a-dihydro-1aH-indeno[1,2-b]oxirane and cis-3-nitro-6,6a-dihydro-1aH-indeno[1,2-b]oxirane (1.98 g, 11.18 mmol, 1.22 equiv.) were added. The mixture was stirred at 140° C. for 6 hours. LCMS indicated the reaction was complete. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S i Purification by 02, petroleum ether / AcOEt = 1 / 0 to 9 / 1 gave trans-5-nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (990 mg, 2.93 mmol, 31.85% yield) as a yellow solid and trans-6-nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (540 mg, 1.60 mmol, 17.37% yield) as a yellow solid.

[0213] trans-5-Nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol. 1 HNMR (400 MHz, DMSO-d6) δ = 8.12 - 8.08 (m, 2H, Ar), 7.49 - 7.44 (m, 1H, Ar), 7.32 (t, J = 8.0 Hz, 1H, Ar), 7.04 - 7.02 (m, 2H, Ar), 6.87 (d, J = 7.6 Hz, 1H, Ar), 6.58 (d, J = 8.4 Hz, 1H, NH), 5.55 (d, J = 5.2 Hz, 1H, OH), 4.82 - 4.79 (m, 1H, CH), 4.31 - 4.27 (m, 1H, CH), 3.27 (d, J = 6.8 Hz, 1H, CH2), 2.85 (dd, J = 6.0, 16.0 Hz, 1H, CH2)

[0214] trans-6-Nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol. 1 HNMR (400 MHz, DMSO-d6) δ = 8.16 (dd, J = 2.0, 8.0 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H, Ar), 7.55 (d, J = 8.4 Hz, 1H, Ar), 7.33 (t, J = 7.6 Hz, 1H, Ar), 7.07 - 7.05 (m, 2H, Ar), 6.88 (d, J = 8.0 Hz, 1H, Ar), 6.56 (d, J = 8.0 Hz, 1H, NH), 5.56 (d, J = 4.8 Hz, 1H, OH), 4.83-4.80 (m, 1H, CH), 4.31-4.25 (m, 1H, CH), 3.28 (d, J = 6.4 Hz, 1H, CH2), 2.86 (dd, J = 5.6, 16.8 Hz, 1H, CH2)

[0215] Step 5: trans-5-amino-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol To a solution of trans-5-nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (370.00 mg, 1.09 mmol, 1 equiv.) in MeOH (10 ml), Pd / C (37 mg, 10% / C) and EtN (72.70 mg, 718.46 μmol, 0.1 ml, 0.66 equiv.) were added. The mixture was degassed with H (15 psi) and stirred at 25 °C under H (15 psi) for 30 min. TLC showed traces of starting material remaining and one new spot was detected. The mixture was filtered and concentrated under reduced pressure to give trans-5-amino-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (370 mg, crude) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 7.26 (t, J = 8.0 Hz, 1H, Ar), 7.00 - 6.97 (m, 2H, Ar), 6.87 (d, J = 7.6 Hz, 1H, Ar), 6.79 (d, J = 7.6 Hz, 1H, Ar), 6.42-6.38 (m, 2H, Ar), 6.23 (d, J = 7.6 Hz, 1H, NH), 5.20 (d, J = 4.8 Hz, 1H, OH), 4.99 (s, 2H, NH2), 4.46 - 4.42 (m, 1H, CH), 4.10 - 4.08 (m, 1H, CH), 3.03 (dd, J = 6.4, 16.0 Hz, 1H, CH2), 2.59 (d, J = 4.8 Hz, 1H, CH2).

[0216] Step 6: trans-N-(2-hydroxy-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of trans-5-amino-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (280 mg, 908.2 μmol, 1 equiv) and DIEA (234.76 mg, 1.82 mmol, 316.39 μl, 2 equiv) in DCM (6 ml) was added a solution of acryloyl chloride (82.20 mg, 908.21 μmol, 74.05 μl, 1 equiv) in DCM (0.5 ml) at 0° C. The mixture was stirred at 25° C. for 1 hour. LCMS showed the reaction was complete. The mixture was diluted with DCM (10 ml) and washed with water (5 ml). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative HPLC (column: Unisil 3-100 C18 ultra 150 × 50 mm × 3 μm; mobile phase: [water (0.225%) FA)-MeCN]; B%: 40%-60%, 10 min) to give trans-N-(2-hydroxy-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)-acrylamide (116.6 mg, 321.9 μmol, 35.44% yield, 100% purity) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.11 (s, 1H, CONH), 7.64 (s, 1H, Ar), 7.40 (dd, J = 1.6, 8.4 Hz, 1H, Ar), 7.29 (t, J = 8.0 Hz, 1H, Ar), 7.18 (d, J = 8.0 Hz, 1H, Ar), 7.02 - 7.00 (m, 2H, Ar), 6.82 (d, J = 7.6 Hz, 1H, Ar), 6.47 - 6.38 (m, 2H, CHCH 2,NH), 6.27 - 6.22 (m, 1H, CHCH2), 5.74 (dd, J = 2.0, 10.0 Hz, 1H, CHCH2), 5.34 (d, J = 4.8 Hz, 1H, OH), 4.62-5.91 (m, 1H, CH), 4.21-4.16 (m, 1H, CH), 3.17 (dd, J = 6.8, 16.4 Hz, 1H, CH2), 2.72 (dd, J = 5.6, 16.0 Hz, 1H, CH2).

