(1H-Indol-5-yl) acrylamide derivatives as inhibitors of TEAD proteins and HIPPO-YAP1 / TAZ signaling cascade for the treatment of cancer

Abstract

The present invention relates to indole compounds of formula (I), their preparation and their therapeutic use.

Description

[0001] The present invention relates to indole compounds, their preparation and their therapeutic use.

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

[0003] TEAD proteins and the HIPPO-YAP1 / TAZ signaling cascade

[0004] Transcription enhancer associated domain (TEAD) proteins are transcription factors composed of four family members (TEAD1-4) whose function is to regulate gene expression in response to the HIPPO pathway. TEAD proteins preferentially associate with the transcriptional coactivator yes-associated protein 1 (YAP1) or transcriptional coactivator with PDZ binding motif (TAZ, also known as WWTR1). YAP1-TEAD or TAZ-TEAD bind to DNA and trigger the transcription of a variety of different genes involved in cell proliferation, survival, motility, stemness, and differentiation (reviewed in Holden and Cunningham, Cancer 2018). YAP1 / TAZ-TEAD activity is strictly controlled by the HIPPO pathway.

[0005] The HIPPO pathway was originally discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signal transduction pathway that regulates a variety of biological processes, including cell growth and fate determination, organ size control, and regeneration. The core of the Hippo pathway in mammals consists of a series of kinases, including MST1 / 2 and LATS1 / 2, their associated adaptor proteins SAV1 and MOB1, and upstream regulatory factors (such as NF2, SCRIBBLE, CRUMBS, and a variety of G protein-coupled receptors). The Hippo pathway is strictly regulated by both internal and external signals (such as mechanical force, cell-to-cell contact, polarity, energy state, stress, and many diffusible hormone factors) (reviewed in Ma et al., Annual Rev of Biochem 2019). After activation of the Hippo pathway kinase (i.e., Hippo "on" state), cytoplasmic YAP1 and TAZ proteins are phosphorylated and therefore, remain inactive by sequestration in the cytoplasm and / or degradation by the proteasome machinery. After the Hippo pathway kinases are inactivated (ie, the Hippo "off" state), cytoplasmic YAP1 and TAZ are no longer phosphorylated and are therefore free to translocate into the nucleus, where they associate with TEAD transcription factors to bind DNA and regulate gene expression. A decrease in pYAP1 / YAP1 levels and an increase in gene expression regulated by YAP1 / TAZ-TEAD activity and an increase in promoter activity at TEAD-regulated genes are common indicators of YAP1 activation (reviewed in Totaro et al., Nature Cell Biol 2019).

[0006] The Hippo-YAP1 / TAZ / TEAD pathway and human cancer

[0007] In recent years, studies have shown that in a variety of different cancer indications and backgrounds, the dysregulation of Hippo-YAP1 / TAZ-TEAD activity is the root cause of tumor progression and resistance to therapy. In mice, systematic genetic studies have clearly shown that knocking out HIPPO pathway components (which are YAP1 inhibitors) or overexpressing YAP1 activators (such as YAP1, TAZ, TEAD) will lead to YAP1 activation and YAP1-TEAD-dependent tumor initiation and tumor progression (Zhang et al., Dev Cell 2010; Lu et al., PNAS 2010; Nishio et al., PNAS 2015; Liu-Chittenden et al., Genes and Dev 2012). In humans, genetic changes in the pathway are most common for NF2 (neurofibromatosis protein) (upstream regulator of the core Hippo pathway), which is associated with heritable cancer syndromes and is classified as a tumor suppressor gene. Hundreds of somatic acquired mutations have been reported in NF2 (mostly in meningiomas, mesotheliomas, and peripheral nerve sheath tumors, but also in other cancer types). (Reviewed in Schroeder et al., Oncotarget 2013). Genetic changes outside of NF2 and directly present in the core Hippo pathway are less observed in patients and are found to occur only at higher rates in certain indications (e.g., malignant mesothelioma). Malignant mesothelioma is a highly lethal serosal cancer and is almost exclusively associated with asbestos exposure. It is a therapeutic indication that shows common changes in the HIPPO signaling pathway as well as high YAP1 activation and high dependence on YAP1-TEAD activity (reviewed in Sekido et al., Cancers 2018).

[0008] Increased YAP1 or YAP1-TEAD activity is not limited to genetic changes in the HIPPO pathway and can also be the result of upregulation through multiple interconnected signals. Many pathways that play a key role in tumorigenesis enter the HIPPO-YAP1 / TAZ / TEAD1 cascade, and detailed examples include RTK-RAS-RAF-MEK-ERK, WNT, TGF-β, and AMPK pathways (reviewed in Han et al., J Transl Med 2019). Therefore, the number of tumor types that are at least partially dependent on YAP1-TEAD activation is huge and covers from breast cancer, ovarian cancer, uterine cancer, and prostate cancer to lung cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer, and liver cancer, and further to sarcoma, esophageal cancer, head and neck cancer, uveal melanoma, and glioma (reviewed in Zanconato et al., Cancer Cell 2016). Recent studies have revealed the crosstalk between the HIPPO-YAP / TAZ / TEAD pathway and human immune responses (reviewed in Yamauchi and Moroishi, Cells 2019).

[0009] YAP1 activation has been observed in the context of resistance to therapy and is considered to be the main mechanism of resistance and survival to anticancer therapy. In esophageal cancer, YAP1 is a positive regulator of EGFR (epidermal growth factor receptor) and the induction of YAP1 is associated with resistance to 5-FU and docetaxel. In the context of targeted therapy, YAP1 in BRAF mutant tumors acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy in melanoma. Similarly, YAP1 activation is a mechanism for survival of EGFR and MEK inhibitor treatment in the context of EGFR mutant lung cancer, and multiple studies have identified YAP1 activation as one of the main bypass mechanisms of 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, androgen deprivation therapy resistance is associated with increased YAP nuclear localization and activity (reviewed in Reggiani et al., 2020; Kurppa et al., Cancer Cell 2020).

[0010] Therefore, the HIPPO-YAP / TAZ / TEAD pathway is a key player in cancer development and tumor maintenance, and targeting this pathway is key to cancer treatment in the first-line therapy setting as well as in the context of overcoming drug resistance in multiple cancer indications.

[0011] Therefore, inhibitors of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription are needed.

[0012] Disclosed herein are compounds of formula (I)

[0013]

[0014] in:

[0015] n is an integer selected from 0 and 1

[0016] R1 is selected from

[0017] - single bond, and

[0018] -(C1-C4)alkylene,

[0019] R2 is selected from:

[0020] -(C1-C4)alkyl or substituted by one or more fluorine atoms,

[0021] - (C1-C3)alkoxy substituted by one or more fluorine atoms,

[0022] - phenyl, which is unsubstituted or substituted by one or more R3 groups,

[0023] - (C4-C8)cycloalkyl, which is unsubstituted or substituted by one or more R5 groups,

[0024] - unsubstituted or substituted by one or more R6 groups (C4-C8) heterocyclyl, and

[0025] -NR9R10 group,

[0026] R3 is selected from

[0027] - unsubstituted or substituted by one or more fluorine atoms (C1-C4) alkyl,

[0028] - cyclopropyl,

[0029] - halogen atoms,

[0030] - unsubstituted or substituted by one or more fluorine atoms (C1-C3) alkoxy,

[0031] -pentafluorosulfanyl group,

[0032] -nitrile group,

[0033] -(C1-C3)trialkylsilyl,

[0034] -(C1-C3)alkylsulfonyl, and

[0035] - unsubstituted or trifluoromethyl-substituted phenyl,

[0036] R4 is selected from a hydrogen atom and a (C1-C4) alkyl group,

[0037] R5 is selected from a fluorine atom and a trifluoromethyl group,

[0038] R6 is selected from

[0039] - phenyl, which is unsubstituted or substituted by one or more fluorine atoms or one or more CF3 groups,

[0040] - (C1-C4)alkyl substituted by one or more fluorine atoms, and

[0041] - fluorine atom,

[0042] R7 is selected from

[0043] - Hydrogen atoms,

[0044] -nitrile group, and

[0045] - unsubstituted or substituted (C1-C3)alkoxy or hydroxy (C1-C4)alkyl,

[0046] -COO(C1-C4)alkyl, and

[0047] -CONH2 group,

[0048] R8 is selected from a hydrogen atom and a (C1-C4)alkyl group which is unsubstituted or substituted by a di(C1-C4)alkylamino group,

[0049] R9 and R10 are the same or different and are selected from (C1-C3)alkyl groups which are unsubstituted or substituted by one or more fluorine atoms,

[0050] R11 is selected from hydrogen atom, fluorine atom and chlorine atom

[0051] or a pharmaceutically acceptable salt thereof.

[0052] The compounds of formula (I) may contain one or more asymmetric carbon atoms and may therefore exist in the form of enantiomers or diastereomers and mixtures thereof.

[0053] The compounds of formula (I) may also exist in tautomeric forms.

[0054] The compounds of formula (I) may exist in the form of bases or addition salts with acids or bases, in particular pharmaceutically acceptable salts.

[0055] Pharmaceutically acceptable salts of the compounds of formula (I) do form part of the present invention.

[0056] As used herein, certain terms have the following definitions:

[0057] - Halogen atom: fluorine, chlorine, bromine or iodine atom;

[0058] -Alkyl: a straight-chain or branched saturated aliphatic group. Examples include methyl, ethyl, propyl, isopropyl, etc.

[0059] - Cycloalkyl: cyclic alkyl, including spiro groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, etc.;

[0060] -Alkylene: a saturated straight or branched divalent alkyl group. Examples include -CH2- (or methylene), ethylene, 1-methylethylene or propylene;

[0061] -Alkoxy: the group -O-alkyl, wherein the alkyl is as defined above. Examples of alkoxy include methoxy, ethoxy, isopropoxy, etc.;

[0062] - Nitrile group: group CN;

[0063] -Hydroxyl: group OH;

[0064] -Aryl: a cyclic aromatic group containing between 5 and 10 carbon atoms. Examples of aryl groups include phenyl;

[0065] - Heterocyclyl: a saturated or unsaturated or cyclic group containing between 4 and 9 carbon atoms and 1 or 2 heteroatoms such as oxygen or nitrogen. Examples of heterocyclyl groups include pyrrolidine, piperazine, piperidine, tetrahydropyran, morpholine and diazepanyl groups;

[0066] -Amino: group -NH2;

[0067] -Dialkylamino: an amino group substituted by two alkyl groups;

[0068] -sulfonyl: substituted SO2 group; and

[0069] -Silyl group: A group containing a silicon atom. Examples of the silyl group include a trimethylsilyl group.

[0070] In one aspect, the compounds of formula (I) comprise a first group of compounds of the formula:

[0071]

[0072] or a pharmaceutically acceptable salt thereof.

[0073] In another aspect, the compounds of formula (I) comprise a second group consisting of compounds wherein R4 is a hydrogen atom.

[0074] In another aspect, the compounds of formula (I) comprise a third group consisting of compounds wherein R7 is a hydrogen atom.

[0075] In another aspect, the compounds of formula (I) comprise a fourth group consisting of compounds wherein R8 is a hydrogen atom.

[0076] In another aspect, the compounds of formula (I) comprise a fifth group consisting of compounds wherein:

[0077] n is 0,

[0078] R1 is a single bond;

[0079] R2 is selected from:

[0080] - phenyl, which is unsubstituted or substituted by one or more R3 groups,

[0081] - (C4-C8)cycloalkyl which is unsubstituted or substituted by one or more R5 groups, and

[0082] - (C4-C8) heterocyclyl which is unsubstituted or substituted by one or more R6 groups.

[0083] Among the fifth group of compounds, mention may be made of the compounds of formula (I) in which R11 is a hydrogen atom.

[0084] Among the compounds of the fifth group, mention may also be made of compounds of formula (I) wherein R2 is phenyl substituted by one or more R3 groups.

[0085] Among the latter group of compounds, mention may be made of compounds of formula (I) wherein R3 is (C1-C4)alkyl, in particular trifluoromethyl, substituted by one or more fluorine atoms.

[0086] In another aspect, the compounds of formula (I) comprise a sixth group consisting of compounds for which R1 is selected from a single bond and a methylene group.

[0087] In another aspect, the compounds of formula (I) comprise a seventh group consisting of the following compounds, for which R2 is selected from:

[0088] -(C1-C4)alkyl or substituted by three fluorine atoms,

[0089] - (C1-C3)alkoxy substituted by three fluorine atoms, in particular trifluoroethoxy,

[0090] - phenyl, which is unsubstituted or substituted by one or more R3 groups,

[0091] - (C4-C8)cycloalkyl, unsubstituted or substituted by one or more R5 radicals, in particular cyclobutyl, cyclopentyl, cyclohexyl or spiro[2.3]hexyl,

[0092] - (C4-C8) heterocyclyl, unsubstituted or substituted by one or more R6 groups, in particular tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl or pyridinyl, and

[0093] -NR9R10 group,

[0094] In another aspect, the compounds of formula (I) comprise an eighth group consisting of the following compounds, for which R3 is selected from:

[0095] - methyl or (C1-C4)trifluoroalkyl, in particular trifluoromethyl,

[0096] - cyclopropyl,

[0097] - iodine or fluorine atoms,

[0098] -methoxy or trifluoromethoxy,

[0099] -pentafluorosulfanyl group,

[0100] -nitrile group,

[0101] -trimethylsilyl,

[0102] -methylsulfonyl, and

[0103] - unsubstituted or trifluoromethyl-substituted phenyl,

[0104] In another aspect, the compounds of formula (I) comprise a ninth group consisting of compounds for which R4 is selected from a hydrogen atom and a methyl group.

[0105] Among the latter group of compounds, mention may be made of the compounds of formula (I) wherein R4 is a hydrogen atom.

[0106] In another aspect, the compounds of formula (I) comprise a tenth group consisting of the following compounds, for which R6 is selected from:

[0107] - unsubstituted or substituted phenyl with three fluorine atoms or trifluoromethyl,

[0108] - (C1-C4)alkyl substituted by three fluorine atoms (especially trifluoromethyl or trifluoroethyl), and

[0109] -Fluorine atom.

[0110] In another aspect, the compounds of formula (I) comprise an eleventh group consisting of compounds for which R7 is selected from a hydrogen atom, a nitrile atom or a methyl group.

[0111] In another aspect, the compounds of formula (I) comprise a twelfth group consisting of compounds for which R7 is located at position 3 (according to the IUPAC convention) of the central indolyl.

[0112] On the other hand, the compound of formula (I) comprises a thirteenth group consisting of compounds for which R8 is a hydrogen atom or a methyl group substituted by a dimethylamino group.

[0113] In another aspect, the compounds of formula (I) comprise a fourteenth group consisting of compounds for which R9 and R10 are selected from methyl and trifluoroethyl.

[0114] In another aspect, the compounds of formula (I) comprise a fifteenth group consisting of compounds for which R11 is located at position 6 or 7 (according to the IUPAC convention) of the central indolyl group.

[0115] In another aspect, the compounds of formula (I) comprise a sixteenth group consisting of the following compounds, for which:

[0116] R11 is selected from a fluorine atom and a chlorine atom,

[0117] n is 0,

[0118] R1 is a single bond or (C1-C4) alkylene, especially a single bond or methylene

[0119] R2 is phenyl which is unsubstituted or substituted with one or more R3 groups, and

[0120] R3 is unsubstituted or substituted by one or more fluorine atoms (C1-C4) alkyl, in particular a CF3 group.

[0121] All of these subgroups, alone or in combination, are part of the present description.

