Tricyclic spirocyclopropane compounds as NF-KB inhibitors

Abstract

The present invention relates to novel compounds of formula (1), pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing diseases or disorders relating to cancer, as well as their use for treatment or prevention of NF-kB-related diseases or disorders.

Description

[0001] P7413PC00

[0002] Tricyclic spirocyclopropane compounds

[0003] Technical field

[0004] The present invention concerns a series of novel compounds, pharmaceutical compositions comprising such compounds and their use for treating, alleviating or preventing cancer, as well as their use for treating or preventing NF-kB-related diseases or disorders. The invention further relates to methods of treating, alleviating and / or preventing diseases and disorders related to cancer, and methods of treating or preventing NF-kB-related diseases or disorders.

[0005] Background

[0006] Cancer continues to be a global health challenge with metastasis being a primary cause of mortality and treatment failure (Parker 2022).

[0007] Metastatic spread involves the dissemination of cancer cells from primary tumors to distant organs through various routes, including the lymphatic system (Paduch et al, 2016).

[0008] The discovery of canonical lymphangiogenic factors, such as vascular endothelial growth factor C (VEGF-C) and VEGF-D, has shed light on the complex molecular mechanisms that govern lymphatic vessel formation in normal human physiology and the involvement of this process in cancer (Joukov et al, 1996, Yamada et al, 1997). Preclinical and clinical studies have demonstrated that tumors can induce lymphangiogenesis by secreting VEGF-C / VEGF-D, activating lymphatic endothelial cells (LECs) via the corresponding receptors VEGFR-3 / 2, thus promoting the sprouting of new lymphatic vessels (Oliver et al, 2020).

[0009] Recently it has been discovered, that the natural product AD0157 displays antiangiogenic effects, and potent inhibition of endothelial and tumor cell lines (García-Caballero et al, 2014 and WO 2015 / 004149), as well as lymphangiogenesis by targeting the VEGF-C / VEGFR-3-signaling axis (García-Caballero et al, 2017).

[0010] Therapeutic antiangiogenic agents, including therapeutic agents targeting lymphangiogenesis emerges as a promising approach to prevent cancer progression and metastasis. Thus, there is a need for novel, effective, therapeutic compounds targeting lymphangiogenesis and lymphatic metastasis, for use in the treatment of cancer.

[0011] Summary

[0012] This invention concerns a series of tricyclic spirocyclopropane compounds which are cytotoxic towards cancer cells and which targets key lymphangiogenic signaling pathways in lymphatic endothelial cells. The series of compounds represent a new class of potential drugs, which can be used for treatment of cancer and / or prevention of cancer progression. P7413PC00

[0013] In one major aspect, the present invention concerns a compound of Formula (1):

[0014] O R2O

[0015] R1-N

[0016] R5

[0017]

[0018] , Formula (1)

[0019] wherein:

[0020] R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, phenyl, benzyl, or 5- or 6-membered heteroaryl is optionally substituted; R2is H, C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, phenyl, benzyl or an alkynyl group A, wherein said C1-10 alkyl, phenyl or benzyl is optionally substituted;

[0021] R3is C1-4 alkyl, C3-6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10aryl, or Cs-9 heteroaryl is optionally substituted;

[0022] R4is H, halogen or C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted;

[0023] R5is H, C1-4 alkyl or C2-4 alkenyl;

[0024] A is an alkynyl group of Formula (A):

[0025] '2 CH2

[0026]

[0027] , Formula (A)

[0028] wherein:

[0029] x is 0, 1, 2, 3, 4 or 5;

[0030] y is 0 or 1; and

[0031] z is 0, 1, 2, 3, 4 or 5;

[0032] the dashed bond represents either a double bond or a single bond;

[0033] or a tautomer or a pharmaceutically acceptable salt thereof.

[0034] In another aspect, the present invention concerns a composition comprising a compound as defined herein.

[0035] In a third aspect, the invention concerns a compound as herein described, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use as a medicament.

[0036] In a fourth aspect, the invention concerns a compound as herein described, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in the prevention of cancer progression, and / or the treatment of cancer. P7413PC00

[0037] In a fifth aspect, the invention concerns a compound as herein described, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in inhibition of lymphangiogenesis and / or lymphatic metastasis.

[0038] In a sixth aspect, the invention concerns a compound as herein described, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treatment or prevention of an NF- kB-related disease or disorder.

[0039] Description of Figures

[0040] Figure 1. Cell viability in U2OS cells 48 hours post treatment with TPP652a and TPP652b. IC50(TTP652a): 3.2 ± 0.8 μM and IC50(TTP652b) = 2.2 ± 0.2 μM. Representative graph with mean IC50-value from three biological replicate experiments.

[0041] Figure 2. Cell viability in 786-O cells 48 hours post treatment with TPP652a and TPP652b. IC50(TTP652a): 13 ± 1 μM and IC50(TTP652b) = 5.6 ± 2.6 μM. Representative graph with mean IC50-value from three biological replicate experiments.

[0042] Figure 3. Cell viability in U2OS cells 48 hours post treatment with GW2366a and GW2366b.

[0043] IC50(GW2366a): 1.06 μM and IC50(GW2366b) = 1.45 μM.

[0044] Figure 4. Cell viability in U2OS cells 48 hours post treatment with GW2377a and GW2377b.

[0045] IC50(GW2377a): 0.862 μM and IC50(GW2377b) = 1.36 μM.

[0046] Figure 5. Cell viability in U2OS cells 48 hours post treatment with GW2387a and GW2387b.

[0047] IC50(GW2387a): 1.51 μM and IC50(GW2387b) = 1.99 μM.

[0048] Figure 6. Cell viability in U2OS cells 48 hours post treatment with GW2361, GW2365a, and GW2374. IC50(GW2361): 5.11 μM, IC50(GW2365a): 5.37 μM, and IC50(GW2374) = 2.17 μM.

[0049] Figure 7. Cell viability in U2OS cells 48 hours post treatment with TPP806a and TPP806b. IC50(TTP806a): 1.67 μM and IC50(TTP806b) = 1.76 μM.

[0050] Figure 8. Cell viability in U2OS cells 48 hours post treatment with TPP814a and TPP814b. IC50(TTP814a): 1.16 μM and IC50(TTP814b) = 1.15 μM.

[0051] Figure 9. Cell viability in U2OS cells 48 hours post treatment with TPP821a and TPP821b. IC50(TTP821a): 1.45 μM and IC50(TTP821b) = 1.09 μM.

[0052] Figure 10. Cell viability in U2OS cells 48 hours post treatment with GW2486a and GW2486b.

[0053] IC50(GW2486a): 0.86 μM and IC50(GW2486b) = 2.18 μM.

[0054] Figure 11. Graphs from two replicate experiment in which both U2OS and 786-0 cells were used as well as one experiment conducted only in U2OS cells: Cell viability in U2OS and 786-0 cells 48 hours post treatment with TPP757a. A) IC50(U2OS): 1.33 μM and IC50(786-O) = 4.24 μM. B) IC50(U2OS): 2.36 μM and IC50(786-O) = 6.22 μM. C) IC50(U2OS) = 2.09 μM). P7413PC00

[0055] Figure 12. Cell viability in human dermal lymphatic endothelial cells (HDLEC) 48 hours post treatment with GW2377a. IC50(GW2377a) = 1.76 ± 0.11 μM. Representative graph with mean IC50-value from three biological replicate experiments.