[0217] Example 96: N-[rac-(2R,3R)-2-hydroxy-3-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide [ka]

[0218] Step 1: trans-6-amino-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol To a solution of trans-6-nitro-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (300.00 mg, 886.84 μmol, 1 equiv.) in MeOH (10 ml) was added Pd / C (30 mg, 10% purity). The mixture was degassed with H2 (15 psi) and stirred under H2 (15 psi) at 25 °C for 4 h. LCMS showed the reaction was complete. The mixture was filtered and concentrated under reduced pressure to give trans-6-amino-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (200 mg, 648.72 μmol, 73.15% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 7.27 (t, J = 8.0 Hz, 1H, Ar), 7.01 - 6.97 (m, 2H, Ar), 6.86 - 6.78 (m, 2H, Ar), 6.45 - 6.39 (m, 3H, Ar, NH), 5.22 (d, J = 5.6 Hz, 1H, OH), 4.89 (s, 2H, NH2), 4.54 - 4.51 (m, 1H, CH), 4.15-4.09 (m, 1H, CH), 2.98 (dd, J = 6.8, 15.2 Hz, 1H, CH2), 2.59 - 2.54 (m, 1H, CH2).

[0219] Step 2: trans-N-(2-hydroxy-3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide To a solution of trans-6-amino-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-2-ol (170 mg, 551.42 μmol, 1 equiv) and DIPEA (142.53 mg, 1.10 mmol, 192.09 μl, 2 equiv) in DCM (10 ml) was added a solution of acryloyl chloride (69.9 mg, 772 μmol, 63 μl, 1.4 equiv) in DCM (0.5 ml) at 0° C. The mixture was stirred at 25° C. for 1 h. LCMS showed the reaction was complete. The mixture was diluted with DCM (10 ml) and washed with water (5 ml). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether / AcOEt=1 / 1) and preparative HPLC (column: Unisil 3-100 C18 ultra 150 × 50 mm × 3 μm; mobile phase: [water (0.225% FA)-MeCN]; B%: 38%-58%, 10 min) to give trans-N-(2-hydroxy-3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide (89.7 mg, 248 μmol, yield 45%, purity 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.07 (s, 1H, CONH), 7.60 (dd, J = 1.2, 8.0 Hz, 1H, Ar), 7.50 (s, 1H, Ar), 7.30 (t, J = 8.0 Hz, 1H, Ar), 7.18 (d, J = 8.4 Hz, 1H, Ar), 7.02 - 7.00 (m, 2H, Ar), 6.83 (d, J = 7.6 Hz, 1H, Ar), 6.49 (d, J = 8.0 Hz, 1H, NH), 6.39 (dd, J = 10.0, 17.2 Hz, 1H, CHCH2), 6.21 (dd, J = 1.6, 16.8 Hz, 1H, CHCH2), 5.71 (dd, J = 2.0, 10.0 Hz, 1H, CHCH2), 5.36 (d, J = 5.2 Hz, 1H, OH), 4.68 - 4.65 (m, 1H, CH), 4.22 - 4.18 (m, 1H, CH), 3.11 (dd, J = 6.8, 15.6 Hz, 1H, CH2), 2.69 (dd, J = 6.0, 15.6 Hz, 1H, CH2).

[0220] The following table shows the chemical structures and physical properties of a number of compounds of formula (I).

[0221] In the table: - Proton magnetic resonance spectrum ( 1 H NMR was recorded at 400 MHz in DMSO-d6 using the DMSO-d6 peak as the reference. Chemical shifts δ are expressed in parts per million (ppm). The observed signals are designated as follows: s = singlet; d = doublet; t = triplet; m = multiplet; or brs = broad singlet; brm = broad multiplet. The LCMS characteristics described below were identified by the following high performance liquid chromatography analytical methods (A and B) and mass spectrometry [M+H]. + or [MH] -The peaks and the retention times (Tr) of the compounds expressed in minutes are shown sequentially.