[0122] Among the compounds of formula (I) that are subject of the present invention, mention may in particular be made of the following compounds:

[0123] N-[1-[[3-(Trifluoromethyl)phenyl]methyl]indol-5-yl]acrylamide

[0124] N-Methyl-N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0125] N-(1-(5,5,5-trifluoropentyl)-1H-indol-5-yl)acrylamide

[0126] N-(1-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H-indol-5-yl)acrylamide

[0127] N-(1-(3-(Pentafluoro-λ6-sulfanyl)benzyl)-1H-indol-5-yl)acrylamide

[0128] N-(1-(4-(pentafluoro-λ6-sulfanyl)benzyl)-1H-indol-5-yl)acrylamide

[0129] N-(1-(4-(trifluoromethoxy)benzyl)-1H-indol-5-yl)acrylamide

[0130] N-(1-(3-(trifluoromethoxy)benzyl)-1H-indol-5-yl)acrylamide

[0131] N-(1-(3-iodobenzyl)-1H-indol-5-yl)acrylamide

[0132] N-(1-(2-Fluoro-5-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0133] N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0134] N-(1-(3-methoxybenzyl)-1H-indol-5-yl)acrylamide

[0135] N-(2-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0136] N-(3-cyano-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0137] N-(1-(3-cyclopropylbenzyl)-1H-indol-5-yl)acrylamide

[0138] N-(2,3-Dimethyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0139] N-(1-(3-methylbenzyl)-1H-indol-5-yl)acrylamide

[0140] N-(1-Benzyl-1H-indol-5-yl)-acrylamide

[0141] N-(1-(3-(Trifluoromethyl)benzyl)-1H-indol-4-yl)acrylamide

[0142] (E)-4-(Dimethylamino)-N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-4-yl)but-2-enamide

[0143] N-(1-(3-(Trifluoromethyl)benzyl)-1H-indol-6-yl)acrylamide

[0144] N-(1-((4,4-difluorocyclohexyl)methyl)-1H-indol-5-yl)acrylamide

[0145] N-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-5-yl)acrylamide

[0146] N-(1-((4-(trifluoromethyl)cyclohexyl)methyl)-1H-indol-5-yl)acrylamide

[0147] N-(1-((1,1-difluorospiro[2.3]hexan-5-yl)methyl)-1H-indol-5-yl)acrylamide

[0148] N-(1-((3-Fluorocyclopentyl)methyl)-1H-indol-5-yl)acrylamide

[0149] N-(1-(Cyclohexylmethyl)-1H-indol-5-yl)acrylamide

[0150] N-(1-((3-(Trifluoromethyl)cyclobutyl)methyl)-1H-indol-5-yl)acrylamide

[0151] N-(1-((3,3-difluorocyclopentyl)methyl)-1H-indol-5-yl)acrylamide

[0152] N-(1-([1,1'-biphenyl]-4-ylmethyl)-1H-indol-5-yl)acrylamide

[0153] N-(1-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)acrylamide

[0154] N-(1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)acrylamide

[0155] N-(1-((trans)-4-(trifluoromethyl)cyclohexyl)-1H-indol-5-yl)acrylamide

[0156] N-(1-((cis)-4-(trifluoromethyl)cyclohexyl)-1H-indol-5-yl)acrylamide

[0157] N-(1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)-1H-indol-5-yl)acrylamide

[0158] N-(1-(2-(methyl(2,2,2-trifluoroethyl)amino)ethyl)-1H-indol-5-yl)acrylamide

[0159] N-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-indol-5-yl)acrylamide

[0160] N-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-indol-5-yl)acrylamide

[0161] N-(1-(4,4-difluorocyclohexyl)-1H-indol-5-yl)acrylamide

[0162] N-(1-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)-1H-indol-5-yl)acrylamide

[0163] N-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-5-yl)acrylamide

[0164] N-(1-(4-(Trimethylsilyl)benzyl)-1H-indol-5-yl)acrylamide

[0165] N-(1-(3-(Trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0166] N-(1-(4-(Trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0167] N-(1-(6-(Trifluoromethyl)pyridin-3-yl)-1H-indol-5-yl)acrylamide

[0168] N-(1-(5-(Trifluoromethyl)pyridin-2-yl)-1H-indol-5-yl)acrylamide

[0169] N-(1-(Pyridin-3-yl)-1H-indol-5-yl)acrylamide

[0170] N-(1-(4-Fluorophenyl)-1H-indol-5-yl)acrylamide

[0171] N-(1-(3,4-difluorophenyl)-1H-indol-5-yl)acrylamide

[0172] N-(1-(3-(Methylsulfonyl)phenyl)-1H-indol-5-yl)acrylamide

[0173] N-(1-(4-cyanophenyl)-1H-indol-5-yl)acrylamide

[0174] N-(1-(3,5-difluorobenzyl)-1H-indol-5-yl)acrylamide

[0175] N-(1-(3,4-difluorobenzyl)-1H-indol-5-yl)acrylamide

[0176] N-(1-(3-cyanobenzyl)-1H-indol-5-yl)acrylamide

[0177] N-(1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indol-5-yl)acrylamide

[0178] N-(1-(Thiazol-4-ylmethyl)-1H-indol-5-yl)acrylamide

[0179] N-(1-((2-(trifluoromethyl)thiazol-4-yl)methyl)-1H-indol-5-yl)acrylamide

[0180] N-(1-(3-(Trifluoromethyl)benzyl)-1H-indol-7-yl)acrylamide

[0181] N-(1-(3-(Methylsulfonyl)benzyl)-1H-indol-5-yl)acrylamide

[0182] N-(3-(methoxymethyl)-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0183] 5-Acrylamido-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxylic acid methyl ester

[0184] N-(1-(3-(Trifluoromethyl)phenyl)-1H-indol-6-yl)acrylamide

[0185] N-(1-(4-(pentafluoro-λ6-sulfanyl)phenyl)-1H-indol-5-yl)acrylamide

[0186] N-(1-(4-(Trifluoromethyl)phenyl)-1H-indol-6-yl)acrylamide

[0187] N-(1-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0188] N-(1-(3,5-difluorophenyl)-1H-indol-5-yl)acrylamide

[0189] N-(1-(5-fluoropyridin-3-yl)-1H-indol-5-yl)acrylamide

[0190] N-(1-(2-(Trifluoromethyl)pyridin-4-yl)-1H-indol-5-yl)acrylamide

[0191] N-[3-Methyl-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide

[0192] N-[2-Methyl-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide

[0193] N-Methyl-N-[2-methyl-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide

[0194] N-(3-(Methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0195] N-(6-Fluoro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0196] N-Methyl-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0197] (E)-N-(1-(4-(Trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide

[0198] (E)-4-(Dimethylamino)-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide

[0199] N-(6-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0200] N-(6-Chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0201] N-(7-Chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0202] N-(6-Fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0203] N-(7-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0204] N-(3-(Hydroxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0205] 5-Acrylamido-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide

[0206] 5-Acrylamido-1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxamide

[0207] or a pharmaceutically acceptable salt thereof.

[0208] The compound of formula (I) can be prepared according to the following method.

[0209] Unless otherwise mentioned, n and R1 to R10 are as defined previously.

[0210] In the following schemes, when the preparation method of the starting compounds and reagents is not described, the starting compounds and reagents are commercially available or described in the literature, or can be prepared according to the methods described in the literature or known to those skilled in the art.

[0211] Solution 1 : Preparation of compounds of formula (I) - General method

[0212]

[0213] All compounds described below can be synthesized according to Scheme 1.

[0214] Step 1 consists in the alkylation procedure of the indole nitrogen in addition to the R1= bond (by using the corresponding alcohol via the Mitsunobu-reaction or the corresponding halogen-alkane derivatives (which themselves can be functionalized in a further step)), where the corresponding iodo-aryl derivatives are used for the direct arylation.

[0215] Step 2 represents the reduction of the nitro group followed in step 3 by amide formation using an appropriate acryloyl chloride or acrylic acid derivative.

[0216] The alkylation of the amide in step 4 is achieved by using an aliphatic halocarbon derivative.

[0217] The following examples describe the preparation of certain compounds of formula (I). The examples are not limiting but merely illustrative of the present invention.

[0218] The following abbreviations and empirical formulas are used:

[0219] AcOEt Ethyl acetate

[0220] CMBP Cyanomethylidene-tributylphosphane

[0221] DCM DCM

[0222] DEA Diethylamine

[0223] DIEA Diisopropylethylamine

[0224] DMEDA N,N'-Dimethyl-1,2-ethylenediamine

[0225] DMF N,N-Dimethylformamide

[0226] DMSO Dimethyl sulfoxide

[0227] DPPF 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0228] EDCI (([3-(dimethylamino)propyl]imino)methylene)(ethyl)amine hydrochloride

[0229] ESI Electrospray ionization

[0230] Et3N Triethylamine

[0231] FA Formic acid

[0232] HATU O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0233] JohnPhos ([1,1'-biphenyl]-2-yl)di-tert-butyl-phosphane

[0234] MeCN Acetonitrile

[0235] MeOH Methanol

[0236] PE Petroleum Ether

[0237] PDA Photodiode Array

[0238] PdCl2(PPh3)2 1,1'-Bis(triphenylphosphine)-palladium(II) chloride

[0239] RT Room temperature

[0240] SFC Supercritical Fluid Chromatography

[0241] TLC Thin Layer Chromatography

[0242] Tr retention time

[0243] XantPhos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

[0244] ℃ Celsius

[0245] ml milliliters

[0246] mmol millimole

[0247] min

[0248] psi pounds per square inch

[0249] μm micrometer

[0250] μmol micromole

[0251] μl microliter

[0252] h hour

[0253] Some representative examples of the synthesis of compounds of formula (I) are described in the following schemes.

[0254] Solution 2 : Preparation of compounds of formula (I)

[0255] Illustrative examples of compounds of formula (I) wherein R1 = (C1-C4) alkylene

[0256]

[0257] 5-Nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole (Step 1 of Scheme 1)

[0258] To a solution of 5-nitroindole (500 mg, 3.02 mmol) in 5 ml DMF was added sodium hydride 60% (121 mg, 3.02 mmol) in mineral oil in portions at 0 ° C. The mixture was allowed to warm up at room temperature, stirred at room temperature for 20 min and cooled to 0 ° C again, then 3-(trifluoromethyl)benzyl bromide (737 mg, 3.02 mmol) dissolved in 2 ml DMF was poured dropwise. The solution was allowed to warm to room temperature and stirred at room temperature for another 3 h. The crude mixture was poured onto ice and water, extracted with AcOEt, dried over Na2SO4, evaporated under reduced pressure to obtain 0.95 g of 5-nitro-1-(3-(trifluoromethyl)-benzyl)-1H-indole as a yellow solid, yield = 98%.

[0259] 1-(3-(Trifluoromethyl)benzyl)-1H-indol-5-amine (Step 2 of Scheme 1)

[0260] 5-Nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole (1 g, 3.12 mmol) obtained in the previous step was dissolved in 30 ml MeOH and 3 ml AcOEt, Pd / C 10% (50% wet) (30 mg 160.0 μmol) was added and the mixture was hydrogenated at 30 psi hydrogen pressure in a Parr apparatus at room temperature for 3 h. After filtration and evaporation under reduced pressure, 858 mg of a slightly brown oil were obtained and used in the next step without further purification in a yield of 95%.

[0261] Example 1 N-(1-(3-(Trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide (Step 3 of Scheme 1)

[0262] 1-(3-(trifluoromethyl)benzyl)-1H-indole-5-amine (150mg, 517μmol) obtained in the step described above was dissolved in DCM (2ml) with EtN (86μl, 620μmol), cooled to 0°C, then acryloyl chloride (53μl, 620μmol) was added. Stirring was continued at room temperature for 2h. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 75mg of N-(1-(3-(trifluoromethyl)benzyl)-1H-indole-5-yl)acrylamide as a white solid, in a yield of 42%.

[0263] Example 2 N-methyl-N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide (Scheme 1) Step 4)

[0264] N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide (270 mg, 784 μmol) obtained in Example 1 was dissolved in 2 ml of DMF, cooled to 0° C., then sodium hydride 60% (31 mg, 784 μmol) in mineral oil was added, the suspension was stirred at 0° C. for 20 min, then iodomethane (49 μl, 784 μmol) was added and the mixture was stirred at room temperature for 3 h, poured into water, extracted with AcOEt, washed with water and saturated aqueous NaCl solution, and dried over Na2SO4. After purification by reverse phase chromatography (C18, water / CH3CN, gradient 95 / 5 to 5 / 95), 130 mg of N-methyl-N-(1-(3-(trifluoromethyl)-benzyl)-1H-indol-5-yl)acrylamide were isolated as a colorless oil in a yield of 45%.

[0265] The following Examples 3-29 (analogs of Example 1) were synthesized using the same reaction sequence as in Scheme 2 using appropriate indole, alkyl bromide and acrylic acid compounds as starting materials, which are known to those skilled in the art. Step 3 of Scheme 1 is described below.

[0266] Example 3 N-(1-(5,5,5-trifluoropentyl)-1H-indol-5-yl)acrylamide

[0267] 1-(5,5,5-trifluoropentyl)-1H-indole-5-amine (200mg, 780μmol) and EtN (131μl, 937μmol) are dissolved in DCM (5ml) together, cooled to 0°C, and then acryloyl chloride (88mg, 937μmol) is added. Stirring is continued at room temperature for 1h 30. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) and then by reverse phase chromatography (C18, water / MeCN, gradient 95 / 5 to 5 / 95) to obtain 23mg of N-(1-(5,5,5-trifluoropentyl)-1H-indole-5-yl) acrylamide in a brown oily state, with a yield of 10%.

[0268] Example 4 N-(1-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H-indol-5-yl)acrylamide

[0269] 1-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H-indole-5-amine (200mg, 657μmol) and EtN (110μl, 789μmol) are dissolved in DCM (5ml) together, cooled to 0°C, then acryloyl chloride (74mg, 789μmol) is added. Stirring is continued for 3h at room temperature. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt, 100 / 0 to 75 / 25) to obtain 66mg N-(1-(1-(3-(trifluoro-methyl)-phenyl)ethyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in ether, yield 28%.

[0270] Example 5 N-(1-(3-(pentafluoro-λ6-sulfanyl)benzyl)-1H-indol-5-yl)acrylamide

[0271] 1-(3-(pentafluoro-λ6-sulfanyl)benzyl)-1H-indole-5-amine (200 mg, 574 μmol) was dissolved in DCM (5 ml) with Et3N (96 μl, 689 μmol), cooled to 0 ° C, and then acryloyl chloride (65 mg, 689 μmol) was added. Stirring was continued for 3 h at room temperature. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt, 100 / 0 to 70 / 30) to obtain 80 mg of N-(1-(3-(pentafluoro-λ6-sulfanyl)benzyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in ether, with a yield of 34%.

[0272] Example 6 N-(1-(4-(pentafluoro-λ6-sulfanyl)benzyl)-1H-indol-5-yl)acrylamide

[0273] 1-(4-(pentafluoro-λ6-sulfanyl)benzyl)-1H-indole-5-amine (200 mg, 574 μmol) was dissolved in DCM (5 ml) with Et3N (120 μl, 861 μmol), cooled to 0 °C, and then acryloyl chloride (65 mg, 689 μmol) was added. Stirring was continued at room temperature for 1 h. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 98 mg of N-(1-(4-(pentafluoro-λ6-sulfanyl)benzyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in ether, with a yield of 42%.

[0274] Example 7 N-(1-(4-(trifluoromethoxy)benzyl)-1H-indol-5-yl)acrylamide

[0275] 1-(4-(trifluoromethoxy)benzyl)-1H-indole-5-amine (200 mg, 653 μmol) was dissolved in DCM (7 ml) with Et3N (192 μl, 1.31 mmol), cooled to 0 °C, and then acryloyl chloride (66 μl, 784 μmol) was added. Stirring was continued at room temperature for 1 h. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt, 100 / 0 to 70 / 30) to obtain 87 mg of N-(1-(4-(trifluoro-methoxy)-benzyl)-1H-indole-5-yl)acrylamide as an amorphous solid in a yield of 42.5%.