[0056] Figure 13. Inhibition of VEGF-C induced Akt-phosphorylation in human dermal lymphatic endothelial cells (HDLEC). A) Representative Western blots against pAkt, Akt, and p-actin. B) Quantification of pAkt signal, normalised to non-VEGF-C-induced DMSO control samples, from two biological replicate experiments. Data is presented as mean + standard deviation. C) Quantification of Akt signal, normalised to non-VEGF-C-induced DMSO control samples, from two biological replicate experiments. Data is presented as mean + standard deviation. CHM-X (AD0157) is a natural product included as a positive control.

[0057] Detailed description

[0058] Definitions

[0059] The terms ‘C alkyl’, ‘C1-6 alkyl’ and ‘C1-10 alkyl’ refers to a monovalent branched or unbranched alkyl group having from one to four, one to six or one to ten carbon atoms, respectively, including but not limited to methyl, hexyl or decanyl.

[0060] The term ‘C3-6 cycloalkyl’ refers to a cyclic hydrocarbon group having from three to six carbon atoms. The term ‘cycloalkyl’ refers to a cyclic form of an alkyl group, created by removing a hydrogen atom from two non-adjacent carbon atoms in the alkyl chain and joining those carbon atoms to form a ring, including but not limited to cyclopropyl, cyclopentyl, or cyclohexyl.

[0061] The term ‘C1-4 haloalkyl’ refers to a monovalent branched or unbranched alkyl group having from one to four carbon atoms in which one or more hydrogen atoms have been replaced by a halogen atom, such as F, Cl, Br, and / or I, including but not limited to trifluoromethyl.

[0062] The term ‘C2-4 alkenyl’ refers to a monovalent branched or unbranched alkyl group from one to four carbon atoms that contains one or more carbon-carbon double bond, including but not limited to vinyl or propenyl.

[0063] The term ‘C2-6 alkynyl’ refers to a monovalent branched or unbranched alkyl group from one to four carbon atoms that contains one carbon-carbon triple bond, including but not limited to propargyl or hexynyl.

[0064] The term ‘C1-3 alkoxy’ refers to a C1-3 alkyl group, linear or branched, bonded to an oxygen atom, including but not limited to methoxy. P7413PC00

[0065] The term ‘Ce-io aryl’ refers to a monovalent aromatic ring system, either monocyclic or bicyclic, comprising six to ten carbon atoms, including but not limited to phenyl, halophenyl, or naphthyl.

[0066] The term ‘5- or 6-membered heteroaryl’ refers to a monovalent aromatic ring system consisting of five or six atoms, wherein one or more of the atoms are heteroatoms, such as nitrogen, oxygen, or sulfur, and the remaining atoms are carbon, including but not limited to pyridyl or oxazolyl.

[0067] The term ‘C3-9 heteroaryl’ refers to a monovalent aromatic ring system, either monocyclic or bicyclic, comprising three to nine carbon atoms, and one or more heteroatoms such as nitrogen, oxygen, or sulfur, including but not limited to furanyl, benzofuranyl, pyridyl, oxazolyl, indazolyl, benzothiazolyl, or diazanaphthalenyl.

[0068] The term ‘treatment’ refers to the combating of a disease or disorder. ‘Treatment’ or ‘treating’, as used herein, includes any desirable effect on the symptoms or pathology of a disease or condition as described herein, and may include even minimal changes or improvements in one or more measurable markers of the disease or condition being treated. ‘Treatment’ or ‘treating’ does not necessarily indicate complete eradication or cure of the disease or condition, or associated symptoms thereof. In some embodiments, the term ‘treatment’ encompasses amelioration and prevention, such as prevention of the progression of cancer.

[0069] The term ‘prevent’ or ‘preventing’ refers to precluding, alleviating, obviating, forestalling, stopping, or hindering something from happening, especially by advance action.

[0070] Compounds

[0071] It is within the scope of the present invention to provide compounds, characterized by a tricyclic spirocyclopropane motif. Moreover it is within the scope of the present invention to provide compounds use in treating diseases, such as cancer.

[0072] In a main aspect, the present invention is a compound of Formula (1):

[0073]

[0074] wherein:

[0075] R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, phenyl, benzyl, or 5- or 6-membered heteroaryl is optionally substituted; P7413PC00

[0076] R2is H, C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, phenyl, benzyl or an alkynyl group A, wherein said C1-10 alkyl, phenyl or benzyl is optionally substituted;

[0077] R3is C1-4 alkyl, C3-6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10aryl, or Cs-9 heteroaryl is optionally substituted;

[0078] R4is H, halogen or C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted;

[0079] R5is H, C1-4 alkyl or C2- alkenyl;

[0080] A is an alkynyl group of Formula (A):

[0081] CH2CH2

[0082]

[0083] , Formula (A)

[0084] wherein:

[0085] x is 0, 1, 2, 3, 4 or 5;

[0086] y is 0 or 1; and

[0087] z is 0, 1, 2, 3, 4 or 5;

[0088] the dashed bond represents either a double bond or a single bond;

[0089] or a tautomer or a pharmaceutically acceptable salt thereof.

[0090] In one embodiment, R1is H, methyl, phenyl, benzyl, 4-methoxybenzyl or pyridyl.

[0091] In one embodiment, R2is H, methyl, ethyl, n-hexyl, 6,6,6-trifluorohexan-1-yl, n-decyl, -(CH2CH2O)2CH3, or 4-(1-butyl)phen-1-yl, 4-phenylbutan-1-yl, or the alkynyl group A of formula (A) according to item 1.

[0092] In one embodiment, R3is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, halophenyl, furanyl, benzofuranyl, naphthyl, pyridyl, diazanaphthalenyl, indazolyl, benzothiazolyl, oxazolyl, or oxetanyl.

[0093] In one embodiment, R4is H, methyl, F, Cl, Br, or I.

[0094] In one embodiment, R5is H, methyl, C2- alk-1 -en-1 -yl or C1-4 alk-1-yl.

[0095] In one embodiment, A is ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, or octynyl.

[0096] In one embodiment, the compound is of Formula (2): P7413PC00

[0097]

[0098] , Formula (2).

[0099] In one embodiment, the compound is of Formula (2):

[0100]

[0101] wherein:

[0102] R1is H or benzyl, optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;

[0103] R2is C1-10 alkyl, C2-10 alkynyl or an alkynyl group A;

[0104] R3is C1-4 alkyl, C5-6 cycloalkyl, C5-6 heterocycloalkyl, Ce aryl or a 5-10 membered heteroaryl, each optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;

[0105] R4is H or a halogen;

[0106] R5is C1- alkyl or C2-4 alkenyl; and

[0107] A is an alkynyl group according to formula (A) of item 1, wherein x = 0, 1, 2, 3, or 4, y = 0 or 1, and z = 0, 1, 2, or 3.

[0108] In one embodiment, the compound is of formula (1) or (2),

[0109] wherein:

[0110] R1is H or 4-methoxybenzyl;

[0111] R2is C1-10 alkyl, C2-10 alkynyl or an alkynyl group A;

[0112] R3is methyl, cyclopentyl, cyclohexyl, phenyl, furanyl, or benzofuranyl optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;

[0113] R4is Cl, Br, or I;

[0114] R5is C1- alkyl or C2-4 alkenyl; and

[0115] A is an alkynyl group according to formula (A) of item 1, wherein x = 0, 1, 2, 3 or 4, y = 0 or 1, and z = 0.