[0222] Method A Column: Acquity UPLC / SQ DCORTECS C18 + 2.1 x 50 mm 1.6 μm (Waters) Gradient: MeCN / 0.1% FA in H2O, 2–100%, 3 min, 1 ml / min

[0223] Method B Column: Acquity UPLC / SQ DCORTECS C18 + 2.1 x 50 mm 1.6 μm (Waters) Gradient: MeCN / H2O with 0.1% FA, 2–100%, 10 min, 1 ml / min

[0224] Method C Column: Kinetex EVO C18 2.1 x 30 mm, 5 μm Gradient: 0.0 min 5% B → 0.8 min 95% B → 1.2 min 95% B → 1.21 min 5% B → 1.55 min 5% B, 1.5 ml / min. Mobile phase: A: 0.0375% TFA (v / v) in water, B: 0.01875% TFA (v / v) in acetonitrile.

[0225] Method D Column: Acquity UPLC / SQD CSH C18 2.1 x 50 mm 1.7 μm (Waters) Gradient: MeCN / H2O with 0.1% FA, 5-100%, 2.5 min, 1 ml / min

[0226] Biochemical studies of compounds of formula (I) were conducted to determine their ability to inhibit YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0227] [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 [Table 1-20] [Table 1-21]

[0228] TEAD-luciferase reporter assay To monitor YAP1-TEAD and TAZ-TEAD activity and study the modulation of YAP1 / TAZ-TEAD activity by small molecule compounds, we used luciferase-based gene reporter assays with TEAD-responsive promoter constructs stably integrated into different human tumor cell lines. Luciferase-based gene reporter assays with GAPDH promoter constructs stably integrated into different human tumor cell lines were used as counterscreening control cell lines.

[0229] Tumor cell lines stably harboring the 8XGTIIC-luciferase construct (Dupont et al., Nature 2011) or GAPDH-luciferase control plasmid were seeded at a density of 8,000 cells / well in 96-well plates. After overnight incubation in a growth chamber at 37°C and 5% CO2, the cells were treated with 10 doses of the compounds listed above, ranging from 1 to 10,000 nM, for 48 hours. After compound incubation, cells were lysed using the Bright-Glo Luciferase Assay System (Promega E2620) and luciferase activity was measured using a luminescence plate reader.

[0230] The inhibitory activity of a compound against luciferase activity is given by the concentration that inhibits 50% of the activity of untreated cells. The IC50 is determined using a nonlinear regression model with XLfit software analysis (IDBS, UK).

[0231] As shown in the table below, the IC50 values ​​of the compounds of the invention were generally less than 1 μM, more particularly between 1 and 550 nM, and even more particularly between 1 and 100 nM.

[0232] [Table 2]

[0233] Therefore, it is clear that the compounds of formula (I), particularly the compounds of formula (I'), have inhibitory activity against YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0234] Thus, the compounds of formula (I), and in particular the compounds of formula (I'), can be used as inhibitors of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0235] Thus, the compounds of formula (I), particularly the compounds of formula (I'), may be used as medicines, particularly medicines that are inhibitors of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0236] Thus, according to another aspect, a subject of the invention is a medicament comprising a compound of formula (I), and in particular a compound of formula (I'), or an addition salt thereof with a pharmaceutically acceptable acid.

[0237] These medicaments are of therapeutic use in the treatment of cancer, particularly in the treatment of breast, ovarian, uterine, prostate, lung, stomach, colorectal, bladder, pancreatic and liver cancer, sarcoma, esophageal cancer, head and neck cancer, uveal melanoma, or glioma.

[0238] In another aspect, the present invention relates to pharmaceutical compositions comprising, as an active ingredient, a compound of formula (I), in particular a compound of formula (I'). These pharmaceutical compositions contain an effective dose of at least one compound of formula (I), in particular a compound of formula (I'), or a pharmaceutically acceptable salt of said compound.

[0239] These pharmaceutical compositions may also include at least one pharmaceutically acceptable excipient.

[0240] Said excipients are chosen according to the pharmaceutical form and the desired mode of administration from the usual excipients known to those skilled in the art.

[0241] The compounds of formula (I), and in particular the compounds of formula (I'), may be used in the treatment of conditions involving YAP1 / TAZ-TEAD or inhibitors of TEAD-dependent gene transcription.

[0242] In particular, the compounds of formula (I), and especially the compounds of formula (I'), may be used as anti-cancer agents, especially in the treatment of breast, ovarian, uterine, prostate, lung, stomach, colorectal, bladder, pancreatic and liver cancer, sarcoma, esophageal cancer, head and neck cancer, uveal melanoma, or glioma.