[0276] Example 8 N-(1-(3-(trifluoromethoxy)benzyl)-1H-indol-5-yl)acrylamide

[0277] 1-(3-(trifluoromethoxy)benzyl)-1H-indole-5-amine (200 mg, 653 μmol) was dissolved in DCM (7 ml) with Et3N (192 μl, 1.31 mmol), cooled to 0 °C, and then acryloyl chloride (66 μl, 784 μmol) was added. Stirring was continued at room temperature for 1 h. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt, 100 / 0 to 70 / 30) to obtain 100 mg of N-(1-(3-(trifluoro-methoxy)-benzyl)-1H-indole-5-yl)acrylamide as an amorphous solid in a yield of 42%.

[0278] Example 9 N-(1-(3-iodobenzyl)-1H-indol-5-yl)acrylamide

[0279] 1-(3-iodobenzyl)-1H-indole-5-amine (280mg, 745μmol) was dissolved in dichloro-methane (7ml) with Et3N (220μl, 1,50mmol), cooled to 0°C, and then acryloyl chloride (73μl, 900μmol) was added. Stirring was continued at room temperature for 1h. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) to obtain 90mg of N-(1-(3-iodobenzyl)-1H-indole-5-yl)acrylamide as an amorphous solid, with a yield of 24%.

[0280] Example 10 N-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0281] 1-(2-fluoro-5-(trifluoromethyl)benzyl)-1H-indole-5-amine (200mg, 645μmol) and EtN (118μl, 844μmol) were dissolved in DCM (5ml), cooled to 0°C, and then acryloyl chloride (74mg, 779μmol) was added. Stirring was continued for 3h at room temperature. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 49mg of N-(1-(2-fluoro-5-(trifluoromethyl)benzyl)-1H-indole-5-yl)acrylamide as a beige solid, in a yield of 21%.

[0282] Example 11 N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0283] 3-Methyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-amine (200mg, 657μmol) and EtN (110μl, 789μmol) are dissolved in DCM (5ml) together, cooled to 0°C, then acryloyl chloride (74mg, 789μmol) is added. Stirring is continued for 2h at room temperature. The reaction mixture is diluted with CHCl, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 28mg N-(1N-(3-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in ether, yield 11%.

[0284] Example 12 N-(1-(3-methoxybenzyl)-1H-indol-5-yl)acrylamide

[0285] 1-(3-methoxybenzyl)-1H-indole-5-amine (227mg, 900μmol) and Et3N (190μl, 1.08mmol) were dissolved in dichloro-methane (5ml), cooled to 0°C, and then acryloyl chloride (80μl, 950μmol) was added. Stirring was continued at 0°C for 40min. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 45mg of N-(1-(3-methoxybenzyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in AcOEt, with a yield of 16%.

[0286] Example 13 N-(2-methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0287] 2-Methyl -1- (3- (trifluoromethyl) benzyl) -1H- indole -5- amine (200mg, 657μmol) and Et N (138μl, 986μmol) are dissolved in DCM (2ml) together, cooled to 0 ° C, then acryloyl chloride (74mg, 789μmol) is added. Stirring is continued for 3h at room temperature. The reaction mixture is diluted with DCM, extracted with water, dried over Na SO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 30mg N- (2-methyl -1- (3- (trifluoromethyl) benzyl) -1H- indole -5- bases) acrylamide as a white solid after grinding in ether, yield 12%.

[0288] Example 14 N-(3-cyano-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0289] 5-amino-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carbonitrile (230 mg, 730 μmol) was dissolved in DCM (2 ml) with Et3N (153 μl, 1,09 mmol), cooled to 0 ° C, and then acryloyl chloride (83 mg, 875 μmol) was added. Stirring was continued at room temperature for 1 h 30. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 69 mg of N-(3-cyano-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-yl)acrylamide as a beige solid after grinding in DCM, with a yield of 25%.

[0290] Example 15 N-(1-(3-cyclopropylbenzyl)-1H-indol-5-yl)acrylamide

[0291] 1-(3-Cyclopropylbenzyl)-1H-indole-5-amine (170mg, 647μmol) and EtN (108μl, 778μmol) were dissolved in DCM (2.5ml) together, cooled to 0°C, and then acryloyl chloride (60μl, 713μmol) was added. Stirring was continued for 30min at 0°C. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain 40mg of N-(1-(3-cyclopropylbenzyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in ether, with a yield of 20%.

[0292] Example 16 N-(2,3-dimethyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0293] 2,3-dimethyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-amine (200mg, 628μmol) and EtN (131μl, 942μmol) are dissolved in DCM (2ml) together, cooled to 0°C, then acryloyl chloride (71mg, 754μmol) is added. Stirring is continued at room temperature for 2h. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 33mg of N-(2,3-dimethyl-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-yl)acrylamide as beige solid after grinding in ether, yield 14%.

[0294] Example 17 N-(1-(3-methylbenzyl)-1H-indol-5-yl)acrylamide

[0295] 1-(3-Methylbenzyl)-1H-indole-5-amine (388mg, 1.64mmol) was dissolved in dichloro-methane (16ml) with Et3N (344μl, 1.97mmol), cooled to 0°C, and then acryloyl chloride (160μl, 1.97mmol) was added. Stirring was continued at 0°C for 45min. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to obtain 252mg of N-(1-(3-methyl-benzyl)-1H-indole-5-yl)acrylamide as a pink solid in a yield of 53%.

[0296] Example 18 N-(1-Benzyl-1H-indol-5-yl)-acrylamide

[0297] 1-Benzyl-1H-indole-5-amine (30 mg, 140 μmol) was dissolved in DCM (2 ml) with Et3N (28 μl, 160 μmol), cooled to 0°C, and then acryloyl chloride (13 μl, 160 μmol) was added. Stirring was continued at 0°C for 45 min. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 6 mg of N-(1-benzyl-1H-indole-5-yl)acrylamide as a solid in a yield of 16%.

[0298] Example 19 N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-4-yl)acrylamide

[0299] 1-(3-(trifluoromethyl)benzyl)-1H-indole-4-amine (150mg, 517μmol) and EtN (108μl, 776μmol) are dissolved in DCM (2ml) together, cooled to 0°C, then acryloyl chloride (56mg, 621μmol) is added. Stirring is continued for 3h at room temperature. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 95mg N-(1-(3-(trifluoromethyl)benzyl)-1H-indole-4-yl)acrylamide as a white solid after grinding in ether, yield 51%.

[0300] Example 20 (E)-4-(dimethylamino)-N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-4-yl)butane-2-yl Enamide

[0301] (E)-4-dimethylaminocroton hydrochloride (176 mg, 1.03 mmol) was suspended in DCM (8 ml) with a catalytic amount of DMF (11 μl, 138 μmol), cooled to 0°C, and then oxalyl chloride (121 μl, 1.38 mmol) was added. Stirring was continued at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure. The crude (E)-4-(dimethylamino)but-2-enoyl chloride was used in the further steps as such:

[0302] 1-(3-(trifluoromethyl)benzyl)-1H-indole-4-amine (200mg, 689μmol) was dissolved in DCM (5ml) with pyridine (223μl, 2.76mmol), cooled to 0°C, and then the previously prepared (E)-4-(dimethylamino)but-2-enoyl chloride diluted in DCM (5ml) was added. Stirring was continued at room temperature for 3h. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient CH2Cl2 / MeOH 100 / 0 to 95 / 5) to obtain 76mg of (E)-4-(dimethylamino)-N-(1-(3-(trifluoromethyl)benzyl)-1H-indole-4-yl)but-2-enoylamide as a white solid in a yield of 27%.

[0303] Example 21 N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-6-yl)acrylamide

[0304] 1-(3-(trifluoromethyl)benzyl)-1H-indole-6-amine (150mg, 517μmol) and EtN (94μl, 672μmol) are dissolved in DCM (2ml) together, cooled to 0°C, then acryloyl chloride (59mg, 620μmol) is added. Stirring is continued at room temperature for 4h. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 110mg of N-(1-(3-(trifluoromethyl)-benzyl)-1H-indole-6-yl)acrylamide as a white solid, in a yield of 62%.

[0305] Example 22 N-(1-((4,4-difluorocyclohexyl)methyl)-1H-indol-5-yl)acrylamide

[0306] 1-((4,4-difluorocyclohexyl)methyl)-1H-indole-5-amine (101mg, 382μmol) and EtN (80μl, 459μmol) are dissolved in DCM (4ml) together, cooled to 0°C, and then acryloyl chloride (38μl, 459μmol) is added. Stirring is continued at 0°C for 45min. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 100 to 50 / 50) to obtain 61mg of N-(1-((4,4-di-fluorocyclohexyl)methyl)-1H-indole-5-yl)acrylamide as a white solid, in a yield of 50%.

[0307] Example 23 N-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-5-yl)acrylamide

[0308] 1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-5-amine (138 mg, 599 μmol) was dissolved in DCM (6 ml) with Et3N (126 μl, 719 μmol), cooled to 0°C, and then acryloyl chloride (58 μl, 718 μmol) was added. Stirring was continued at 0°C for 45 min. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient DCM / MeOH 100 / 0 to 95 / 5) to obtain 106 mg of N-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-5-yl)acrylamide as a white solid in 62% yield.

[0309] Example 24 N-(1-((4-(trifluoromethyl)cyclohexyl)methyl)-1H-indol-5-yl)acrylamide

[0310] 1-((4-(trifluoromethyl)cyclohexyl)methyl)-1H-indol-5-amine (114 mg, 384 μmol) was dissolved in DCM (4 ml) with Et3N (81 μl, 461 μmol), cooled to 0°C, and then acryloyl chloride (38 μl, 461 μmol) was added. Stirring was continued at 0°C for 45 min. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 50 / 50) to obtain 70 mg of N-(1-((4-(trifluoromethyl)-cyclohexyl)methyl)-1H-indol-5-yl)acrylamide as a pink solid in 52% yield.

[0311] Example 25 N-(1-((1,1-difluorospiro[2.3]hex-5-yl)methyl)-1H-indol-5-yl)acrylamide

[0312] 1-((1,1-difluorospiro[2.3]hex-5-yl)methyl)-1H-indol-5-amine (110 mg, 419 μmol) was dissolved in DCM (2 ml) with Et3N (70 μl, 503 μmol), cooled to 0°C, and then acryloyl chloride (38 μl, 461 μmol) was added. Stirring was continued for 30 min at 0°C. The reaction mixture was diluted with CH2Cl2, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt) to obtain 75 mg of N-(1-((1,1-difluorospiro[2.3]hex-5-yl)methyl)-1H-indol-5-yl)acrylamide as a solid after grinding in ether in a yield of 57%.

[0313] Example 26 N-(1-((3-fluorocyclopentyl)methyl)-1H-indol-5-yl)acrylamide

[0314] 1-((3-fluorocyclopentyl)methyl)-1H-indole-5-amine (130mg, 560μmol) and EtN (94μl, 672μmol) were dissolved in DCM (2ml) together, cooled to 0°C, and then acryloyl chloride (52μl, 616μmol) was added. Stirring was continued for 30min at 0°C. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain 72mg of N-(1-((3-fluorocyclopentyl)methyl)-1H-indole-5-yl)acrylamide as a solid after grinding in ether, with a yield of 45%.

[0315] Example 27 N-(1-(Cyclohexylmethyl)-1H-indol-5-yl)acrylamide

[0316] 1-(Cyclohexylmethyl)-1H-indol-5-amine (260 mg, 1.14 mmol) was dissolved in DCM (10 ml) with Et3N (218.76 μl, 1.25 mmol), cooled to 0°C, and then acryloyl chloride (97 μl, 1.20 mmol) was added. Stirring was continued at 0°C for 45 min. The reaction mixture was diluted with CH2Cl2, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 77 mg of N-(1-(cyclohexylmethyl)-1H-indol-5-yl)acrylamide as a solid after grinding in AcOEt in a yield of 24%.

[0317] Example 28 N-(1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-indol-5-yl)acrylamide

[0318] 1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-indol-5-amine (138 mg, 514 μmol) was dissolved in DCM (2 ml) with Et3N (86 μl, 617 μmol), cooled to 0°C, and then acryloyl chloride (48 μl, 566 μmol) was added. Stirring was continued at 0°C for 45 min. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain 47 mg of N-(1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-indol-5-yl)acrylamide as a solid after grinding in ether in a yield of 28%.

[0319] Example 29 N-(1-((3,3-difluorocyclopentyl)methyl)-1H-indol-5-yl)acrylamide

[0320] 1-((3,3-difluorocyclopentyl)methyl)-1H-indole-5-amine (67mg, 268μmol) and EtN (45μl, 321μmol) were dissolved in DCM (2ml), cooled to 0°C, and then acryloyl chloride (25μl, 295μmol) was added. Stirring was continued for 1h at 0°C. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain 34mg of N-(1-((3,3-difluorocyclopentyl)methyl)-1H-indole-5-yl)acrylamide as a solid, in a yield of 42%.

[0321] The diaryl derivatives are introduced via the alkylation already described in step 1 of the general scheme (see Example 30), or in a variant of the general synthesis scheme in which a Suzuki coupling step allows the synthesis of the corresponding diaryl derivatives for building blocks that are not commercially available after the first step of the general scheme (see Example 31).

[0322] Example 30 N-(1-([1,1'-biphenyl]-4-ylmethyl)-1H-indol-5-yl)acrylamide

[0323] 1-([1,1'-biphenyl]-4-ylmethyl)-1H-indole-5-amine (106mg, 355μmol) was dissolved in DCM (5ml) with Et3N (74μl, 533μmol), cooled to 0°C, and then acryloyl chloride (40mg, 426μmol) was added. Stirring was continued at room temperature for 2h. The reaction mixture was diluted with DCM, extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) to obtain 56mg of N-(1-([1,1'-biphenyl]-4-ylmethyl)-1H-indole-5-yl) acrylamide as a white solid, in a yield of 42%.

[0324] Example 31 N-(1-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)- Acrylamide

[0325]

[0326] 1-(4-iodobenzyl)-5-nitro-1H-indole was synthesized as described in Example 1 (Step 1).

[0327] 5-Nitro-1-[[4-[3-(trifluoromethyl)phenyl]phenyl]methyl]indole

[0328] To a suspension of 1-(4-iodobenzyl)-5-nitro-1H-indole (300 mg, 793 μmol) in 1,4-dioxane (5 ml) and water (1 ml) were added 3-(trifluoromethyl)phenylboronic acid (158 mg, 793 μmol), cesium carbonate (516 mg, 1,59 mmol), DPPF (22 mg, 40 μmol) and PdCl2(PPh3)2 (28 mg, 40 μmol), the mixture was heated to 80°C (all components dissolved at this temperature) and stirring was continued at 80°C for 4 h. The reaction mixture was diluted with AcOEt, extracted with water and saturated aqueous NaCl solution, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 75 / 25) to afford 253 mg of 5-nitro-1-[[4-[3-(trifluoromethyl)phenyl]-phenyl]methyl]indole as a yellow resin in 90% yield.

[0329] 1-([1,1′-biphenyl]-4-ylmethyl)-1H-indol-5-amine was synthesized and purified as described in Example 1 (Step 2).

[0330] N-(1-([1,1'-biphenyl]-4-ylmethyl)-1H-indol-5-yl)acrylamide

[0331] 1-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-amine (188mg, 513μmol) was dissolved in DCM (5ml) with Et3N (86μl, 616μmol), cooled to 0°C, and then acryloyl chloride (58mg, 616μmol) was added. Stirring was continued at room temperature for 2h. The reaction mixture was diluted with DCM, extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 31mg of N-(1-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)acrylamide (Example 31), yield 14% as a white solid.