[0116] In one embodiment, R4is Cl, Br, or I, and R5is C3 alkyl or C3 alkenyl. In one embodiment, R4is Cl, Br, or I, and R5is prop-1 -en-1-yl or prop-1-yl. In one embodiment, R1is H, R4is Cl, Br, or I, P7413PC00

[0117] and R5is prop-1 -en-1-yl or prop-1-yl. In one embodiment, R1is H, R4is Cl, Br, or I, and R5is prop-1 -en-1-yl or prop-1 -yl.

[0118] In one embodiment, R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl or alkynyl group A, wherein said C1-4 alkyl, phenyl, benzyl, 5- or 6-membered heteroaryl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is H. In one embodiment, R1is C1-6 alkyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is C1-6 alkyl. In one embodiment, R1is methyl. In one embodiment, R1is phenyl optionally substituted with C1- alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, or C2-6 alkynyl. In one embodiment, R1is phenyl. In one embodiment, R1is benzyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is benzyl. In one embodiment, R1is methoxybenzyl. In one embodiment, R1is 4-methoxybenzyl. In one embodiment, R1is a 5-membered heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is a 6-membered heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is pyridyl. In one embodiment, R1is pyridyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is 2-pyridyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is 3-pyridyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R1is 4-pyridyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0119] In one embodiment, R1is 2-pyridyl. In one embodiment, R1is 3-pyridyl. In one embodiment, R1is 4-pyridyl. In one embodiment, R1is an alkynyl group of formula (A). In one embodiment, R1is an alkynyl group of formula (A), wherein x = 1, y = 0, and z = 0. In one embodiment, R2is H, Ci-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, phenyl, benzyl or alkynyl group A, wherein said C1-10 alkyl, phenyl or benzyl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0120] In one embodiment, R2is H. In one embodiment, R2is C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R2is C1-10 alkyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R2is C1-10 alkyl wherein one or more methylene unit(s) is replaced with -O-, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R2is C1-10 alkyl wherein one or more methylene unit(s) is replaced with -O-. In one embodiment, R2is C1-10 alkyl.

[0121] In one embodiment, R2is methyl. In one embodiment, R2is ethyl. In one embodiment, R2is n-hexyl. In one embodiment, R2is n-hexyl substituted with halogen. In one embodiment, R2is n- P7413PC00

[0122] hexyl substituted with one or more fluorine. In one embodiment, R2is 6,6,6-trifluorohexan-1-yl. In one embodiment, R2is n-decyl. In one embodiment, R2is 4-phenylbutan-1-yl. In one embodiment, R2is -(CH2CH2O)nCH3 wherein n is 1, 2, or 3. In one embodiment, R2is -(CH2CH2O)nCH3wherein n is 2. In one embodiment, R2is phenyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl or C2-6 alkynyl. In one embodiment, R2is phenyl. In one embodiment, R2is 4-(1-butyl)phen-1-yl. In one embodiment, R2is benzyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl or C2-6 alkynyl. In one embodiment, R2is benzyl. In one embodiment, R2is an alkynyl group of formula (A). In one embodiment, R2is benzyl substituted with a group of formula (A). In one embodiment, R2is an alkynyl group of formula (A), wherein x = 4, y = 0, and z = 0. In one embodiment, R2is an alkynyl group of Formula (A), wherein x + z = 1, 2, 3, 4, 5, or 6, and y = 0. In one embodiment, R2is an alkynyl group of Formula (A), wherein x + z = 4 and y = 0. In one embodiment, R2is n-hex-1-yn-6-yl.

[0123] In one embodiment, R3is C1-4 alkyl, C3-6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, or C3-9 heteroaryl is optionally substituted with C1- alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is C1-4 alkyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R3is C1-4 alkyl. In one embodiment, R3is methyl. In one embodiment, R3is C3-6 cycloalkyl wherein one methylene unit(s) is optionally replaced with -O-, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R3is C3-6 cycloalkyl wherein one methylene unit is optionally replaced with -O-. In one embodiment, R3is C3-6 cycloalkyl wherein one methylene unit is replaced with -O-. In one embodiment, R3is oxetanyl. In one embodiment, R3is C3-6 cycloalkyl. In one embodiment, C3-6 cycloalkyl is cyclopentyl or cyclohexyl. In one embodiment, R3is cyclopentyl. In one embodiment, R3is cyclohexyl. In one embodiment, R3is cyclopentyl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is cyclohexyl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is cyclopentyl, substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is cyclopentyl, substituted with C1-4 alkyl. In one embodiment, R3is cyclopentyl, substituted with C1-3 alkoxy. In one embodiment, R3is cyclopentyl, substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is cyclopentyl, substituted with haloalkyl. In one embodiment, R3is cyclopentyl, substituted with phenyl. In one embodiment, R3is cyclopentyl, substituted C2-6 alkynyl. In one embodiment, R3is cyclopentyl. In one embodiment, R3is cyclohexyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is cyclohexyl, substituted with C1-4 alkyl. In one embodiment, R3is cyclohexyl, substituted with C1-3 alkoxy. In one embodiment, R3is cyclohexyl, substituted with halogen, P7413PC00

[0124] such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is cyclohexyl, substituted with C1-4 haloalkyl. In one embodiment, R3is cyclohexyl, substituted with phenyl. In one embodiment, R3is cyclohexyl, substituted with C2-6 alkynyl. In one embodiment, R3is cyclohexyl. In one embodiment, R3is cyclopropyl. In one embodiment, R3is C6-10 aryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R3is C6-10 aryl. In one embodiment, R3is Ca aryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is Ce aryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is Ce aryl substituted with C1-4 alkyl. In one embodiment, R3is Ce aryl substituted with C1-3 alkoxy. In one embodiment, R3is Ce aryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is Ce aryl substituted with C1- haloalkyl. In one embodiment, R3is Ce aryl substituted with phenyl. In one embodiment, R3is Ce aryl substituted with C2-6 alkynyl. In one embodiment, R3is phenyl substituted with one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is 4-halophenyl. In one embodiment, R3is 4-chlorophenyl. In one embodiment, R3is phenyl. In one embodiment, R3is naphthyl. In one embodiment, R3is C3-9 heteroaryl optionally substituted with C1- alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl. In one embodiment, R3is C3-9 heteroaryl. In one embodiment, R3is C heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is C heteroaryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is C heteroaryl substituted with C1-4 alkyl. In one embodiment, R3is C heteroaryl substituted with C1-3 alkoxy. In one embodiment, R3is C heteroaryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is C heteroaryl substituted with C1-4 haloalkyl. In one embodiment, R3is C heteroaryl substituted with phenyl. In one embodiment, R3is C heteroaryl substituted with C2-6 alkynyl. In one embodiment, R3is C heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is C heteroaryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is C heteroaryl substituted with C1-4 alkyl. In one embodiment, R3is C heteroaryl substituted with C1- 3 alkoxy. In one embodiment, R3is C heteroaryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is C heteroaryl substituted with C1- 4 haloalkyl. In one embodiment, R3is C heteroaryl substituted with phenyl. In one embodiment, R3is C heteroaryl substituted with C2-6 alkynyl. In one embodiment, C heteroaryl is furanyl. In one embodiment, R3is Ca heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is Ca heteroaryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is Ca heteroaryl substituted with C1-4 alkyl. In one embodiment, R3is Ca heteroaryl substituted with C1-3 alkoxy. In one embodiment, R3is Ca heteroaryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is Ca P7413PC00

[0125] heteroaryl substituted with C1-4 haloalkyl. In one embodiment, R3is Ca heteroaryl substituted with phenyl. In one embodiment, R3is Ca heteroaryl substituted with C2-6 alkynyl.