[0243] The compounds of formula (I), and in particular the compounds of formula (I'), may also be used to treat patients who have developed resistance to previous anti-cancer treatments.

[0244] The present invention also provides, according to another aspect thereof, a method for treating the above-mentioned conditions.

[0245] Therefore, also described is a method for treating cancer, particularly breast, ovarian, uterine, prostate, lung, stomach, colorectal, bladder, pancreatic and liver cancer, sarcoma, esophageal cancer, head and neck cancer, uveal melanoma, or glioma, comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I), particularly a compound of formula (I'), or a pharmaceutically acceptable salt thereof.

[0246] The compounds of formula (I), and particularly the compounds of formula (I'), may also be used in methods for treating cancer in patients who have developed resistance to previous anti-cancer treatments.

[0247] These compounds can be used as monotherapy or in combination with radiation or chemotherapy.

Claims

1. Compounds of formula (I) 【Chemistry 1】 [In the formula, R1 is - oxygen atoms, and - -N(H)- or -N(R8)- group, where R8 is a (C1-C4) alkyl group, in particular a methyl group; is selected from R2 is a phenyl group, unsubstituted or substituted by one or more R groups, a benzyl group, unsubstituted or substituted by one or more R5 groups, (C4-C8)cycloalkyl groups, in particular cyclohexyl or cyclopentyl groups, more particularly cyclohexyl groups, wherein said (C4-C8)cycloalkyl groups are unsubstituted or substituted by one or more R5 groups, heteroaryl groups, in particular pyridinyl groups, wherein the heteroaryl groups are unsubstituted or substituted by one or more R groups, (C1-C6) alkyl groups, in particular (C1-C4) alkyl groups, wherein said (C1-C6) alkyl groups are substituted by one or more fluorine atoms, is selected from R4 is, halogen atoms, in particular fluorine or chlorine atoms, (C1-C4) alkyl groups, unsubstituted or substituted by one or more fluorine atoms, in particular methyl or trifluoromethyl groups, (C1-C4)alkoxy groups, unsubstituted or substituted by one or more fluorine atoms, in particular methoxy or trifluoromethoxy groups, and C(O)—O—(C1-C4) alkyl groups, in particular C(O)—O-methyl groups, (C3-C6)cycloalkyl groups, in particular cyclopropyl groups, (C1-C4) alkylthio groups, in particular methylthio groups, - Pentafluorosulfanyl group is selected from R5 is, halogen atoms, in particular fluorine atoms, and (C1-C4) alkyl groups which are unsubstituted or substituted by one or more fluorine atoms, in particular trifluoromethyl groups, is selected from R3 is, - hydrogen atoms, and - (C1-C4) alkyl groups, especially methyl groups is selected from R6 is selected from a hydrogen atom or a halogen atom, in particular a fluorine atom; R7 is independently halogen atoms, in particular fluorine atoms, (C1-C4) alkyl groups, in particular methyl groups, a hydroxy group, - (C1-C4) alkoxy groups, especially methoxy groups is selected from n is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

2. Formula (Ia) below 【Chemistry 2】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3 is a hydrogen atom.

4. R1 is an oxygen atom and R2 is a phenyl group, unsubstituted or substituted by one or more R groups, (C4-C8)cycloalkyl groups, in particular cyclohexyl groups, where the cycloalkyl groups are unsubstituted or substituted with one or more R5 groups, and (C1-C5) alkyl groups, in particular (C1-C4) alkyl groups, wherein the alkyl groups are substituted by one or more fluorine atoms, in particular CF3-substituted (C1-C4) alkyl groups, in particular (C2-C3) alkyl groups, or alternatively, R1 is —N(H)— and R2 is selected from: a phenyl group which is unsubstituted or substituted by one or more R groups, and heteroaryl groups, in particular pyridinyl groups, wherein said heteroaryl groups are unsubstituted or substituted by one or more R groups, The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from:

5. R2 is a phenyl group, unsubstituted or substituted by one or more R groups, (C4-C8)cycloalkyl groups, in particular cyclohexyl or cyclopentyl groups, wherein the cycloalkyl groups are substituted with one or more R5 groups, with the proviso that R1 is an oxygen atom; and (C1-C5) alkyl groups, in particular (C1-C4) alkyl groups, which are substituted by one or more fluorine atoms, in particular CF3-substituted (C1-C4) alkyl groups, in particular (C2-C3) alkyl groups, in which R1 is an oxygen atom, 5. The compound of claim 4, selected from:

6. 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is a phenyl group substituted with one or more R4 groups.