[0332] Example 32 N-(1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)- Acrylamide1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-amine (158mg, 431μmol) was dissolved in DCM (5ml) with Et3N (72μl, 518μmol), cooled to 0°C, and then acryloyl chloride (49mg, 518μmol) was added. Stirring was continued at room temperature for 1h. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient DCM / MeOH 100 / 0 to 95 / 5) to obtain 60mg of N-(1-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)acrylamide as a white solid after grinding in DCM, with a yield of 30%.

[0333] An alternative to step 1 in Scheme 2 is depicted in the following examples. The Mitsunobu reaction method is used with primary or secondary alcohols as starting materials. Steps 2 and 3 are accomplished in the same manner as shown in the previous schemes.

[0334] Example 33 trans-N-[1-[4-(trifluoromethyl)cyclohexyl]indol-5-yl]acrylamide and

[0335] Example 34 cis-N-[1-[4-(trifluoromethyl)cyclohexyl]indol-5-yl]acrylamide

[0336]

[0337] 5-Nitro-1-[4-(trifluoromethyl)cyclohexyl]indole

[0338] 4-(Trifluoromethyl) cyclohexanol (341 μl, 2.42mmol) is introduced into toluene (30ml) under nitrogen, and 5-nitroindole (200mg, 1.21mmol) and CMPB (988 μl, 3.63mmol) are added in sequence. The resulting mixture is heated at 90°C for 18h and stirred for the next 24h at room temperature, then diluted by AcOEt and washed twice with water and washed twice with a saturated aqueous solution of NaCl. The organic layer is dried over solid Na2SO4 and the solvent is removed under reduced pressure to obtain 194mg of 5-nitro-1-[4-(trifluoromethyl) cyclohexyl] indole as a solid after column chromatography purification (silica gel, eluent DCM / MeOH 100 / 0 to 99 / 1), in a yield of 51%.

[0339] 1-(4-(Trifluoromethyl)cyclohexyl)-1H-indol-5-amine

[0340] 5-Nitro-1-(4-(trifluoromethyl)cyclohexyl)-1H-indole (194 mg, 621 μmol) was dissolved in 5 ml methanol and 5 ml AcOEt, Pd / C 10% (50% wet) (66 mg) was added and the mixture was hydrogenated at 20 psi hydrogen pressure in a Parr apparatus at room temperature for 45 min. After filtration and evaporation under reduced pressure, 180 mg of 1-(4-(trifluoro-methyl)cyclohexyl)-1H-indole-5-amine was obtained and used without further purification, original yield 100%.

[0341] N-[1-[4-(Trifluoromethyl)cyclohexyl]indol-5-yl]acrylamide

[0342] 1-(4-(Trifluoromethyl)cyclohexyl)-1H-indol-5-amine (175 mg, 620 μmol) was dissolved in DCM (2 ml) along with Et3N (104 μl, 744 μmol), cooled to 0°C, and then acryloyl chloride (57 μl, 682 μmol) was added. Stirring was continued at room temperature for 45 min. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to afford 23 mg of cis-N-[1-[4-(trifluoromethyl)cyclohexyl]indol-5-yl]acrylamide (Example 33) as a white solid (yield 7%) and 52 mg of trans-N-[1-[4-(trifluoromethyl)-cyclohexyl]indol-5-yl]acrylamide (Example 34) as a white powder (yield 16%) after further trituration in diethyl ether.

[0343] The following compounds were synthesized in a similar manner to Example 33 and Example 34 by using appropriate indoles and primary or secondary alcohols known to those skilled in the art as starting materials.

[0344] Example 35 N-(1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)-1H-indol-5-yl)-propane Enamide1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)-1H-indol-5-amine (280mg, 900μmol) was dissolved in DCM (7ml) with EtN (220μl, 1.50mmol), cooled to 0°C, and then acryloyl chloride (73μl, 1.1mmol) was added. Stirring was continued at room temperature for 1h. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) to obtain 30mg foam (80% purity), which was further purified via reverse phase column chromatography to obtain 12mg of N-(1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)-1H-indol-5-yl)-acrylamide as an amorphous solid in a yield of 3.7%.

[0345] Example 36 N-(1-(2-(methyl(2,2,2-trifluoroethyl)amino)ethyl)-1H-indol-5-yl)acryloyl amine

[0346] 1-(2-(methyl(2,2,2-trifluoroethyl)amino)ethyl)-1H-indole-5-amine (150mg, 550μmol) and EtN (120μl, 830μmol) were dissolved in DCM (2ml) together, cooled to 0°C, and then acryloyl chloride (56μl, 660μmol) was added. Stirring was continued at room temperature for 2h. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 86mg of N-(1-(2-(methyl(2,2,2-trifluoroethyl)amino)ethyl)-1H-indole-5-yl)acrylamide as a light beige solid after grinding in pentane, yield 48%.

[0347] Example 37 N-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-indol-5-yl)acrylamide

[0348] 1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-indole-5-amine (224mg, 0.87mmol) and EtN (180μl, 1.3mmol) are dissolved in DCM (5ml) together, cooled to 0°C, then acryloyl chloride (88μl, 1.04mmol) is added. Stirring is continued at room temperature for 4h. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 64mg N-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in ether, yield 23%.

[0349] Example 38 N-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-indol-5-yl)acrylamide

[0350] 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-indol-5-amine (73mg, 246μmol) was dissolved in DCM (3ml) with EtN (72μl, 491μmol), cooled to 0°C, and then acryloyl chloride (24μl, 295μmol) was added. Stirring was continued at room temperature for 1h. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) to obtain 20mg of N-(1-(1-(2,2,2-trifluoro-ethyl)-piperidin-4-yl)-1H-indol-5-yl) acrylamide as an amorphous solid, in a yield of 23%.

[0351] Example 39 N-(1-(4,4-difluorocyclohexyl)-1H-indol-5-yl)acrylamide

[0352] 1-(4,4-difluorocyclohexyl)-1H-indole-5-amine (134 mg, 540 μmol) was dissolved in DCM (3 ml) with Et3N (90 μl, 640 μmol), cooled to 0 °C, and then acryloyl chloride (88 μl, 1.04 mmol) was added. Stirring was continued for 15 min at 0 °C. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain 42 mg of powdered N-(1-(2-(2,2,2-trifluoro-ethoxy)ethyl)-1H-indole-5-yl)acrylamide in 68% yield.

[0353] Example 40 N-(1-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)-1H-indol-5-yl)acrylamide

[0354] 1-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)-1H-indol-5-amine (60 mg, 167 μmol) was dissolved in DCM (2 ml) with Et3N (28 μl, 200 μmol), cooled to 0°C, and then acryloyl chloride (16 μl, 184 μmol) was added. Stirring was continued for 30 min at 0°C. The reaction mixture was diluted with DCM, extracted with water and a saturated aqueous solution of NaCl, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain 32 mg of N-(1-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)-1H-indol-5-yl)acrylamide as a white powder in a yield of 51%.

[0355] Another variation of the general procedure is depicted in Example 41 below, in which the halohydrin is introduced in a first step via the Mitsunobu reaction already described and then further substituted with a secondary amine.

[0356] Example 41 N-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-5-yl)acrylamide

[0357]

[0358] 1-(3-Bromopropyl)-5-nitro-1H-indole

[0359] 5-nitroindole (1g, 6.04mmol) is dissolved in toluene (100ml), then 3-bromo-1-propanol (1.77g, 12.09mmol) and CMPB (4.61g, 18.13mmol) are added. The mixture is heated at 100 ℃ for 2h, cooled to room temperature, diluted with AcOEt, washed with water and NaCl saturated aqueous solution, dried over sodium sulfate and concentrated under reduced pressure. Purified by silica gel column chromatography (eluent heptane / AcOEt 100 / 0 to 50 / 50), 2.2g yellow solid is provided, productive rate 37%.

[0360] 1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-5-nitro-1H-indole

[0361] 3,3-difluoropyrrolidine hydrochloride (136mg, 918μmol), potassium carbonate (225mg, 1.62mmol) and 1-(3-bromopropyl)-5-nitro-1H-indole (200mg, 706μmol) are dissolved in acetonitrile (5ml). The mixture is heated at 70 ° C overnight, then cooled to room temperature, poured into water and extracted with AcOEt. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent heptane / AcOEt 100 / 0 to 50 / 50), to obtain 136mg of 1-(3-(3,3-difluoropyrrolidine-1-yl) propyl)-5-nitro-1H-indole in yellow oil, yield 62%.

[0362] 1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-5-amine

[0363] 1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-5-nitro-1H-indole (136 mg, 440 μmol) was dissolved in MeOH (10 ml). Pd / C 10% (50% wet) (47 mg, 22 μmol) was added and the mixture was hydrogenated at 20 psi hydrogen pressure in a Parr apparatus at room temperature for 2 h. After filtration and evaporation under reduced pressure, 100 mg of pink oil was obtained and used in the next step without further purification in 81% yield.

[0364] N-(1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indol-5-yl)acrylamide (Example 41)

[0365] 1-(3-(3,3-difluoropyrrolidin-1-yl) propyl)-1H-indole-5-amine (100mg, 358μmol) and EtN (75μl, 537μmol) are dissolved in DCM (2ml) together, cooled to 0°C, then acryloyl chloride (36μl, 430μmol) is added. Stirring is continued for 2h at room temperature. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 50 / 50) to obtain 22mg of N-(1-(3-(3,3-difluoropyrrolidin-1-yl) propyl)-1H-indole-5-yl) acrylamide as solid after grinding in ether, yield 18%.

[0366] The following examples present alternatives to the reduction of the nitro group (step 2 of Scheme 2) in order to tolerate functional groups that are sensitive to catalytic hydrogenation.

[0367] Example 42 N-(1-(4-(trimethylsilyl)benzyl)-1H-indol-5-yl)acrylamide

[0368]

[0369] 5-Nitro-1-(4-(trimethylsilyl)benzyl)-1H-indole

[0370] 4-(Trimethylsilyl)phenyl)methanol (556mg, 3.08mmol) is introduced into toluene (15ml) under nitrogen. 5-nitroindole (250mg, 1.54mmol) and CMPB (1.3ml, 4.63mmol) are added in sequence. The resulting mixture is heated at 90°C for 18h, then diluted by AcOEt and washed twice with water and washed twice with a saturated aqueous solution of NaCl. The organic layer is dried over solid Na2SO4 and the solvent is removed under reduced pressure. After column chromatography purification (silica gel, eluent DCM / MeOH 100 / 0 to 99 / 1), 194mg of 5-nitro-1-(4-(trimethylsilyl)benzyl)-1H-indole is obtained as a light yellow solid, with a yield of 51%.

[0371] 1-(4-(Trimethylsilyl)benzyl)-1H-indol-5-amine

[0372] To a solution of 5-nitro-1-(4-(trimethylsilyl)benzyl)-1H-indole (200 mg, 0.62 mmol) in 4.5 ml ethanol and 1.5 ml water was added ammonium chloride (87 mg, 1.54 mmol) and iron powder (87 mg, 1.54 mmol). The pale yellow solution darkened rapidly and was heated under reflux for 2 h. After cooling to room temperature, 3 ml of water was added. The resulting gel was filtered through a Whatman filter-pad and rinsed with AcOEt. The aqueous layer was separated and extracted twice with AcOEt. The combined organic layers were washed with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and evaporated under reduced pressure to obtain 110 mg of jelly, which was used in the next step without further purification, with an original yield of 60%.

[0373] N-(1-(4-(trimethylsilyl)benzyl)-1H-indol-5-yl)acrylamide (Example 42)

[0374] N-(1-(4-(Trimethylsilyl)benzyl)-1H-indol-5-amine (105 mg, 36 μmol) was dissolved in DCM (6 ml) together with Et3N (99 μl, 713 μmol), cooled to 0°C and then acryloyl chloride (36 μl, 430 μmol) was added. Stirring was continued at room temperature for 18 h. The reaction mixture was diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) to afford 50 mg of N-(1-(4-(trimethylsilyl)-benzyl)-1H-indol-5-yl)acrylamide as a white solid in 36% yield.

[0375] Another sequence is demonstrated in the following examples, where the first step of the general scheme is achieved via an Ullmann-coupling using iodo-aryl or iodo-hetero-aryl derivatives:

[0376] Example 43 N-(1-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0377]

[0378] 5-Nitro-1-(3-(trifluoromethyl)phenyl)-1H-indole

[0379] As described in patent application US 2016 / 318864, 5-nitroindole (500mg, 3.02mmol), 1-iodo-3-(trifluoromethyl)benzene (536μl, 3.02mmol), DMEDA (331μl, 3.05mmol), copper (I) iodide (587mg, 3.08mmol) and potassium carbonate (852mg, 6.16mmol) were added to DMSO (5ml) and heated at 140°C for 6h. AcOEt was added to the mixture and washed with water and saturated aqueous solution of NaCl. The organic layer was dried over MgSO4. After filtering and evaporating the solvent under reduced pressure, 850mg 5-nitro-1-(3-(trifluoromethyl)phenyl)-1H-indole was obtained and used without further purification, with a yield of 92%.

[0380] 1-(3-(Trifluoromethyl)phenyl)-1H-indol-5-amine

[0381] 5-Nitro-1-(3-(trifluoromethyl)phenyl)-1H-indole (0.85 g, 2.78 mmol) was dissolved in 20 ml MeOH and 5 ml AcOEt, Pd / C 10% (50% wet) (30 mg) was added and the mixture was hydrogenated at 30 psi hydrogen pressure in a Parr apparatus at room temperature for 2 h. After filtration and evaporation under reduced pressure, 714 mg of 1-(3-(trifluoro-methyl)phenyl)-1H-indole-5-amine was obtained as a brown oil and used without further purification in a yield of 93%.

[0382] 1-(3-(trifluoromethyl)phenyl)-1H-indole-5-amine (200 mg, 724 μmol) obtained in the step described above was dissolved in DCM (2 ml) with EtN (121 μl, 869 μmol), cooled to 0 ° C, and then acryloyl chloride (82 mg, 869 μmol) was added. Stirring was continued at room temperature for 1 h 30. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain after grinding in ether, 102 mg of N-(1-(3-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide (Example 43) as a white solid, with a yield of 42%.

[0383] The following compounds were synthesized in a similar manner to Example 43 by using appropriate indole and iodo-aryl derivatives known to those skilled in the art as starting materials.

[0384] Example 44 N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0385] 1-(4-(trifluoromethyl)phenyl)-1H-indole-5-amine (200mg, 724μmol) and EtN (121μl, 869μmol) are dissolved in DCM (2ml) together, cooled to 0°C, then acryloyl chloride (82mg, 869μmol) is added. Stirring is continued for 3h at room temperature. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 95 / 5 to 60 / 40) to obtain 105mg N-(1-(4-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide as a white solid after grinding in ether, yield 42%.

[0386] Example 45 N-(1-(6-(trifluoromethyl)pyridin-3-yl)-1H-indol-5-yl)acrylamide

[0387] 1-(6-(trifluoromethyl)pyridin-3-yl)-1H-indole-5-amine (173mg, 603μmol) is dissolved in DCM (5ml) together with DIEA (160μl, 909μmol), cooled to 0°C, then acryloyl chloride (50μl, 617μmol) is added. Stirring is continued at room temperature overnight. The reaction mixture is diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 80 / 20), to obtain 67mg N-(1-(6-(trifluoro-methyl)-pyridin-3-yl)-1H-indole-5-yl) acrylamide as a white solid after grinding in diisopropyl ether, yield 32%.

[0388] Example 46 N-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indol-5-yl)acrylamide

[0389] 1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole-5-amine (167mg, 572μmol) is dissolved in DCM (5ml) together with DIPA (160μl, 909μmol), cooled to 0°C, then acryloyl chloride (50μl, 617μmol) is added. Stirring is continued at room temperature overnight. The reaction mixture is diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 80 / 20) to obtain 67mg N-(1-(5-(trifluoromethyl)pyridin-2-yl)-1H-indole-5-yl)acrylamide as a white solid after grinding in diisopropyl ether, yield 35%.