[0126] In one embodiment, Ca heteroaryl is benzofuranyl. In one embodiment, R3is pyridyl. In one embodiment, R3is 2-pyridyl. In one embodiment, R3is 3-pyridyl. In one embodiment, R3is 4-pyridyl. In one embodiment, R3is oxazolyl. In one embodiment, R3is diazanaphthalenyl. In one embodiment, R3is indazolyl. In one embodiment, R3is benzothiazolyl. In one embodiment, R3is furanyl. In one embodiment, R3is benzofuranyl. In one embodiment, R3is furanyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is furanyl, substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is furanyl, substituted with C1-4 alkyl. In one embodiment, R3is furanyl, substituted with C1-3 alkoxy. In one embodiment, R3is furanyl, substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is furanyl, substituted with C1-4 haloalkyl. In one embodiment, R3is furanyl, substituted with phenyl. In one embodiment, R3is furanyl, substituted with C2-6 alkynyl. In one embodiment, R3is furanyl. In one embodiment, R3is furan-2-yl. In one embodiment, R3is benzofuranyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is benzofuranyl, substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. In one embodiment, R3is benzofuranyl, substituted with C1-4 alkyl. In one embodiment, R3is benzofuranyl, substituted with C1-3 alkoxy. In one embodiment, R3is benzofuranyl, substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. In one embodiment, R3is benzofuranyl, substituted with C1-4 haloalkyl. In one embodiment, R3is benzofuranyl, substituted with phenyl. In one embodiment, R3is benzofuranyl, substituted with C2-6 alkynyl. In one embodiment, R3is benzofuranyl.

[0127] In one embodiment, R3is benzofuran-2-yl. In one embodiment, R3is an alkynyl group of formula (A).

[0128] In one embodiment, R4is H, halogen or C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted. In one embodiment, R4is H, halogen or C1-4 alkyl. In one embodiment, R4is H. In one embodiment, R4is halogen. In one embodiment, R4is F. In one embodiment, R4is Cl. In one embodiment, R4is Br. In one embodiment, R4is I. In one embodiment, R4is C1-4 alkyl optionally substituted. In one embodiment, R4is methyl.

[0129] In one embodiment, R5is H, C1-4 alkyl or C2-4 alkenyl. In one embodiment, R5is H. In one embodiment, R5is C1-4 alkyl. In one embodiment, R5is C3 alkyl. In one embodiment, R5is methyl. In one embodiment, R5is C2-4 alkenyl. In one embodiment, R5is C2-4 alk-1 -en-1 -yl. In one embodiment, R5is vinyl. In one embodiment, R5is C3 alkenyl. In one embodiment, R5is prop-1 -en-1 -yl. In one embodiment, R5is c / s-prop-1-en-1-yl. In one embodiment, R5is trans-prop-1-en-1-yl. In one embodiment, R5is prop-1 -yl. P7413PC00

[0130] In one embodiment, A is an alkynyl group of formula (A):

[0131] ‘2 CH2

[0132]

[0133] , Formula (A)

[0134] wherein:

[0135] x is 0, 1, 2, 3, 4 or 5;

[0136] y is 0 or 1; and

[0137] z is 0, 1, 2, 3, 4 or 5.

[0138] In one embodiment, A is the alkynyl group of formula (A), wherein x = 0, 1, 2, 3, 4 or 5. In one embodiment, A is the alkynyl group of formula (A), wherein y = 0 or 1. In one embodiment, A is the alkynyl group of formula (A), wherein z = 0, 1, 2, 3, 4 or 5. In one embodiment, A is a group of Formula (A), wherein x + z = 1, 2, 3, 4, 5, or 6; and y = 0. In one embodiment, A is a group of Formula (A), wherein x + z = 4; and y = 0. In one embodiment, A is a group of formula (A), wherein x = 4, y = 0, and z = 0. In one embodiment, A is a group of formula (A), wherein x = 1, y = 0, and z = 0. In one embodiment, A is hexynyl. In one embodiment, A is propargyl.

[0139] In one embodiment, the compound is of Formula (1 a) or (1 b):

[0140] O p2 O

[0141] N

[0142]

[0143] , Formula (1a),, Formula (1b).

[0144] In one embodiment, the compound is of Formula (1a):

[0145] R2

[0146] N

[0147] , Formula (1a).

[0148] In one embodiment, the compound is of Formula (1b):

[0149] R2

[0150]

[0151] , Formula (1b). P7413PC00

[0152] In one embodiment, the compound is of Formula (1 a-1), (1a-2), (1a-3), (1a-4), (1 b-1), (1b-2), (1b-3), or (1b-4):

[0153]

[0154] In one embodiment, the compound is of Formula (1 a-1), (1a-4), (1 b-1), or (1b-4):

[0155]

[0156] , Formula (1 b-1),, Formula (1b-4). P7413PC00

[0157] In one embodiment, the compound is of Formula (1 a-1):

[0158] Formula (1 a-1 ).

[0159] In one embodiment, the compound is of Formula (1a-4):

[0160]

[0161] Formula (1a-4),

[0162] In one embodiment, the compound is of Formula (1 b-1):

[0163] O R2

[0164] R1-N

[0165] R5

[0166] O O

[0167] R3

[0168] , Formula (1 b-1).

[0169] In one embodiment, the compound is of Formula (1 b-4):

[0170]

[0171] , Formula (1b-4).

[0172] In one embodiment, the dashed bond of Formula (1) is a double bond.

[0173] In one embodiment, the compound is of Formula (2a) or (2b):

[0174]

[0175] , Formula (2a),, Formula (2b). P7413PC00

[0176] In one embodiment, the compound is of Formula (2a):

[0177] , Formula (2a).

[0178] In one embodiment, the compound is of Formula (2b):

[0179]

[0180] , Formula (2b).

[0181] In one embodiment, the compound is of Formula (2a-1), (2a-2), (2a-3), (2a-4), (2b-1), (2b-2), (2b-3), or (2b-4):

[0182] , Formula (2a-2),

[0183] , Formula (2a-4),

[0184]

[0185] , Formula (2b-1),, Formula (2b-2), P7413PC00

[0186]

[0187] In one embodiment, the compound is of Formula (2a-1), (2a-4), (2b-1), or (2b-4):

[0188]

[0189] , Formula (2b-4). In one embodiment, the compound is of Formula (2a-1):

[0190] , Formula (2a-1).

[0191] In one embodiment, the compound is of Formula (2a-4):

[0192]

[0193] , Formula (2a-4).

[0194] In one embodiment, the compound is of Formula (2b-1): P7413PC00

[0195] , Formula (2b-1).

[0196] In one embodiment, the compound is of Formula (2b-4):

[0197]

[0198] , Formula (2b-4).