7. R4 is, halogen atoms, in particular fluorine or chlorine atoms, more particularly fluorine atoms, and (C1-C4) alkyl groups, unsubstituted or substituted by one or more fluorine atoms, in particular methyl or trifluoromethyl groups, The compound according to any one of claims 4 to 6, or a pharmaceutically acceptable salt thereof, selected from:

8. The compound according to any one of claims 4 to 7, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from a fluorine atom and a trifluoromethyl group.

9. 9. The compound of claim 4, wherein the R4 group is located at the meta and / or para position relative to the R2 phenyl group, or a pharmaceutically acceptable salt thereof.

10. 6. The compound according to claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from a fluorine atom and a trifluoromethyl group.

11. N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (R)—N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (S)—N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-methyl-N-(1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (S)—N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (R)—N-(1-((4-fluorophenyl)amino)-2,3-dihydro-1H-isothiazolinone (inden-5-yl)acrylamide; N-(1-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((4-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((3,4-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((3-methoxyphenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-(m-tolylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((6-fluoropyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((6-(trifluoromethyl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((5-fluoropyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; Methyl-3-((5-acrylamido-2,3-dihydro-1H-inden-1-yl)amino)benzoate; N-(3-(benzylamino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((3-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((4-(trifluoromethyl)benzyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-(((cis)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-(((trans)-4-(trifluoromethyl)cyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-((4,4,4-trifluorobutyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-((3-fluoropropyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1 H-inden-5-yl)acrylamide; N-(3-(4,4,4-trifluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-fluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((4,4-difluorocyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(((trans)-4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-phenoxy-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-fluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3,5-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(2,4-difluorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-(3-(trifluoromethoxy)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; Methyl 3-[6-(prop-2-enoylamino)-2,3-dihydro-1H-inden-1-yl]oxybenzoate; (S)—N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (R)—N-(2-((3-fluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (R)—N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (S)—N-(2-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-[2-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-(3-((3,5-difluorophenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((3-(pentafluoro-16-sulfanyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (R)—N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; (S)—N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-[(1S)-1-[[4-(trifluoromethyl)pyridin-2-yl]amino]- 2,3-dihydro-1H-inden-5-yl]acrylamide; N-[(1R)-1-[[4-(trifluoromethyl)pyridin-2-yl]amino]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-(1-((4-(trifluoromethyl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide 2,2,2-trifluoroacetate; N-(1-((6-(trifluoromethyl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-((5-(trifluoromethyl)pyridin-3-yl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-(methyl(3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-(methyl(phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-(methyl(4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3,3-dimethyl-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3,3-dimethyl-1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-[7-fluoro-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-[4-fluoro-1-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-methyl-N-(1-((4-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((4,4-difluorocyclohexyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((3-(trifluoromethyl)cyclopentyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-((5,5,5-trifluoropentyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4,4-difluorobutoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(2,2,2-trifluoroethoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3,3,3-trifluoropropoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-methyl-N-(1-((4-(trifluoromethyl)cyclohexyl)oxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(4-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3-chlorophenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(m-tolyloxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3-(methylthio)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(3-(3-cyclopropylphenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-methyl-N-(1-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (S)—N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (R)—N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (S)—N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; (R)—N-(3-(4-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-[3-[[5-(trifluoromethyl)pyridin-2-yl]oxy]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-methyl-N-(1-(3-(trifluoromethyl)phenoxy)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-[2-fluoro-3-[4-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-(2-fluoro-3-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-[2-fluoro-3-[4-(trifluoromethyl)phenoxy]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-methyl-N-(2-methyl-1-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-1H-inden-5-yl)acrylamide; N-[(cis)-3-methoxy-1-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; N-[(trans)-2-hydroxy-1-[3-(trifluoromethyl)anilino]2,3-dihydro-1H-inden-5-yl]acrylamide; N-[rac-(2R,3R)-2-hydroxy-3-[3-(trifluoromethyl)anilino]-2,3-dihydro-1H-inden-5-yl]acrylamide; 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

14. A compound of formula (I) according to any one of claims 1 to 11 for use as an anti-cancer agent.

15. 12. A compound of formula (I) according to any one of claims 1 to 11 for use in the treatment of breast cancer, ovarian cancer, uterine cancer, prostate cancer, lung cancer, stomach cancer, colorectal cancer, bladder cancer, pancreatic cancer and liver cancer, sarcoma, esophageal cancer, head and neck cancer, uveal melanoma, or glioma.

16. A compound of formula (I) according to any one of claims 1 to 11 for use in the treatment of patients who have developed resistance to previous anti-cancer treatments.

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