[0390] Example 47 N-(1-(Pyridin-3-yl)-1H-indol-5-yl)acrylamide

[0391] 1-(Pyridin-3-yl)-1H-indole-5-amine (224mg, 867μmol) is dissolved in dichloro-methane (5ml) together with DIPA (230μl, 1.31mmol), cooled to 0°C, then acryloyl chloride (80μl, 988μmol) is added. Stirring is continued at room temperature overnight. The reaction mixture is diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient cyclohexane / AcOEt 100 / 0 to 60 / 40) to obtain 136mg N-(1-(pyridin-3-yl)-1H-indole-5-yl) acrylamide as a white solid after grinding in diisopropyl ether, yield 57%.

[0392] Example 48 N-(1-(4-fluorophenyl)-1H-indol-5-yl)acrylamide

[0393] 1-(4-fluorophenyl)-1H-indole-5-amine (183mg, 809μmol) and EtN (169μl, 1.21mmol) are dissolved in dichloro-methane (4ml) together, cooled to 0°C, then acryloyl chloride (92mg, 971μmol) is added. Stirring is continued at room temperature for 4h. The reaction mixture is diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30), to obtain 38mg N-(1-(4-fluorophenyl)-1H-indole-5-yl)-acrylamide as a white solid, yield 17%.

[0394] Example 49 N-(1-(3,4-difluorophenyl)-1H-indol-5-yl)acrylamide

[0395] 1-(3,4-difluorophenyl)-1H-indole-5-amine (310mg, 1.27mmol) and Et3N (265μl, 1.90mmol) are dissolved in DCM (4ml) together, cooled to 0°C, and then acryloyl chloride (144mg, 1.52mmol) is added. Stirring is continued for 4h at room temperature. The reaction mixture is diluted with DCM, extracted with water, dried over Na2SO4, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) to obtain 5mg of N-(1-(3,4-difluorophenyl)-1H-indole-5-yl)acrylamide as a light pink solid, in a yield of 2%.

[0396] Example 50 N-(1-(3-(methylsulfonyl)phenyl)-1H-indol-5-yl)acrylamide

[0397] 1-(3-(Methylsulfonyl)phenyl)-1H-indole-5-amine (255mg, 891μmol) and EtN (186μl, 1.34mmol) were dissolved in DCM (5ml) together, cooled to 0°C, and then acryloyl chloride (101mg, 1.07mmol) was added. Stirring was continued at room temperature for 4h. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 70 / 30) to obtain 115mg of N-(1-(3-(methylsulfonyl)-phenyl)-1H-indole-5-yl)acrylamide as a white solid, in a yield of 34%.

[0398] Example 51 N-(1-(4-cyanophenyl)-1H-indol-5-yl)acrylamide

[0399] 4-(5-amino-1H-indol-1-yl)benzonitrile (32mg, 137μmol) was dissolved in dichloro-methane (3ml) with EtN (29μl, 206μmol), cooled to 0°C, and then acryloyl chloride (16mg, 165μmol) was added. Stirring was continued at room temperature for 2h. The reaction mixture was diluted with DCM, extracted with water, dried over NaSO, evaporated under reduced pressure and purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 60 / 40) to obtain 8mg of N-(1-(4-cyanophenyl)-1H-indol-5-yl)acrylamide as a white solid, in a yield of 20%.

[0400] The following examples were synthesized as already described in Scheme 2.

[0401] Example 52 N-(1-(3,5-difluorobenzyl)-1H-indol-5-yl)acrylamide

[0402] To a solution of 1-(3,5-difluorobenzyl)-1H-indole-5-amine (297mg, 1.09mmol) in DCM (5ml) at 0°C, Et was added under N2N (185 μl, 1.31mmol) and acryloyl chloride (102 μl, 1.31mmol), and the mixture was stirred overnight at 25°C. The reaction mixture was diluted with DCM and washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt, 100 / 0 to 80 / 20) to obtain 120mg of N-(1-(3,5-difluoro-benzyl)-1H-indole-5-yl) acrylamide as a white solid, 35% yield after grinding in diisopropyl ether.

[0403] Example 53 N-(1-(3,4-difluorobenzyl)-1H-indol-5-yl)acrylamide

[0404] To a solution of 1-(3,4-difluorobenzyl)-1H-indole-5-amine (255mg, 938mmol) in DCM (5ml) at 0°C, under N2, Et3N (159 μl, 1.13mmol) and acryloyl chloride (88 μl, 1.13mmol) were added, and the mixture was stirred overnight at 25°C. The reaction mixture was diluted with DCM and washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient cyclohexane / AcOEt, 100 / 0 to 80 / 20) to obtain 143mg of N-(1-(3,4-difluoro-benzyl)-1H-indole-5-yl) acrylamide as a white solid, 49% yield after grinding in diisopropyl ether.

[0405] Example 54 N-(1-(3-cyanobenzyl)-1H-indol-5-yl)acrylamide

[0406] To a solution of 3-((5-amino-1H-indol-1-yl)methyl)benzonitrile (132 mg, 534 μmol) in DCM (6 ml) was added EtN (91 μl, 6,46 μmol) and acryloyl chloride (50 μl, 644 μmol) at 0 ° C., and the mixture was stirred overnight at 25 ° C. The reaction mixture was diluted with DCM and washed with water, dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (mobile phase [A: H2O (0.2% FA), B: MeCN, gradient B: 20%-80%, 18 min]) to obtain 70 mg of N-(1-(3-cyanobenzyl)-1H-indol-5-yl)acrylamide as a white solid after grinding in diisopropyl ether, 42% yield.

[0407] The following example depicts a variation of Scheme 2 with slightly altered reaction conditions for the alkylation in step 1 and the reduction of the nitro group in step 2.

[0408] Example 55 N-(1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indol-5-yl)acrylamide

[0409]

[0410] 5-Nitro-1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indole (Step 1 )

[0411] To a solution of 5-nitro-1H-indole (200 mg, 1.21 mmol) in DMF (15 ml) at 0 ° C., K2CO3 (845 mg, 6.05 mmol) was added under N2, and the mixture was stirred at 0 ° C. for 10 min, and then 2-(bromomethyl)-5-(trifluoromethyl)furan (423 μl, 3.03 mmol) was poured. The mixture was stirred overnight at 0 ° C. The reaction mixture was concentrated under reduced pressure to obtain a yellow oil, which was purified by column chromatography (SiO2, cyclohexane / AcOEt 6 / 4) to obtain 385 mg of 5-nitro-1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indole as a yellow solid, 100% yield.

[0412] 1-((5-(Trifluoromethyl)furan-2-yl)methyl)-1H-indol-5-amine (Step 2)

[0413] To a solution of 5-nitro-1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indole (236 mg, 753 μmol) in EtOH (14 ml) under N was added tin(II) chloride hydrate (1.39 g, 6.04 mmol) and the mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO and brine, filtered on a hydrophobic cartridge and concentrated under reduced pressure to give 223 mg of crude 1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indole-5-amine as a brown oil, which was used in the next step without further purification.

[0414] N-(1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indol-5-yl)acrylamide (Step 3)

[0415] To a solution of 1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indol-5-amine (221 mg, 749 μmol) in DCM (14 ml) was added DIEA (200 μl, 1.14 mmol) and acryloyl chloride (58 μl, 716 μmol) at 0° C. under N2, and the mixture was stirred overnight at 25° C. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column CSH 250x50mm 5μm (Waters), mobile phase [A: H2O (0.1% FA), B: MeCN (0.1% FA)]; gradient B 31%-51%, 20 min) to afford, after trituration in diisopropyl ether, 42 mg of N-(1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indol-5-yl)acrylamide as a white solid in 17% yield.

[0416] The following Examples 56 and 57 were synthesized as described for Example 55.

[0417] Example 56 N-(1-(thiazol-4-ylmethyl)-1H-indol-5-yl)acrylamide

[0418] To a solution of 1-(thiazol-4-ylmethyl)-1H-indol-5-amine (215 mg, 844 μmol) in DCM (10 ml) was added DIEA (253 μl, 1.44 mmol) and acryloyl chloride (65 μl, 802 μmol) at 0° C. under N2, and the mixture was stirred overnight at 25° C. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient DCM / MeOH, 100 / 0 to 97 / 3) to afford 138 mg of crude product (90% purity LCMS), which was purified by reverse phase chromatography (Gilson GX271 column CSH 250x50mm 5μm (Waters), mobile phase [A: H2O (0.1% FA), B: MeCN (0.1% FA)]; gradient B%: 17%-37%; 20min) to afford, after trituration in diisopropyl ether, 75 mg of N-(1-(thiazol-4-yl-methyl)-1H-indol-5-yl)acrylamide as a white solid in 31% yield.

[0419] Example 57 N-(1-((2-(trifluoromethyl)thiazol-4-yl)methyl)-1H-indol-5-yl)acrylamide

[0420] To a solution of N-1-((2-(trifluoromethyl)thiazol-4-yl)methyl)-1H-indol-5-amine (188 mg, 626 μmol) in DCM (10 ml) was added DIEA (165 μl, 938 μmol) and acryloyl chloride (49 μl, 605 μmol) at 0° C. under N2, and the mixture was stirred overnight at 25° C. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column CSH 250*50mm 5μm (Waters), mobile phase [A: H2O (0.1% FA), B: MeCN (0.1% FA)]; gradient B%: 32%-52%; 25min) to obtain 102 mg of N-(1-((2-(trifluoro-methyl)thiazol-4-yl)methyl)-1H-indol-5-yl)acrylamide as a white solid in 46% yield after trituration in diisopropyl ether.

[0421] The following Examples 58 to 60 were synthesized as described in Scheme 2 by using the appropriate indoles as starting materials.

[0422] Example 58 N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-7-yl)acrylamide

[0423] To a solution of 1-(3-(trifluoromethyl)benzyl)-1H-indol-7-amine (200 mg, 689 μmol) in DCM (2 ml) was added EtN (144 μl, 1.03 mmol) and acryloyl chloride (78 mg, 827 μmol) at 0°C under N and the mixture was stirred at 25°C for 1 h 30. The reaction mixture was diluted with DCM and washed with water, dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient heptane / AcOEt 100 / 0 to 80 / 20) to obtain 77 mg of N-(1-(3-(trifluoro-methyl)benzyl)-1H-indol-7-yl)acrylamide as a cream solid in 30% yield after trituration in ether.

[0424] Example 59 N-(1-(3-(methylsulfonyl)benzyl)-1H-indol-5-yl)acrylamide

[0425] To 1-(3-(methylsulfonyl)benzyl)-1H-indole-5-amine (187mg, 610μmol) in DCM (5ml) solution under N2, Et3N (103μl, 732μmol) and acryloyl chloride (57μl, 735μmol) were added at 0°C, and the mixture was stirred overnight at 25°C. The reaction mixture was diluted with DCM and washed with NaHCO3saturated aqueous solution and water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient DCM / MeOH, 0 / 100 to 5 / 95) to obtain 107mg of N-(1-(3-(methylsulfonyl)benzyl)-1H-indole-5-yl)acrylamide, 47% yield, as a light pink solid after grinding in diisopropyl ether.

[0426] Example 60 N-(3-(methoxymethyl)-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acryloyl amine

[0427] To a solution of 3-(methoxymethyl)-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-amine (300mg, 897μmol) in DCM (4ml) at 0°C, DIEA (313μl, 1.79mmol) was added, followed by acryloyl chloride (88μl, 1.08mmol) at 0°C. The mixture was allowed to warm to 25°C and stirred at room temperature for 2 hours. The mixture was diluted with DCM (20ml) and washed with water (5ml x 2). The organic phase was dried over NaSO, filtered and concentrated under reduced pressure. The mixture was purified by preparative TLC (PE / AcOEt, 1 / 1) to give the crude product, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 34%-64%, 8min) to obtain 216mg of N-(3-(methoxy-methyl)-1-(3-(trifluoromethyl)-benzyl)-1H-indol-5-yl)acrylamide as an off-white solid in 62% yield.

[0428] Example 61 5-Acrylamide-1-(3-(trifluoromethyl)benzyl)-1 H -Indole-3-carboxylic acid methyl ester

[0429] At 0 ℃, add DIEA (1.35ml, 7.75mmol) and acryloyl chloride (368mg, 4.07mmol) to the solution of 5-amino-1-(3-(trifluoromethyl) benzyl)-1H-indole-3-methyl formate (1.35g, 3.88mmol) in DCM (15ml).Allow the mixture to be warmed to 25 ℃ and stir for 2 hours.Mixture is diluted with DCM (150ml) and washed with water (40ml x 3).Organic phase is through Na2SO4Dry, filter and concentrate under reduced pressure to obtain crude product, grind it with 20ml PE / AcOEt (20 / 1), to obtain 1.1g 5-acrylamido-1-(3-(trifluoromethyl) benzyl)-1H-indole-3-methyl formate, 71% yield in yellow solid.

[0430] The following Examples 62 to 76 were synthesized as already described for Example 43, except for Examples 62, 64 and 65, the reaction conditions for Step 2 (reduction of the nitro group) in these three Examples were the same as those described for Step 2 in Example 42.

[0431] Example 62 N-(1-(3-(trifluoromethyl)phenyl)-1 H -indol-6-yl)acrylamide

[0432] To a solution of 1-(3-(trifluoromethyl)phenyl)-1H-indol-6-amine (220 mg, 796 μmol) in DCM (4 ml) was added DIEA (309 mg, 2.39 mmol) and acryloyl chloride (79 mg, 876 μmol) at 0°C. The mixture was allowed to warm to 25°C and stirred for 1 hour. The reaction mixture was diluted with DCM (10 ml) and washed with H2O (10 ml). The organic phase was washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [A: water (0.225% FA), B: MeCN]; gradient B%: 45%-75%, 7min) to obtain 163 mg of N-(1-(3-(trifluoromethyl)phenyl)-1H-indol-6-yl)acrylamide as a purple solid in 62% yield.

[0433] Example 63 N-(1-(4-(pentafluoro-λ 6 -sulfanyl)phenyl]indol-5-yl)acrylamide

[0434] To a solution of 1-(4-(pentafluoro-λ6-sulfanyl)phenyl)indol-5-amine (210 mg, 628 μmol) in DCM (3 ml) was added DIEA (219 μl, 1.26 mmol) and acryloyl chloride (62 μl, 754 μmol) at 0°C. The mixture was allowed to warm to 25°C and stirred for 2 hours. The mixture was diluted with DCM (20 ml) and washed with water (10 ml x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a mixture which was triturated with 20 ml PE / AcOEt 10 / 1 solution to obtain 160 mg of crude product. Final purification was achieved by reverse phase chromatography (column: Waters Xbridge 150*25 mm 5 μm; mobile phase [A: H2O (10 mM NH4HCO3), B: MeCN]; gradient B%: 52%-82%, 10 min) to obtain 103 mg of N-(1-(4-(pentafluoro-λ)- 6 -sulfanyl)phenyl)indol-5-yl)-acrylamide, 42% yield.

[0435] Example 64 N-(1-(4-(trifluoromethyl)phenyl)-1 H -indol-6-yl)acrylamide

[0436] To a solution of 1-(4-(trifluoromethyl)phenyl)-1H-indol-6-amine (240 mg, 869 μmol) in DCM (3 ml) was added DIEA (337 mg, 2.61 mmol) and acryloyl chloride (86 mg, 956 μmol) at 0°C. The mixture was allowed to warm to 25°C and stirred for 2 hours. The reaction mixture was diluted with DCM (10 ml) and washed with H2O (10 ml). The organic phase was washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [H2O(0.225% FA)-MeCN]; gradient B%: 45%-75%, 7min) to obtain 150 mg of N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-6-yl)acrylamide as a yellow solid in 52% yield.