[0199] In one embodiment, the dashed bond of Formula (1) is a single bond.

[0200] In one embodiment, the compound is of Formula (3):

[0201] , Formula (3).

[0202] In one embodiment, the compound is of Formula (3a) or (3b):

[0203]

[0204] , Formula (3

[0205]

[0206] a),, Formula (3b). In one embodiment, the compound is of Formula (3a):

[0207]

[0208] , Formula (3a). P7413PC00

[0209] In one embodiment, the compound is of Formula (3b):

[0210]

[0211] , Formula (3b).

[0212] In one embodiment, the compound is of Formula (3a-1), (3a-2), (3a-3), (3a-4), (3b-1), (3b-2), (3b-3), or (3b-4):

[0213]

[0214] In one embodiment, the compound is of Formula (3a-1), (3a-4), (3b-1), or (3b-4):

[0215]

[0216] , Formula (3a-1),, Formula (3a-4), P7413PC00

[0217]

[0218] Formula (3b-4). In one embodiment, the compound is of Formula (3a-1):

[0219] , Formula (3a-1).

[0220] In one embodiment, the compound is of Formula (3a-4):

[0221]

[0222] , Formula (3a-4).

[0223] In one embodiment, the compound is of Formula (3b-1):

[0224] , Formula (3b-1).

[0225] In one embodiment, the compound is of Formula (3b-4):

[0226]

[0227] , Formula (3b-4). P7413PC00

[0228] In one embodiment, the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is cyclopentyl, R4is Cl, and R5is prop-1 -en-1yl. In one embodiment, the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is cyclopentyl, R4is Cl, and R5is prop-1 -en-1yl. In one embodiment, the compound is of Formula (3), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is methyl, R4is H, and R5is H. In one embodiment, the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is phenyl, R4is Cl, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is phenyl, R4is Cl, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is 4-chlorophenyl, R4is Cl, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2-yl, R4is Cl, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is furan-2-yl, R4is Cl, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is cyclohexyl, R4is Cl, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is benzofuran-2-yl, R4is Cl, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2-yl, R4is Br, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2-yl, R4is Cl, and R5is prop-1 -yl. In one embodiment, the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2-yl, R4is I, and R5is prop-1 -en-1-yl. In one embodiment, the compound is of Formula (2), R1is H, R2is n-hex-1-yn-6-yl, R3is cyclopentyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0229] In one embodiment, the compound is

[0230]

[0231] P7413PC00

[0232]

[0233] In one embodiment, the compound is

[0234]

[0235] P7413PC00

[0236]

[0237] stereoisomer thereof, or a combination of stereoisomers thereof.

[0238] In one embodiment, the compound is any one of

[0239]

[0240] combination thereof.

[0241] In one embodiment, the compound is a mixture of

[0242]

[0243] In one embodiment, the compound is a mixture of

[0244]

[0245] and P7413PC00

[0246] In one embodiment, the compound is any one of

[0247]

[0248] or a combination thereof.

[0249] In one embodiment, the compound is a mixture of

[0250]

[0251] In one embodiment, the compound is a mixture of

[0252]

[0253] In one embodiment, the compound is any one of P7413PC00

[0254]

[0255] combination thereof.

[0256] In one embodiment, the compound is a mixture of

[0257]

[0258] In one embodiment, the compound is a mixture of

[0259]

[0260] In one embodiment, the compound is any one of P7413PC00

[0261]

[0262] combination thereof.

[0263] In one embodiment, the compound is a mixture of

[0264]

[0265] In one embodiment, the compound is a mixture of

[0266]

[0267] In one embodiment, the compound is any one of P7413PC00

[0268]

[0269] In one embodiment, the compound is a mixture of

[0270]

[0271] In one embodiment, the compound is a mixture of

[0272]

[0273] In one embodiment, the compound is any one of P7413PC00

[0274]

[0275] combination thereof.

[0276] In one embodiment, the compound is a mixture of

[0277]

[0278] In one embodiment, the compound is a mixture of

[0279]

[0280] In one embodiment, the compound is any one of P7413PC00

[0281]

[0282] combination thereof.

[0283] In one embodiment, the compound is a mixture of

[0284]

[0285] In one embodiment, the compound is a mixture of

[0286]

[0287] In one embodiment, the compound is any one of P7413PC00

[0288]

[0289] In one embodiment, the compound is a mixture of

[0290]

[0291] In one embodiment, the compound is a mixture of

[0292]

[0293] In one embodiment, the compound is any one of P7413PC00

[0294]

[0295] In one embodiment, the compound is a mixture of

[0296]

[0297] In one embodiment, the compound is a mixture of P7413PC00

[0298]

[0299] In one embodiment, the compound is a mixture of

[0300]

[0301] In one embodiment, the compound is any one of

[0302]

[0303] or a combination thereof. In one embodiment, the compound is a mixture of

[0304]

[0305] In one embodiment, the compound is a mixture of

[0306]

[0307] In one embodiment, the compound is a mixture of

[0308]

[0309] 10 In one embodiment, the compound is any one of P7413PC00

[0310]

[0311] combination thereof.

[0312] In one embodiment, the compound is a mixture of

[0313]

[0314] In one embodiment, the compound is a mixture of

[0315]

[0316] In one embodiment, the compound is any one of P7413PC00

[0317]

[0318] combination thereof.

[0319] In one embodiment, the compound is a mixture of

[0320]

[0321] In one embodiment, the compound is a mixture of

[0322]

[0323] In one embodiment, the mixture as described herein is a racemic mixture.

[0324] Tautomers

[0325] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include: ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine- P7413PC00

[0326] imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0327] Stereoisomers

[0328] The compounds of the present invention may contain, for example, one or more asymmetric carbon atoms, or one or more alkenes, and therefore may exist as stereoisomers, enantiomers, cis-trans isomers or diastereomers. Accordingly, the scope of the instant invention is to be understood to encompass all possible isomers of the illustrated compounds, including the stereoisomerically pure form and mixtures of any chemical structures disclosed herein, unless the stereochemistry is specifically identified.

[0329] If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure ora portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated.

[0330] If an alkene is illustrated as a cis-isomer, it should be understood, that small quantities of the trans-isomer may be present.

[0331] Pharmaceutically acceptable salts

[0332] The chemical compound of the present invention may be provided in any form suitable for the intended administration, including pharmaceutically (i.e. physiologically) acceptable salts. The pharmaceutically acceptable salts of the compound may be formed by reacting the compound with any appropriate acid or base to give an addition salt. Such appropriate acids and bases will be known to the person of skill in the art and may be used to obtain such addition salts by following procedures well known and described in the art.

[0333] All compounds described herein, including pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates), as well as with residual impurities typically resulting from their synthesis, purification, or storage, without departing from the scope of the invention.

[0334] Labelled compounds:

[0335] The chemical compound of the present invention may be used in its labelled or un-labelled form. In the context of this invention the labelled compound has one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The labelling will allow easy quantitative detection of said compound. P7413PC00

[0336] The labelled compounds of the invention may be useful as diagnostic tools, radio tracers, or monitoring agents in various diagnostic methods, and for in vivo receptor imaging. The labelled isomer of the invention preferably contains at least one radionuclide as a label. Positron emitting radionuclides are all candidates for usage. In the context of this invention the radionuclide is preferably selected from2H (deuterium),3H (tritium),13C,14C,131I,125I,123I, and18F.