[0437] Example 65 N-(1-(2-methyl-4-(trifluoromethyl)phenyl)-1 H -indol-5-yl)acrylamide

[0438] To a solution of 1-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-5-amine (90 mg, 310 μmol) and DIEA (108 μl, 620 μmol) in DCM (4 ml) was added a solution of acryloyl chloride (30 μl, 372 μmol) in DCM (0.4 ml) at 0° C. The mixture was allowed to warm to 25° C. and stirred for 1 hour. The mixture was diluted with DCM (15 ml) and washed with water (5 ml x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Waters Xbridge 150*25mm 5μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 46%-76%, 8min) to obtain 75 mg of N-(1-(2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide as a yellow solid in 70% yield.

[0439] Example 66 N-(1-(3,5-difluorophenyl)-1H-indol-5-yl)acrylamide

[0440] To 1-(3,5-difluorophenyl)-1H-indole-5-amine (104mg, 426μmol) in DCM (4ml) solution under N2, Et3N (89μl, 639μmol) and acryloyl chloride (48mg, 511μmol) were added at 0°C, and the mixture was stirred for 2h at 25°C. The reaction mixture was diluted with DCM and washed with water, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient heptane / AcOEt, 65 / 35) to obtain 52mg N-(1-(3-(trifluoromethyl)benzyl)-1H-indole-7-yl)acrylamide as a white solid after grinding in ether, 41% yield.

[0441] Example 67 N-(1-(5-fluoropyridin-3-yl)-1H-indol-5-yl)acrylamide

[0442] To 1- (5- fluoropyridin-3-yl) -1H- indole -5- amine (148mg, 645μmol) in DCM (4ml) solution under N2 DIEA (195μl, 1.11mmol) and acryloyl chloride (60μl, 741μmol) were added at 0°C, and the mixture was stirred overnight at 25°C. The reaction mixture was diluted with DCM, washed with NaHCO3 saturated aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient DCM / MeOH, 100 / 0 to 97 / 3) to obtain 109mg N- (1- (5- fluoropyridin-3-yl) -1H- indole -5-yl) acrylamide as a white solid, 60% yield after grinding in diisopropyl ether.

[0443] Example 68 N-(1-(2-(trifluoromethyl)pyridin-4-yl)-1H-indol-5-yl)acrylamide

[0444] To a solution of 1-(2-(trifluoromethyl)pyridin-4-yl)-1H-indole-5-amine (210 mg, 636 μmol) in DCM (10 ml) at 0 ° C. under N2, DIEA (167 μl, 950 μmol) and acryloyl chloride (55 μl, 679 μmol) were added, the mixture was stirred at 25 ° C. and allowed to warm to room temperature overnight. The reaction mixture was diluted with DCM, washed with NaHCO3 saturated aqueous solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient DCM / MeOH, 100 / 0 to 97 / 3) to obtain 144 mg of N-(1-(2-(trifluoromethyl)pyridin-4-yl)-1H-indole-5-yl)acrylamide as a cream solid, 68% yield after grinding in diisopropyl ether.

[0445] Example 69 N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0446] DIEA (200 mg, 1.55 mmol) and acryloyl chloride (46 μl, 568 μmol) were added to a solution of 3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-amine (150 mg, 517 μmol) in DCM (2 ml) at 0 °C. The mixture was stirred for 1 hour at 25 °C. The reaction mixture was diluted with DCM (10 ml) and washed with H2O (10 ml). The organic phase was washed with saline (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography (column: Waters Xbridge 150*25mm 5μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 50%-83%, 10min) to obtain 95 mg of N-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide as a white solid in 54% yield.

[0447] Example 70 N-(2-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0448] To a mixture of 2-methyl-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole (500mg, 1.72mmol) and DIEA (668mg, 5.17mmol) in DCM (20ml) was added acryloyl chloride (171mg, 1.89mmol) under N at 0°C. The mixture was stirred at 20°C for 2 hours. The residue was poured into water (15ml). The aqueous phase was extracted with AcOEt (80ml). The organic phase was washed with brine (20ml), dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column: Phenomenex Synergi C18 150*25mm 10μm; mobile phase: [A: H2O (0.225% FA), B: MeCN]; gradient B%: 54%-84%, 10min) to obtain 185 mg of N-(2-methyl-1-(4-(trifluoromethyl)-phenyl)-1H-indol-5-yl)acrylamide as a white solid in 31% yield.

[0449] Example 71 N-methyl-N-(2-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0450] To a mixture of N-(2-methyl-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (Example 70, 350 mg, 1.02 mmol) in DMF (8 ml) was added NaH 60%) (81 mg, 2.03 mmol) in mineral oil under N at 0°C. The mixture was stirred at 0°C for 30 min. Iodomethane (95 μl, 1.52 mmol) was added dropwise and the mixture was allowed to rise to 20°C and stirred for 1 hour. The residue was poured into water (10 ml). The aqueous phase was extracted with AcOEt (10 ml). The combined organic phases were washed with brine (10 ml), dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase [A: H2O (0.225% FA), B: MeCN]; gradient B%: 52%-82%, 7min) to obtain 203 mg of N-methyl-N-(2-methyl-1-(4-(tri-fluoromethyl)phenyl)-1H-indol-5-yl)acrylamide as a yellow solid in 55% yield.

[0451] Example 72 N-[3-(Methoxymethyl)-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide

[0452] To a solution of 3-(methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-amine (430 mg, 1.34 mmol) in DCM (6 ml) was added DIEA (468 μl, 2.68 mmol) and acryloyl chloride (131 μl, 1.61 mmol) at 0°C. The mixture was then allowed to warm to 25°C and stirred for 2 hours. The mixture was diluted with DCM (15 ml) and washed with water (10 ml x 2). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 38%-68%, 8min) to obtain 348mg of N-[3-(methoxy-methyl)-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide as a yellow solid in 69% yield.

[0453] Example 73 N-(6-Fluoro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0454] To a solution of 6-fluoro-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-amine (350mg, 1.19mmol) in DCM (5ml) was added DIEA (414 μl, 2.38mmol) and acryloyl chloride (116 μl, 1.43mmol) at 0°C. The mixture was then allowed to warm to 25°C and stirred for 2 hours. The mixture was diluted with DCM (100ml) and washed with water (15ml x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product, which was ground by AcOEt (15ml), to obtain 211mg of N-(6-fluoro-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-yl)acrylamide, 50% yield as a white solid.

[0455] The following Examples 74 to 76 were synthesized based on the intermediate 1-(4-(trifluoro-methyl)-phenyl)-1H-indol-5-amine already described for Example 43.

[0456] Example 74 N-methyl-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0457] To a solution of N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (Example 44, 200 mg, 605 μmol) in THF (3 ml) was added NaH 60% (36.33 mg, 908 μmol) in mineral oil at 0°C. After stirring for 0.5 hours, iodomethane (75 μl, 1.21 mmol) was added. The mixture was then allowed to rise to 20°C and stirred for 1 hour. The mixture was poured into HCl solution (8 ml, 0.5 M) at 0°C. The aqueous phase was extracted with AcOEt (10 ml x 2). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 40%-70%, 8min) to obtain 103 mg of N-methyl-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide as a white solid in 49% yield.

[0458] Example 75 (E)-N-(1-(4-(Trifluoromethyl)phenyl)-1H-indol-5-yl)-but-2-enamide

[0459] To a solution of 1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine (300 mg, 1.09 mmol) in DCM (3 ml) was added Et3N (181 μl, 1.30 mmol) and (E)-but-2-enoyl chloride (125 μl, 1.30 mmol) at 0°C. The mixture was then warmed to 20°C and stirred for 2 hours. The mixture was diluted with DCM (20 ml) and washed with water (15 ml). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a mixture, which was purified by reverse phase chromatography (column: Waters Xbridge 150*25mm 5μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 48%-78%, 10min) and by two subsequent SFC purifications (column 1: DAICEL CHIRALCEL OD-H (250mm*30mm 5μm); mobile phase: [A: CO2, B: EtOH]; gradient B%: 35%-35%, 4.0min; 40min, column 2: Cellucoat 50*4.6mm 3μm; mobile phase: [A: CO2, B: EtOH (0.05% DEA); gradient B%: 5%-40%, flow rate: 3ml / min; detector: PDA; column temperature: 35°C; back pressure: 100 bar) was separated from its observed isomer N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)but-3-enamide (not described in this patent) to obtain 124mg of (E)-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)-but-2-enamide as a white solid, with a yield of 33%.

[0460] Example 76 (E)-4-(dimethylamino)-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)butane-2-yl Enamide

[0461]

[0462] (E)-4-Bromo-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide

[0463] To a solution of (E)-4-bromobut-2-enoic acid (896 mg, 5.43 mmol) in DMF (10 ml) was added 1-[4-(trifluoromethyl)phenyl]indol-5-amine (1 g, 3.62 mmol), HATU (2.06 g, 5.4 mmol) and DIEA (1.26 ml, 7.24 mmol) at 0°C. The mixture was stirred at 25°C for 2 hours. The mixture was diluted with AcOEt (80 ml) and washed with water (30 ml x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, PE / AcOEt, 1 / 0 to 3 / 1) and reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [H2O(0.225% FA)-MeCN]; gradient B%: 50%-80%, 7min) to obtain 300 mg of (E)-4-bromo-N-(1-(4-(trifluoromethyl)-phenyl)-1H-indol-5-yl)but-2-enamide as a yellow solid in 20% yield.

[0464] 1 H NMR (400MHz, CDCl3) δ = 8.03 (s, 1H, Ar), 7.79 (d, J = 8.4Hz, 2H, Ar), 7.62 (d, J = 8.0Hz, 2H, Ar), 7.53 (d, J = 8.8Hz, 1H, Ar), 7.45-7.36 (m, 2H, CON H,Ar),7.32(d,J=8.8Hz,1H,Ar),7.13-7.05(m,1H,Ar),6.71(d,J=2.4Hz,1H,CHCH),6.22(d,J=15.2Hz,1H,CHCH),4.10(d,J=6.8Hz,2H,CH2)

[0465] (E)-4-(Dimethylamino)-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide

[0466] To a solution of (E)-4-bromo-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide (300 mg, 709 μmol) in DMF (3 ml) was added dimethylamine (360 μl, 7.09 mmol). The mixture was stirred at 25° C. for 5 hours. The mixture was purified by reverse phase chromatography (column: Waters Xbridge 150*25mm 5 μm; mobile phase: [A: H2O(10 mMNH4HCO3), B: MeCN]; gradient B%: 39%-69%, 9 min) to obtain 93 mg of (E)-4-(dimethylamino)-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide as a white solid in 34% yield.

[0467] The following examples demonstrate some novel methods for disubstituted indoles (R11 = Cl, F in Scheme 1): the amino group is introduced via a Buchwald-coupling reaction using the corresponding appropriately substituted bromoindoles, followed by a deprotection step.

[0468] Example 77 N-(6-chloro-1-(4-(trifluoromethyl)phenyl)-1 H -indol-5-yl)acrylamide

[0469]

[0470] 5-Bromo-6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole (Step 1)

[0471] To a solution of 1-iodo-4-(trifluoromethyl)benzene (1.42 g, 5.21 mmol) in DMSO (10 ml) were added 5-bromo-6-chloro-1H-indole (1 g, 4.34 mmol), K2CO3 (1.20 g, 8.68 mmol), DMEDA (38 mg, 433.86 μmol) and CuI (992 mg, 5.21 mmol) under N2, and the mixture was stirred for 2 h at 110° C. The reaction mixture was diluted with AcOEt (20 ml) and washed with water (20 ml×3). The combined organic layers were washed with brine (20 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, PE / AcOEt, 1 / 0) to afford 1.25 g of 5-bromo-6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole as a white solid in 77% yield.

[0472] 1H NMR (400MHz, CDCl3) δ = 7.93 (s, 1H), 7.82 (d, J = 8.4Hz, 2H), 7.70-7.65 (m, 1H), 7.59 (d, J = 8.4Hz, 2H), 7.35 (d, J = 1.8Hz, 1H), 6.70-6.62 (m, 1H).

[0473] Tert-butyl (6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)carbamate (Step 2)

[0474] Under N2, t-BuONa (257mg, 2.67mmol), JohnPhos (40mg, 133μmol) and Pd2(dba)3 (122mg, 133μmol) are added to a solution of 5-bromo-6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole (500mg, 1.33mmol), tert-butyl carbamate (188mg, 1.60mmol) in toluene (5ml). The mixture is stirred at 90°C for 3h. The residue is purified by column chromatography (SiO2, PE / AcOEt, 50 / 1 to 20 / 1) to obtain 270mg of tert-butyl (6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)carbamate, 49% yield as a yellow solid.

[0475] 1 H NMR (400MHz, DMSO-d6) δ = 8.60 (s, 1H), 7.96-7.92 (m, 2H), 7.89-7.83 (m, 2H), 7 .81(d,J=1.8Hz,1H),7.75(s,1H),7.72(s,1H),6.79-6.76(m,1H),1.46(s,9H)

[0476] 6-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine (Step 3)

[0477] A solution of (6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)-carbamic acid tert-butyl ester (270 mg, 657 μmol) in HCl / AcOEt (4M, 5.09 ml) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to afford 200 mg of 6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine (HCl salt) as a white solid, which was used in the next step without further purification in 81% yield.

[0478] N-(6-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (Step 4)

[0479] To a solution of 6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine HCl salt (200 mg, 576 μmol) in DCM (2 ml) was added DIEA (223 mg, 1.73 mmol), acryloyl chloride (57 mg, 634 μmol) at 0° C. and the mixture was stirred for 2 h at 25° C. The reaction mixture was diluted with DCM (10 ml) and washed with H 2 O (10 ml). The combined organic layers were washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Waters Xbridge 150*25mm 5μm; mobile phase: [A: H2O (10mM NH4HCO3), B: -MeCN]; gradient B%: 46%-76%, 10min) to obtain 74 mg of N-(6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide as a white solid in 35% yield.

[0480] The following Examples 78 to 79 were synthesized using the same procedure as described for Example 77 (except the first step) by using the appropriate indole as the starting material.

[0481] Example 78 N-(6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0482] 5-Bromo-6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indole (Step 1 of Modified Example 77)

[0483] To a solution of 5-bromo-6-chloro-1H-indole (1 g, 4.34 mmol) in DMF (10 ml) was added NaH 60% (191 mg, 4.77 mmol) in mineral oil at 0 ° C and stirred at 25 ° C for 30 min, then 1-(bromomethyl)-3-(trifluoromethyl)benzene (1.04 g, 4.34 mmol) was added at 0 ° C and the mixture was stirred at 25 ° C for 3 h. The reaction mixture was diluted with AcOEt (20 ml) and washed with water (20 ml x 3). The combined organic layers were washed with brine (20 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, PE) to obtain 1.3 g of 5-bromo-6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indole as a white solid, 77% yield.

[0484] 1H NMR (400MHz, CDCl3) δ = 7.89 (s, 1H), 7.55 (m, 1H), 7.45-7.38 (m, 2H), 7.35 (s, 1H), 7.19-7.12 (m, 2H), 6.54-6.49 (m, 1H), 5.31 (s, 2H).

[0485] Tert-butyl (6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)carbamate (Step 2 of Example 77)

[0486] Under N2, to a solution of 5-bromo-6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indole (500mg, 1.29mmol) in toluene (5ml), tert-butyl carbamate (181mg, 1.54mmol), t-BuONa (247mg, 2.57mmol), JohnPhos (39mg, 129μmol) and Pd2(dba)3(118mg, 129μmol). The mixture is stirred at 90°C for 3h and then concentrated under reduced pressure. Residue is purified by column chromatography (SiO2, PE / AcOEt, 50 / 1 to 30 / 1), to obtain 300mg of (6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-yl)-tert-butyl carbamate, 55% yield as a yellow solid.

[0487] 6-Chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-amine (Step 3 of Example 77)

[0488] A solution of tert-butyl (6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)carbamate (300 mg, 706 μmol) in HCl / AcOEt (4M, 5.09 ml) was stirred at 25° C. for 0.5 h. The reaction mixture was concentrated under reduced pressure to afford 240 mg of 6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-amine, HCl salt, as a white solid in 94% yield.

[0489] N-(6-Chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide (Step 4 of Example 77)

[0490] To a solution of 6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-amine, HCl salt (190 mg, 526 μmol) in DCM (3 ml) was added DIEA (204 mg, 1.58 mmol), acryloyl chloride (43 μl, 526 μmol) at 0° C. and the mixture was stirred for 2 h at 25° C. The reaction mixture was diluted with DCM (10 ml) and washed with H 2 O (10 ml). The combined organic layers were washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 38%-68%, 8min) to obtain 108 mg of N-(6-chloro-1-(3-(trifluoromethyl)-benzyl)-1H-indol-5-yl)acrylamide as a white solid in 54% yield.

[0491] Example 79 N-(7-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0492] Under N2 at 0 ℃, to the solution of 7-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-amine (150mg, 462μmol) in DCM (4ml), add DIEA (161μl, 924μmol) and acryloyl chloride (41μl, 508μmol).The mixture was stirred at 0 ℃ for 2 hours, then poured into water (10ml).The aqueous phase was extracted with DCM (10ml x 2).The organic phase merged was washed with saline (5ml x 2), used Na2SO4, dried, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 40%-70%, 8min) to obtain 154 mg of N-(7-chloro-1-(3-(trifluoro-methyl)benzyl)-1H-indol-5-yl)acrylamide as a white solid in 88% yield.

[0493] The following examples demonstrate variations in the introduction of the amino group in Steps 2 and 3 compared to the methods used in Examples 77 to 79.

[0494] Example 80 N-(6-Fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide

[0495]

[0496] 5-Bromo-6-fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indole (Step 1)

[0497] To a solution of 5-bromo-6-fluoro-1H-indole (600 mg, 2.80 mmol) in DMF (6 mL) was added NaH 60% (135 mg, 3.36 mmol) in mineral oil at 0°C, followed by dropwise addition of 1-(bromomethyl)-3-(trifluoromethyl)-benzene (491 μl, 3.22 mmol) at 0°C over 0.5 hours. The mixture was allowed to warm to 20°C and stirred for 2 hours. The mixture was poured into ice water (20 ml) and extracted with AcOEt (80 ml x 2). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was combined with another batch (starting from 100 mg of 5-bromo-6-fluoro-1H-indole as described) and purified by column chromatography (SiO2, PE / AcOEt, 1 / 0) to afford 1 g of 5-bromo-6-fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indole as a white solid.

[0498] 1 H NMR (400MHz, DMSO-d6) δ = 7.88 (d, J = 6.8 Hz, 1H), 7.68-7.62 (m, 4H), 7.50 (t, J =8.0Hz, 1H), 7.44 (d, J = 7.6Hz, 1H), 6.52 (dd, J = 0.8, 3.2Hz, 1H), 5.52 (s, 2H).

[0499] N-(Diphenylmethylene)-6-fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-amine (Step 2)

[0500] To a solution of 5-bromo-6-fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indole (550mg, 1.48mmol) in dioxane (8ml) was added diphenylformimine (322μl, 1.92mmol), CsCO (1.44g, 4.43mmol), XantPhos (171mg, 295μmol) and Pd(dba) (135mg, 148μmol). The mixture was stirred at 100°C under N for 12 hours. The mixture was diluted with AcOEt (100ml) and washed with water (30x 3ml). The organic phase was dried over NaSO, filtered and concentrated under reduced pressure to obtain a residue, which was directly used in the next step.

[0501] 6-Fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-amine (Step 3)

[0502] HCl (2M, 13ml) was added dropwise to a solution of N-(diphenylmethylene)-6-fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-amine (1.2g, 2.54mmol, crude product) in THF (27ml) at 0°C. The mixture was then stirred for 2 hours at 25°C. The mixture was adjusted to pH 9 with a saturated aqueous solution of NaHCO and extracted with AcOEt (100ml x 2). The combined organic phases were dried over NaSO, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO, PE / AcOEt, 1 / 0 to 10 / 3) to obtain 0.4g of 6-fluoro-1-(3-(trifluoro-methyl)benzyl)-1H-indole-5-amine, 51% yield, as a black solid.

[0503] 1 H NMR (400MHz, DMSO-d6) δ = 7.60 (d, J = 7.6Hz, 1H), 7.57-7.51 (m, 2H), 7.41 (d, J = 7.6Hz, 1H), 7.35 (d, J = 3.2Hz ,1H),7.20(d,J=12.0Hz,1H),6.87(d,J=8.8Hz,1H),6.25(dd,J=0.4,3.2Hz,1H),5.39(s,2H),4.54(s,2H).

[0504] N-(6-Fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide (Step 4)

[0505] To a solution of 6-fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indole-5-amine (400 mg, 1.30 mmol) in DCM (7 ml) was added EtN (361 μl, 2.60 mmol) and acryloyl chloride (127 μl, 1.56 mmol) at 0°C. The mixture was then allowed to warm to 25°C and stirred for 2 hours. The mixture was diluted with DCM (20 ml) and washed with water (10 ml x 2). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by reverse phase chromatography (column: Phenomenex luna C18 150*40mm 15μm; mobile phase: [A: H2O (0.225% FA), B: MeCN]; gradient B%: 50%-80%, 10min) to obtain 300 mg of N-(6-fluoro-1-(3-(trifluoromethyl)-benzyl)-1H-indol-5-yl)acrylamide as a white solid in 63% yield.

[0506] The following example depicts a novel combination of reaction conditions that has been presented: slightly modified Ullmann coupling conditions were used in step 1, and steps 2 and 3 were the same conditions as set forth in Example 80.

[0507] Example 81 N-(7-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0508] 5-Bromo-7-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole (Step 1)

[0509] Under N2, 5-bromo-7-chloro-1H-indole (400mg, 1.74mmol) and 1-iodo-4-(trifluoro-methyl)benzene (566mg, 2.08mmol) were added to a mixture of dioxane (30ml) CsCO (1.70g, 5.21mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (41mg, 173μmol) and [BuNCuI] (194mg). The mixture was stirred at 140 ° C for 12 hours and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (PE) to obtain 630mg of 5-bromo-7-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole in a yellow oily state, in a 97% yield.

[0510] 1 H NMR (400MHz, CDCl3) δ=7.75-7.73(m,3H),7.52-7.50(m,2H),7.34(d,J=1.6Hz,1H),7.19(d,J=3.2Hz,1H),6.66(d,J=3.6Hz,1H)

[0511] 7-Chloro-N-(diphenylmethylene)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine (Step 2)

[0512] To a solution of 5-bromo-7-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole (300 mg, 801 μmol) and diphenylformimide (160 mg, 881 μmol) in dioxane (10 ml) was added CsCO (783 mg, 2.40 mmol), XantPhos (46 mg, 80 μmol) and Pd(dba) (73 mg, 80 μmol) at once under N. The mixture was stirred at 100°C for 6 hours and poured into water (30 ml). The aqueous phase was extracted with AcOEt (40 ml x 2). The combined organic phases were washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 760 mg of crude 7-chloro-N-(diphenyl-methylene)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine as a brown oil, which was used in the next step without further purification.

[0513] 7-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-amine (Step 3)

[0514] Under N2, HCl (2M, 6ml) was added to a solution of 7-chloro-N-(diphenylmethylene)-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-amine (760mg, 1.60mmol) in THF (15ml) at 0°C. The mixture was stirred at 20°C for 2 hours. The mixture was quenched by NaHCO3saturated aqueous solution (40ml). The aqueous phase was extracted with AcOEt (40ml x 2). The combined organic phases were washed with brine (10ml x 2), dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / AcOEt, gradient 30 / 1 to 10 / 1), to obtain 290mg 7-chloro-1-(4-(trifluoro-methyl)-phenyl)-1H-indole-5-amine, 53% yield as a brown solid.

[0515] 1 H NMR (400MHz, DMSO-d6) δ = 7.83 (d, J = 8.4Hz, 2H), 7.60 (d, J = 8.0Hz, 2H), 7.38 (d, J = 3.2H z,1H),6.76(d,J=1.2Hz,1H),6.63(d,J=2.0Hz,1H),6.51(d,J=3.2Hz,1H),4.96(s,2H)

[0516] N-(7-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (Step 4)

[0517] To a solution of 7-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indole-5-amine (320 mg, 1.03 mmol) in DCM (5 ml) was added DIEA (399 mg, 3.09 mmol), acryloyl chloride (102 mg, 1.13 mmol) at 0°C and stirred for 2 hours at 25°C. The reaction mixture was diluted with DCM (10 ml) and H2O (10 ml) was added. The organic phase was washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography (FA conditions; column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [H2O (0.225% FA)-MeCN]; gradient B%: 50%-80%, 7min) to obtain 198 mg of N-(7-chloro-1-(4-(trifluoro-methyl)-phenyl)-1H-indol-5-yl)acrylamide as a white solid in 53% yield.

[0518] The following example demonstrates a reaction sequence using the common synthetic intermediate already used in Example 72 to introduce R7=CH2OH (Scheme 1).

[0519] Example 82 N-(3-(Hydroxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide

[0520]

[0521] (5-Nitro-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methanol (Step 1)

[0522] To a solution of 3-(methoxymethyl)-5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indole (600mg, 1.71mmol) in DCM (60ml) was added BCl3(1M, 5.14ml) at -78°C. The mixture was stirred at -78°C for 1 hour. The mixture was allowed to warm to 0°C and poured into an ice-cold NaHCO3 saturated aqueous solution (60ml). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, PE / AcOEt, 1 / 0 to 3 / 1) to obtain 470mg of (5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methanol), 82% yield as a yellow solid.

[0523] 1H NMR (400MHz, DMSO-d6) δ = 8.74 (d, J = 2.4Hz, 1H, Ar), 8.12 (dd, J = 2.4, 9.2Hz, 1H, Ar), 7.98 (d, J = 8.4Hz, 2H, A r),7.93(s,1H,Ar),7.88(d,J=8.4Hz,2H,Ar),7.78(d,J=9.2Hz,1H,Ar),5.27(s,1H,OH),4.79(s,2H,CH2).

[0524] (5-Amino-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methanol (Step 2)

[0525] Pd / C 10% (50 mg) was added to a solution of (5-nitro-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methanol (470 mg, 1.40 mmol) in MeOH (10 ml) and AcOEt (2.5 ml). The mixture was stirred at 25 ° C under H2 (15 psi) for 2 hours. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, PE / AcOEt, 1 / 0 to 1 / 2) to obtain 360 mg of (5-amino-1-(4-(trifluoromethyl)-phenyl)-1H-indol-3-yl)methanol) as a yellow solid, 84% yield.

[0526] 1 H NMR (400MHz, DMSO-d6) δ = 7.87 (d, J = 8.4Hz, 2H, Ar), 7.75 (d, J = 8.0Hz, 2H, Ar), 7.50 (s, 1H, Ar), 7.42 (d, J = 8.8Hz, 1H, Ar), 6.85 ( d, J=2.0Hz, 1H, Ar), 6.62 (dd, J=2.0, 8.8Hz, 1H, Ar), 4.87 (t, J=5.2Hz, 1H, OH), 4.79 (s, 2H, ArNH2), 4.60 (d, J=5.2Hz, 2H, CH2).

[0527] N-(3-(Hydroxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (Step 3)

[0528] To a mixture of (5-amino-1-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methanol (360 mg, 1.18 mmol) and DIEA (409 μl, 2.35 mmol) in DCM (10 ml) at 0°C was added a solution of acryloyl chloride (96 μl, 1.18 mmol) in DCM (0.5 ml) dropwise. The mixture was allowed to warm to 25°C and stirred for 1 hour. The mixture was diluted with DCM (80 ml) and washed with water (50 ml x 2). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C1875*30mm 3μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 28%-58%, 8min) to obtain 197 mg of N-(3-(hydroxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide as a yellow solid in 47% yield.

[0529] Examples 83 and 84 below illustrate the reaction sequence for introducing R7=CONH2 starting from methyl 5-nitro-1H-indole-3-carboxylate functionalized as already described.

[0530] Example 83 5-Acrylamide-1-(3-(trifluoromethyl)benzyl)-1 H -Indole-3-carboxamide

[0531]

[0532] 5-Nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxylic acid (step 1)

[0533] To a solution of methyl 5-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxylate (500 mg, 1.32 mmol) in H2O (5 ml) and MeOH (5 ml) was added LiOH. . 4-nitro-1-(3-(trifluoro-methyl)benzyl)-1H-indole-3-carboxylic acid (100% purity LCMS), 100% yield.

[0534] 1H NMR (400MHz, DMSO-d6) δ = 8.90 (d, J = 2.0Hz, 1H, Ar), 8.56 (s, 1H, Ar), 8.12 (dd, J = 2.4, 9.2Hz, 1H, Ar), 7.84 (d ,J=9.2Hz,1H,Ar),7.79(s,1H,Ar),7.68-7.66(d,J=7.6Hz,1H,Ar),7.60-7.52(m,2H,Ar),5.71(s,2H,CH2)

[0535] 5-Nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide (Step 2)

[0536] 1-Benzotriazolyl oxide (221mg, 1.45mmol), EDCI (278mg, 1.45mmol) and DIEA (459 μl, 2.64mmol) were added to a solution of 5-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxylic acid (480mg, 1.32mmol) in DMF (7ml). The mixture was stirred at 25 °C for 5 hours. The mixture was diluted with AcOEt (30ml) and washed with water (10ml x 3). The aqueous phase was extracted with AcOEt (10ml x 1). The combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was ground with DCM (6ml) to obtain 450mg of 5-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide, 94% yield as a white solid.

[0537] HNMR (400MHz, DMSO-d6) δ = 9.09 (d, J = 2.4Hz, 1H, Ar), 8.37 (s, 1H, Ar), 8.10 (dd, J = 2.4, 9.2Hz, 1H, Ar), 7.83 (d, J = 9.2Hz, 1 H, Ar), 7.73-7.68 (m, 3H, Ar, NH2), 7.59 (t, J = 7.6Hz, 1H, Ar), 7.47 (d, J = 7.6Hz, 1H, Ar), 7.15 (s, 1H, Ar), 5.69 (s, 2H, CH2).

[0538] 5-Amino-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide (Step 3)

[0539] To a solution of 5-nitro-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide (450 mg, 1.24 mmol) in MeOH (12 ml) and AcOEt (3 ml) was added Pd / C 10% (45 mg) under N2. The mixture was stirred at 25 °C for 2 hours under H2 atmosphere (15 psi). The mixture was filtered and concentrated under reduced pressure to obtain 400 mg of 5-amino-1-(3-(trifluoro-methyl)benzyl)-1H-indole-3-carboxamide as a white solid in 97% yield.

[0540] 1 HNMR (400MHz, DMSO-d6) δ = 7.94 (s, 1H, Ar), 7.65-7.54 (m, 3H, Ar), 7.43 (d, J = 7.6Hz, 1H, Ar), 7.36 (d, J = 2.0H z,1H,Ar),7.16(d,J=8.8Hz,1H,Ar),6.52(dd,J=2.0,8.8Hz,1H,Ar),5.43(s,2H,CH2),4.69(s,2H,ArNH2).