[0337] The physical method for detecting the labelled isomer of the present invention may be selected from Position Emission Tomography (PET), Single Photon Imaging Computed Tomography (SPECT), Magnetic Resonance Spectroscopy (MRS), Magnetic Resonance Imaging (MRI), and Computed Axial X-ray Tomography (CAT), or combinations thereof.

[0338] Pharmaceutical composition

[0339] The present invention also relates to a pharmaceutical composition comprising, as an active ingredient, a compound of Formula (1), as defined above.

[0340] In a main aspect, the present invention is a pharmaceutical composition comprising a compound of Formula (1) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0341] In one embodiment, the present invention is a pharmaceutical composition comprising one or more compounds of formula (1) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0342] In one embodiment, the pharmaceutical composition may contain the compound of Formula (1) in any stereochemical form, including its enantiomers, diastereoisomers, or mixtures thereof in any proportion, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0343] In one embodiment, the present invention is a composition comprising one or more compounds of Formula (1) or a salt thereof.

[0344] Medical use

[0345] In one embodiment, the present invention is a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament.

[0346] In one embodiment, the present invention is a method of treating a disease, comprising administering a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof. P7413PC00

[0347] Cancer

[0348] It is known, that AD0157 displays antiangiogenic effects and potent inhibition of endothelial and tumor cell lines, including bovine aortic endothelial cells (BAECs), HT-1080 fibrosarcoma cells, HT-29 colon adenocarcinoma cells, MDA-MB-231 breast carcinoma cells and U2OS osteosarcoma cells (Garcia-Caballero et al, 2014 and WO 2015 / 004149).

[0349] The compounds of the present invention are cytotoxic towards cancer cells, as demonstrated in Example 2 (U-2OS bone cancer (Osteosarcoma) cells and 786-0 kidney cancer (renal, adenocarcinoma) cells).

[0350] In one embodiment, the compound of Formula (1), is an anticancer agent.

[0351] In one embodiment, the present invention is a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of cancer.

[0352] In one embodiment, the present invention is a method of treating cancer, comprising administering a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0353] In one embodiment, the present invention is the use of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer.

[0354] Lymphangiogenesis, the formation of new lymphatic vessels, plays a pivotal role in cancer progression by facilitating both metastatic dissemination [Brown 2018, Perreira 2018] and modulation of the immune microenvironment (Reticker-Flynn et al, 2022). Tumor-associated lymphatic vessels provide conduits for cancer cells to access regional lymph nodes, which often serve as the first site of metastasis and a prognostic indicator of disease progression. Beyond their structural role, lymphatic endothelial cells (LECs) actively shape the tumor microenvironment by regulating immune cell trafficking and antigen presentation, thereby influencing anti-tumor immunity (Deng et al, 2023; Sun et al, 2025). Central to this process is the vascular endothelial growth factor-C (VEGF-C) / VEGF receptor-3 / 2 (VEGFR-3 / 2) signaling axis (Joukov et al, 1996), the primary molecular pathway governing lymphangiogenesis (Kuonqui et al, 2025). Activation of VEGF-C / VEGFR-3 / 2 not only stimulates lymphatic vessel proliferation and remodeling but also enhances metastatic potential by creating permissive routes for tumor cell dissemination (Oliver et al, 2020; Sainz-Jaspeado et al, 2018). Moreover, VEGFR-3 signaling in lymphatic endothelial cells and tumor-associated macrophages fosters an P7413PC00

[0355] immunosuppressive milieu, further enabling tumor growth and immune escape (Tacconi et al, 2019). Inhibition of VEGF-C stimulated VEGFR-3 / 2 signaling can be evaluated by measuring the inhibition of phosphorylation of the kinase Akt (pAkt).

[0356] Compounds of the present invention have been demonstrated to inhibit key lymphangiogenic signalling pathways (including pAkt) in lymphatic endothelial cells (Example 4).

[0357] Thus, in one embodiment, the compound of Formula (1), is a lymphangiogenesis inhibitor.

[0358] In one embodiment, the present invention is a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in inhibiting lymphangiogenesis.

[0359] In one embodiment, the present invention is a method of inhibiting lymphangiogenesis, comprising administering a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0360] In one embodiment, the present invention is the use of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition thereof, for the manufacture of a medicament for inhibiting lymphangiogenesis.

[0361] In one embodiment, the present invention is a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in inhibiting lymphatic metastasis.

[0362] In one embodiment, the present invention is a method of inhibiting lymphatic metastasis, comprising administering a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0363] In one embodiment, the present invention is the use of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition thereof, for the manufacture of a medicament for inhibiting lymphatic metastasis.

[0364] In one embodiment, the present invention is a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in prevention of lymphatic metastasis.

[0365] In one embodiment, the present invention is a method of preventing lymphatic metastasis, comprising administering a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof. P7413PC00

[0366] In one embodiment, the present invention is the use of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition thereof, for the manufacture of a medicament for prevention of lymphatic metastasis.

[0367] In one embodiment, the present invention is a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention of cancer progression.

[0368] In one embodiment, the present invention is a method of preventing cancer progression, comprising administering a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0369] In one embodiment, the present invention is the use of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition thereof, for the manufacture of a medicament for the prevention of cancer progression.

[0370] NF-KB-related disease or disorders

[0371] A number of inflammatory and immune diseases and disorders have been associated to the dysregulation, and in particular to the overactivation, of NF-KB, including rheumatoid arthritis, multiple sclerosis or MS, asthma, inflammatory bowel disease or IBD (WO 2020 / 109297).

[0372] The present inventors have demonstrated that the chemical structure of the NF-KB inhibitor of WO 2020 / 109297, “Compound 1” and the compound known as “AD0157” (Garcia-Caballero et al, 2014 and WO 2015 / 004149) and are identical (Example 3).

[0373] In one embodiment, the compound of Formula (1) is an NF- kB modulator.

[0374] In one embodiment, the present invention is a compound of Formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of an NF- kB-related disease or disorder.

[0375] In one embodiment, the present invention is a method of treating or preventing an NF- kB-related disease or disorder, comprising administering a compound of Formula (1), ora pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject in need thereof.

[0376] In one embodiment, the present invention is the use of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition thereof, for the P7413PC00

[0377] manufacture of a medicament for the treatment or prevention of an NF- kB-related disease or disorder.

[0378] In one embodiment the NF- kB-related disease or disorder is rheumatoid arthritis; multiple sclerosis; asthma; inflammatory bowel disease; colonic inflammation; chronic obstructive pulmonary disease; diabetes and obesity, in particular diabetes- or obesity-associated inflammation; transplantation rejection, in particular GVFID; liver injury and liver fibrosis; dermatitis; systemic lupus erythematosus; and / or psoriasis. P7413PC00

[0379] Items 1

[0380] 1. A compound of Formula (1):

[0381] R1-N

[0382]

[0383] , Formula (1)

[0384] wherein:

[0385] R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, phenyl, benzyl, or 5- or 6-membered heteroaryl is optionally substituted;

[0386] R2is H, C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, phenyl, benzyl or an alkynyl group A, wherein said C1-10 alkyl, phenyl or benzyl is optionally substituted;

[0387] R3is C1-4 alkyl, C3-6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10aryl, or Cs-9 heteroaryl is optionally substituted;

[0388] R4is H, halogen or C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted; R5is H, C1-4 alkyl or C2-4 alkenyl;

[0389] A is an alkynyl group of Formula (A):

[0390] CH2

[0391]

[0392] , Formula (A)

[0393] wherein:

[0394] x is 0, 1, 2, 3, 4 or 5;

[0395] y is 0 or 1; and

[0396] z is 0, 1, 2, 3, 4 or 5;

[0397] the dashed bond represents either a double bond or a single bond; or a tautomer or a pharmaceutically acceptable salt thereof.