[0541] 5-Acrylamido-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide (Step 4)

[0542] To a solution of 5-amino-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide (400 mg, 1.20 mmol) and DIEA (627 μl, 3.60 mmol) in DCM (5 ml) was added a solution of acryloyl chloride (108 μl, 1.32 mmol) in DCM (0.3 ml) at 0°C. The mixture was allowed to warm to 25°C and stirred for 4 hours. The mixture was diluted with DCM (30 ml) and washed with water (10 ml x 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Waters Xbridge 150*25mm 5μm; mobile phase: [A: H2O (10mM NH4HCO3), B: MeCN]; gradient B%: 30%-60%, 8min) to obtain 170 mg of 5-acrylamido-1-(3-(trifluoro-methyl)benzyl)-1H-indole-3-carboxamide as a white solid in 36% yield.

[0543] The following examples were synthesized using the same reaction sequence as described for Example 83.

[0544] Example 84 5-Acrylamide-1-(4-(trifluoromethyl)phenyl)-1 H -Indole-3-carboxamide

[0545] To a solution of 5-amino-1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxamide (430 mg, 1.35 mmol) in DCM (2 ml) was added DIEA (522 mg, 4.04 mmol), acryloyl chloride (134 mg, 1.48 mmol) at 0° C. The mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with DCM (10 ml) and washed with H 2 O (10 ml). The organic phase was washed with brine (10 ml x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase chromatography (column: Phenomenex Gemini-NX C18 75*30mm 3μm; mobile phase: [A: H2O (0.225% FA), B: MeCN]; gradient B%: 30%-60%, 7min) to obtain 173 mg of 5-acrylamido-1-(4-(trifluoromethyl)-phenyl)-1H-indole-3-carboxamide as an off-white solid in 34% yield.

[0546] The table below shows the chemical structures and physical properties of several compounds of formula (I).

[0547] In the table:

[0548] - Proton magnetic resonance spectra were recorded in DMSO-d6 at 400 MHz, 500 MHz or 600 MHz using the DMSO-d6 peak as reference ( 1 H NMR) as described below. Chemical shifts δ are expressed in parts per million (ppm). Observed signals are represented as follows: s = singlet; d = doublet; t = triplet; m = multiplet or br s = broad singlet; br m = broad multiplet

[0549] - The LCMS characteristics as described below indicate in turn the HPLC analysis methods (A and B) used and described in detail below, [M+H] identified by mass spectrometry + Retention time (Tr) of peaks and compounds (expressed in minutes)

[0550] -Except where otherwise indicated in Examples 60, 72 and 82, the observed ion type was always [M+H] +

[0551] Method A

[0552] Column: Acquity UPLC / SQD CORTECS C18+2.1x50mm 1.6μm (Waters), mobile phase [A: H2O (+0.1% FA), B: MeCN (+0.1% FA)], gradient B from 2% to 100% in 3min, 1ml / min

[0553] Method A'

[0554] Column: Acquity UPLC / SQD CORTECS C18+2.1x50mm 1.6μm (Waters), mobile phase [A: H2O (+0.1% FA), B: MeCN (+0.1%.FA)], gradient B from 2% to 100% in 10 min, 1 ml / min

[0555] Method B

[0556] Column: Acquity UPLC / SDS BEH C18 2.1x50mm 1.7μm (Waters), mobile phase [A: H2O (+0.05% FA), B: MeCN (+0.035% FA), gradient B from 5% to 95% in 3 min, 0.9 ml / min

[0557] Method C

[0558] Column: Kinetex EVO C18 2.1×30 mm, 5 μm, mobile phase [A: H2O (+0.0375% TFA), B: MeCN (+0.01875% TFA)], gradient B from 5% to 95% in 0.8 min, 95% 0.4 min, 1.5 ml / min, column temperature: 50°C, detector: PDA (220 and 254 nm), ionization source: ESI

[0559] Method D

[0560] Column: Kinetex EVO C18 2.1×30 mm, 5 μm, mobile phase [A: H2O (+0.025% NH3), B: MeCN], gradient B: from 5% to 95% in 0.8 min, 95% 0.4 min, 1.5 ml / min, column temperature: 40°C, detector: PDA (220 and 254 nm), ionization source: ESI

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575] To determine the ability of the compounds of formula (I) to inhibit YAP1 / TAZ-TEAD or TEAD-dependent gene transcription, biochemical studies were performed on the compounds.

[0576] TEAD-luciferase reporter assay

[0577] Luciferase-based gene reporter assays were used with TEAD-responsive promoter elements stably integrated into different human tumor cell lines to monitor YAP1-TEAD and TAZ-TEAD activities and to study the modulation of YAP1 / TAZ-TEAD activities by small molecule compounds. Luciferase-based gene reporter assays with GAPDH promoter elements stably integrated into different human tumor cell lines were used to counter-screen control cell lines.

[0578] Tumor cell lines stably integrated with 8XGTIIC-luciferase constructs (Dupont et al., Nature 2011) or GAPDH-luciferase control plasmids were seeded in culture medium in 96-well plates at a density of 8000 cells / well. After overnight incubation in a 37°C, 5% CO2 growth chamber, cells were treated with 10 doses of the compounds described above at a range of 1 to 10000 nM for 48 h. After compound incubation, cells were lysed with a Bright-Glo luciferase assay system (Promega E2620) and luciferase activity was measured using a fluorescence plate reader.

[0579] The inhibitory activity of the compounds with respect to luciferase activity was given by the concentration that inhibited 50% of the activity of untreated cells. The IC50 was determined using a non-linear regression model analyzed with XLfit software (IDBS, UK).

[0580] The IC50 values ​​of the compounds of the invention are generally less than 1 μM, more specifically between 1 and 550 nM, and even more specifically between 1 and 100 nM, as indicated in the following table:

[0581]

[0582]

[0583] Therefore, it is clear that the compound of formula (I) has inhibitory activity on YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0584] Therefore, the compounds of formula (I) can be used as inhibitors of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0585] Therefore, the compounds of formula (I) can be used as medicaments, especially as inhibitors of YAP1 / TAZ-TEAD or TEAD-dependent gene transcription.

[0586] Therefore, according to another of its aspects, a subject of the present invention is a medicament comprising a compound of formula (I) or an addition salt thereof with a pharmaceutically acceptable acid.

[0587] These agents are used therapeutically to treat cancer, particularly breast, ovarian, uterine, prostate, lung, stomach, colorectal, bladder, pancreatic and liver cancers, sarcomas, esophageal cancer, head and neck cancer, uveal melanoma or glioma.

[0588] According to another of its aspects, the present invention relates to pharmaceutical compositions comprising as active ingredient a compound of formula (I). These pharmaceutical compositions contain an effective dose of at least one compound of formula (I) or a pharmaceutically acceptable salt of said compound.

[0589] These pharmaceutical compositions may also contain at least one pharmaceutically acceptable excipient.

[0590] The excipient is selected according to the pharmaceutical form and the desired mode of administration from useful excipients known to those skilled in the art.

[0591] The compounds of formula (I) may be used to treat conditions involving YAP1 / TAZ-TEAD or TEAD-dependent gene transcription inhibitors.

[0592] In particular, the compounds of formula (I) can be used as anticancer agents, in particular for use in the treatment of breast, ovarian, uterine, prostate, lung, stomach, colorectal, bladder, pancreatic and liver cancers, sarcomas, esophageal cancers, head and neck cancers, uveal melanomas or gliomas.

[0593] The compounds of formula (I) may also be used to treat patients who have developed resistance to previous anti-cancer therapy.

[0594] According to another of its aspects, the present invention also provides a method for treating the conditions indicated above.

[0595] Thus, also described are methods of treating cancer, in particular breast cancer, ovarian cancer, uterine cancer, prostate cancer, lung cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer 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) or a pharmaceutically acceptable salt thereof.

[0596] The compounds of formula (I) may also be used in methods of treating cancer in patients who have exhibited resistance to previous anti-cancer therapy.

[0597] These compounds can be used as monotherapy or in combination with radiation therapy or chemotherapy.

Claims

1. A compound of formula (I) in n is an integer selected from 0 and 1, R1 is selected from - single bond, and -(C1-C4)alkylene, R2 is selected from: - (C1-C4)alkyl substituted by one or more fluorine atoms, - phenyl, which is unsubstituted or substituted by one or more R3 groups, - (C5-C8)cycloalkyl substituted by one or more R5 groups, - (C4-C8) heterocyclyl substituted by one or more R6 groups, and -NR9R10 group, R3 is selected from - unsubstituted or substituted by one or more fluorine atoms (C1-C4) alkyl, - cyclopropyl, - a halogen atom selected from a chlorine atom, a bromine atom or an iodine atom, - unsubstituted (C1-C3)alkoxy, -pentafluorosulfanyl group, -nitrile group, -(C1-C3)trialkylsilyl, -(C1-C3)alkylsulfonyl, and -phenyl substituted by trifluoromethyl, R4 is selected from a hydrogen atom and a (C1-C4) alkyl group, R5 is a fluorine atom, R6 is selected from - phenyl which is unsubstituted or substituted by one or more fluorine atoms, R7 is selected from - Hydrogen atoms, -nitrile group, and - unsubstituted or substituted (C1-C3)alkoxy or hydroxy (C1-C4)alkyl, -COO(C1-C4)alkyl, and -CONH2 group, R8 is selected from a hydrogen atom and a (C1-C4)alkyl group which is unsubstituted or substituted by a di(C1-C4)alkylamino group, R9 and R10 are the same or different and are selected from (C1-C3)alkyl groups which are unsubstituted or substituted by one or more fluorine atoms, R11 is selected from hydrogen atom, fluorine atom and chlorine atom or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which has the formula wherein R1, R2, R4, R7, R8 and R11 are as defined in claim 1 or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or 2, wherein R4 is a hydrogen atom or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or 2, wherein R7 is a hydrogen atom or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 or 2, wherein R8 is a hydrogen atom or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 or 2, wherein R11 is a hydrogen atom or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 or 2, wherein n is 0, R1 is a single bond, R2 is selected from: - phenyl, which is unsubstituted or substituted by one or more R3 groups, - (C5-C8)cycloalkyl substituted by one or more R5 groups, and - (C4-C8) heterocyclyl substituted by one or more R6 groups, or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7, wherein R2 is phenyl substituted with one or more R3 groups, or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 7, wherein R3 is (C1-C4) alkyl substituted by one or more fluorine atoms, or a pharmaceutically acceptable salt thereof.

10. A compound selected from the following list: N-[1-[[3-(Trifluoromethyl)phenyl]methyl]indol-5-yl]acrylamide N-Methyl-N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(1-(5,5,5-trifluoropentyl)-1H-indol-5-yl)acrylamide N-(1-(1-(3-(trifluoromethyl)phenyl)ethyl)-1H-indol-5-yl)acrylamide N-(1-(3-(Pentafluoro-λ6-sulfanyl)benzyl)-1H-indol-5-yl)acrylamide N-(1-(4-(Pentafluoro-λ6-sulfanyl)benzyl)-1H-indol-5-yl)acrylamide N-(1-(3-iodobenzyl)-1H-indol-5-yl)acrylamide N-(3-Methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(1-(3-methoxybenzyl)-1H-indol-5-yl)acrylamide N-(2-Methyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(3-cyano-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(1-(3-cyclopropylbenzyl)-1H-indol-5-yl)acrylamide N-(2,3-Dimethyl-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(1-(3-methylbenzyl)-1H-indol-5-yl)acrylamide N-(1-Benzyl-1H-indol-5-yl)-acrylamide N-(1-(3-(Trifluoromethyl)benzyl)-1H-indol-4-yl)acrylamide (E)-4-(dimethylamino)-N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-4-yl)but-2-enamide N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-6-yl)acrylamide N-(1-((4,4-difluorocyclohexyl)methyl)-1H-indol-5-yl)acrylamide N-(1-((1,1-difluorospiro[2.3]hex-5-yl) )methyl)-1H-indol-5-yl)acrylamide N-(1-((3-fluorocyclopentyl)methyl)-1H-indol-5-yl)acrylamide N-(1-((3,3-difluorocyclopentyl)methyl)-1H-indol-5-yl)acrylamide N-(1-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)acrylamide N-(1 -((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1H-indol-5-yl)acrylamide N-(1-(2-(methyl(2,2,2-trifluoroethyl)amino)ethyl)-1H-indol-5-yl)acrylamide N-(1-(4,4-difluorocyclohexyl)-1H-indol-5-yl)acrylamide N-(1-(4-(trimethylsilyl)benzyl )-1H-indol-5-yl)acrylamide N-(1-(3-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide N-(1-(3-(methylsulfonyl)phenyl)-1H-indol-5-yl)acrylamide N-(1-(4-cyanophenyl)-1H-indol-5-yl)acrylamide N-(1-(3-cyanobenzyl)-1H-indol-5-yl)acrylamide N-(1-(3-(trifluoromethyl)benzyl)-1H-indol-7-yl)acrylamide N-(1-(3-(methylsulfonyl)benzyl)-1H-indol-5-yl)acrylamide N-(3-(methoxymethyl)-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide 5-acrylamide-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxylic acid methyl ester N-(1-(3-(trifluoromethyl)phenyl)-1H-indol-6-yl)acrylamide N-(1-(4-(pentafluoro-λ6-sulfanyl)phenyl)-1H-indol-5-yl)acrylamide N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-6-yl)acrylamide Acrylamide N-[2-methyl-4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide N-[3-methyl-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide N-[2-methyl-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide N-Methyl-N-[2-methyl-1-[4-(trifluoromethyl)phenyl]indol-5-yl]acrylamide N-(3-(methoxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide N-(6-fluoro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide N-Methyl-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide (E)-N-(1-(4-(Trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide (E)-4-(Dimethylamino)-N-(1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)but-2-enamide N-(6-chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide N-(6-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(7-chloro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(6-Fluoro-1-(3-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(7-Chloro-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide N-(3-(Hydroxymethyl)-1-(4-(trifluoromethyl)phenyl)-1H-indol-5-yl)acrylamide 5-Acrylamido-1-(3-(trifluoromethyl)benzyl)-1H-indole-3-carboxamide 5-Acrylamido-1-(4-(trifluoromethyl)phenyl)-1H-indole-3-carboxamide or a pharmaceutically acceptable salt thereof.

11. A compound selected from the following list: N-(1-(3-(trifluoromethoxy)benzyl)-1H-indol-5-yl)acrylamide N-(1-(2-Fluoro-5-(trifluoromethyl)benzyl)-1H-indol-5-yl)acrylamide N-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-indol-5-yl)acrylamide N-(1-((4-(trifluoromethyl)cyclohexyl)methyl)-1H-indol-5-yl)acrylamide N-(1-((trans)-4-(trifluoromethyl)cyclohexyl)-1H-indol-5-yl)acrylamide N-(1-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)methyl)-1H-indol-5-yl)acrylamide N-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-indol-5-yl)acrylamide N-(1-(6-(Trifluoromethyl)pyridin-3-yl)-1H-indol-5-yl)acrylamide N-(1-(3,5-difluorobenzyl)-1H-indol-5-yl)acrylamide N-(1-(3,4-difluorobenzyl)-1H-indol-5-yl)acrylamide N-(1-((5-(trifluoromethyl)furan-2-yl)methyl)-1H-indol-5-yl)acrylamide N-(1-((2-(trifluoromethyl)thiazol-4-yl)methyl)-1H-indol-5-yl)acrylamide N-(1-(3,5-difluorophenyl)-1H-indol-5-yl)acrylamide N-(1-(5-fluoropyridin-3-yl)-1H-indol-5-yl)acrylamide N-(1-(2-(Trifluoromethyl)pyridin-4-yl)-1H-indol-5-yl)acrylamide or a pharmaceutically acceptable salt thereof.

12. A medicament, characterized in that The medicament comprises the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

14. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer.

15. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating breast cancer, ovarian cancer, uterine cancer, prostate cancer, lung cancer, gastric cancer, colorectal cancer, bladder cancer, pancreatic cancer and liver cancer, sarcoma, esophageal cancer, head and neck cancer, uveal melanoma or glioma.

16. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a patient who has exhibited resistance to previous anticancer therapy.

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