[0398] 2. The compound according to any one of the preceding items, wherein R1is H, methyl, phenyl, benzyl, 4-methoxybenzyl or pyridyl.

[0399] 3. The compound according to any one of the preceding items, wherein R2is H, methyl, ethyl, n-hexyl, 6,6,6-trifluorohexan-1-yl, n-decyl, -(CH₂CH₂O)₂CH₃, or4-(1-butyl)phen-1- yl, 4-phenylbutan-1-yl, or the alkynyl group A of formula (A) according to item 1. P7413PC00

[0400] 4. The compound according to any one of the preceding items, wherein R3is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, halophenyl, furanyl, benzofuranyl, naphthyl, pyridyl, diazanaphthalenyl, indazolyl, benzothiazolyl, oxazolyl, or oxetanyl.

[0401] 5. The compound according to any one of the preceding items, wherein R4is H, methyl, F, Cl, Br, or I.

[0402] 6. The compound according to any one of the preceding items, wherein R5is H, methyl, C2-4 alk-1 -en-1 -yl or C1-4 alk-1-yl.

[0403] 7. The compound according to any one of the preceding items, wherein A is ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, or octynyl.

[0404] 8. The compound according to any one of the preceding items, wherein the compound is of Formula (2):

[0405]

[0406] 9. The compound according to any one of the preceding items, wherein the compound is of Formula (2):

[0407]

[0408] wherein:

[0409] R1is H or benzyl, optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;

[0410] R2is C1-10 alkyl, C2-10 alkynyl or an alkynyl group A;

[0411] R3is C1-4 alkyl, C5-6 cycloalkyl, C5-6 heterocycloalkyl, Ce aryl or a 5-10 membered heteroaryl, each optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;

[0412] R4is H or a halogen;

[0413] R5is C1- alkyl or C2-4 alkenyl; and P7413PC00

[0414] A is an alkynyl group according to formula (A) of item 1, wherein x = 0, 1, 2, 3, or 4, y = 0 or 1, and z = 0, 1, 2, or 3.

[0415] 10. The compound according to any one of the preceding items,

[0416] wherein:

[0417] R1is H or 4-methoxybenzyl;

[0418] R2is C1-10 alkyl, C2-10 alkynyl or an alkynyl group A;

[0419] R3is methyl, cyclopentyl, cyclohexyl, phenyl, furanyl, or benzofuranyl optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;

[0420] R4is Cl, Br, or I;

[0421] R5is C1- alkyl or C2-4 alkenyl; and

[0422] A is an alkynyl group according to formula (A) of item 1, wherein x = 0, 1, 2, 3 or 4, y = 0 or 1, and z = 0.

[0423] 11. The compound according to any one of the preceding items, wherein R4is Cl, Br, or I, and R5is C3 alkyl or C3 alkenyl.

[0424] 12. The compound according to any one of the preceding items, wherein R4is Cl, Br, or I, and R5is prop-1 -en-1-yl or prop-1 -yl.

[0425] 13. The compound according to any one of the preceding items, wherein R1is H, R4is Cl, Br, or I, and R5is prop-1 -en-1-yl or prop-1 -yl.

[0426] 14. The compound according to any one of the preceding items, wherein R1is H, R4is Cl, Br, or I, and R5is prop-1 -en-1-yl or prop-1 -yl.

[0427] 15. The compound according to any one of the preceding items, wherein R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl or alkynyl group A, wherein said C1-4 alkyl, phenyl, benzyl, 5- or 6-membered heteroaryl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0428] 16. The compound according to any one of the preceding items, wherein R1is H.

[0429] 17. The compound according to any one of the preceding items, wherein R1is C1-6 alkyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0430] 18. The compound according to any one of the preceding items, wherein R1is C1-6 alkyl.

[0431] 19. The compound according to any one of the preceding items, wherein R1is methyl. 20. The compound according to any one of the preceding items, wherein R1is phenyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, or C2-6 alkynyl. P7413PC00

[0432] 21. The compound according to any one of the preceding items, wherein R1is phenyl. 22. The compound according to any one of the preceding items, wherein R1is benzyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0433] 23. The compound according to any one of the preceding items, wherein R1is 4- methoxybenzyl.

[0434] 24. The compound according to any one of the preceding items, wherein R1is benzyl. 25. The compound according to any one of the preceding items, wherein R1is a 5- membered heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0435] 26. The compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0436] 27. The compound according to any one of the preceding items, wherein R1is pyridyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0437] 28. The compound according to any one of the preceding items, wherein R1is 2-pyridyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0438] 29. The compound according to any one of the preceding items, wherein R1is 3-pyridyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0439] 30. The compound according to any one of the preceding items, wherein R1is 4-pyridyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0440] 31. The compound according to any one of the preceding items, wherein R1is pyridyl. 32. The compound according to any one of the preceding items, wherein R1is 2-pyridyl. 33. The compound according to any one of the preceding items, wherein R1is 3-pyridyl. 34. The compound according to any one of the preceding items, wherein R1is 4-pyridyl. 35. The compound according to any one of the preceding items, wherein R1is an alkynyl group of Formula (A).

[0441] 36. The compound according to any one of the preceding items, wherein R1is an alkynyl group of Formula (A), wherein x = 1, y = 0, and z = 0.

[0442] 37. The compound according to any one of the preceding items, wherein R2is H, C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, phenyl, benzyl or alkynyl group A, wherein said C1-10 alkyl, phenyl or benzyl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0443] 38. The compound according to any one of the preceding items, wherein R2is H. P7413PC00

[0444] 39. The compound according to any one of the preceding items, wherein R2is C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0445] 40. The compound according to any one of the preceding items, wherein R2is C1-10 alkyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0446] 41. The compound according to any one of the preceding items, wherein R2is C1-10 alkyl wherein one or more methylene unit(s) is replaced with -O-, optionally substituted with C1- alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

[0447] 42. The compound according to any one of the preceding items, wherein R2is C1-10 alkyl wherein one or more methylene unit(s) is replaced with -O-.

[0448] 43. The compound according to any one of the preceding items, wherein R2is C1-10 alkyl.

[0449] 44. The compound according to any one of the preceding items, wherein R2is methyl. 45. The compound according to any one of the preceding items, wherein R2is ethyl. 46. The compound according to any one of the preceding items, wherein R2is n-hexyl. 47. The compound according to any one of the preceding items, wherein R2is n-hexyl substituted with halogen.

[0450] 48. The compound according to any one of the preceding items, wherein R2is n-hexyl substituted with one or more fluorine.

[0451] 49. The compound according to any one of the preceding items, wherein R2is 6,6,6- trifluorohexan-1-yl.

[0452] 50. The compound according to any one of the preceding items, wherein R2is n-decyl. 51. The compound according to any one of the preceding items, wherein R2is 4- phenylbutan-1-yl.

[0453] 52. The compound according to any one of the preceding items, wherein R2is -(CH2CH2O)nCH3wherein n is 1, 2, or 3.

[0454] 53. The compound according to any one of the preceding items, wherein R2is -(CH2CH2O)nCH3wherein n is 2.

[0455] 54. The compound according to any one of the preceding items, wherein R2is phenyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl or C2-6 alkynyl.

[0456] 55. The compound according to any one of the preceding items, wherein R2is phenyl. 56. The compound according to any one of the preceding items, wherein R2is 4-(1- butyl)phen-1-yl.

[0457] 57. The compound according to any one of the preceding items, wherein R2is benzyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl or C2-6 alkynyl.

[0458] 58. The compound according to any one of the preceding items, wherein R2is benzyl. 59. The compound according to any one of the preceding items, wherein R2is an alkynyl group of Formula (A). P7413PC00

[0459] 60. The compound according to any one of the preceding items, wherein R2is benzyl substituted with a group of Formula (A).

[0460] 61. The compound according to any one of the preceding items, wherein R2is an alkynyl group of Formula (A), wherein x = 4, y = 0, and z = 0.

[0461] 62. The compound according to any one of the preceding items, wherein R2is an alkynyl group of Formula (A), wherein x + z = 1, 2, 3, 4, 5, or 6, and y = 0.

[0462] 63. The compound according to any one of the preceding items, wherein R2is an alkynyl group of Formula (A), wherein x + z = 4 and y = 0.

[0463] 64. The compound according to any one of the preceding items, wherein R2is n-hex-1-yn- 6-yl.

[0464] 65. The compound according to any one of the preceding items, wherein R3is C1-4 alkyl, C3- 6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, or C3-9 heteroaryl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0465] 66. The compound according to any one of the preceding items, wherein R3is C1-4 alkyl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0466] 67. The compound according to any one of the preceding items, wherein R3is C1-4 alkyl. 68. The compound according to any one of the preceding items, wherein R3is methyl. 69. The compound according to any one of the preceding items, wherein R3is C3-6 cycloalkyl wherein one methylene unit(s) is optionally replaced with -O-, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. 70. The compound according to any one of the preceding items, wherein R3is C3-6 cycloalkyl wherein one methylene unit is optionally replaced with -O-.

[0467] 71. The compound according to any one of the preceding items, wherein R3is C3-6 cycloalkyl wherein one methylene unit is replaced with -O-.

[0468] 72. The compound according to any one of the preceding items, wherein R3is oxetanyl. 73. The compound according to any one of the preceding items, wherein R3is C3-6 cycloalkyl.

[0469] 74. The compound according to any one of the preceding items, wherein C3-6 cycloalkyl is cyclopentyl or cyclohexyl.

[0470] 75. The compound according to any one of the preceding items, wherein R3is cyclopentyl.

[0471] 76. The compound according to any one of the preceding items, wherein R3is cyclohexyl.

[0472] 77. The compound according to any one of the preceding items, wherein R3is cyclopentyl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. 78. The compound according to any one of the preceding items, wherein R3is cyclohexyl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. P7413PC00

[0473] 79. The compound according to any one of the preceding items, wherein R3is cyclopentyl, substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0474] 80. The compound according to any one of the preceding items, wherein R3is cyclopentyl, substituted with C1-4 alkyl.

[0475] 81. The compound according to any one of the preceding items, wherein R3is cyclopentyl, substituted with C1-3 alkoxy.

[0476] 82. The compound according to any one of the preceding items, wherein R3is cyclopentyl, substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. 83. The compound according to any one of the preceding items, wherein R3is cyclopentyl, substituted with haloalkyl.

[0477] 84. The compound according to any one of the preceding items, wherein R3is cyclopentyl, substituted with phenyl.

[0478] 85. The compound according to any one of the preceding items, wherein R3is cyclopentyl, substituted C2-6 alkynyl.

[0479] 86. The compound according to any one of the preceding items, wherein R3is cyclopentyl.

[0480] 87. The compound according to any one of the preceding items, wherein R3is cyclohexyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0481] 88. The compound according to any one of the preceding items, wherein R3is cyclohexyl, substituted with C1-4 alkyl.

[0482] 89. The compound according to any one of the preceding items, wherein R3is cyclohexyl, substituted with C1-3 alkoxy.

[0483] 90. The compound according to any one of the preceding items, wherein R3is cyclohexyl, substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. 91. The compound according to any one of the preceding items, wherein R3is cyclohexyl, substituted with C1-4 haloalkyl.

[0484] 92. The compound according to any one of the preceding items, wherein R3is cyclohexyl, substituted with phenyl.

[0485] 93. The compound according to any one of the preceding items, wherein R3is cyclohexyl, substituted with C2-6 alkynyl.

[0486] 94. The compound according to any one of the preceding items, wherein R3is cyclohexyl.

[0487] 95. The compound according to any one of the preceding items, wherein R3is cyclopropyl.

[0488] 96. The compound according to any one of the preceding items, wherein R3is C6-10 aryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0489] 97. The compound according to any one of the preceding items, wherein R3is C6-10 aryl.

[0490] 98. The compound according to any one of the preceding items, wherein R3is Ce aryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. P7413PC00

[0491] 99. The compound according to any one of the preceding items, wherein R3is Ce aryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. 100. The compound according to any one of the preceding items, wherein R3is Ce aryl substituted with C1-4 alkyl.

[0492] 101. The compound according to any one of the preceding items, wherein R3is Ce aryl substituted with C1-3 alkoxy.

[0493] 102. The compound according to any one of the preceding items, wherein R3is Ce aryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof.

[0494] 103. The compound according to any one of the preceding items, wherein R3is Ce aryl substituted with C1-4 haloalkyl.

[0495] 104. The compound according to any one of the preceding items, wherein R3is Ce aryl substituted with phenyl.

[0496] 105. The compound according to any one of the preceding items, wherein R3is Ce aryl substituted with C2-6 alkynyl.

[0497] 106. The compound according to any one of the preceding items, Ce aryl is phenyl. 107. The compound according to any one of the preceding items, wherein R3is phenyl substituted with one or more Cl, Br, or I, or a combination thereof.

[0498] 108. The compound according to any one of the preceding items, wherein R3is 4- halophenyl.

[0499] 109. The compound according to any one of the preceding items, wherein R3is 4- chlorophenyl.

[0500] 110. The compound according to any one of the preceding items, wherein R3is phenyl.

[0501] 111. The compound according to any one of the preceding items, wherein R3is napthyl.

[0502] 112. The compound according to any one of the preceding items, wherein R3is C3-9 heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0503] 113. The compound according to any one of the preceding items, wherein R3is C3-9 heteroaryl.

[0504] 114. The compound according to any one of the preceding items, wherein R3is C heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0505] 115. The compound according to any one of the preceding items, wherein R3is C heteroaryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0506] 116. The compound according to any one of the preceding items, wherein R3is C heteroaryl substituted with C1-4 alkyl. P7413PC00

[0507] 117. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C1-3 alkoxy.

[0508] 118. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof.

[0509] 119. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C1-4 haloalkyl.

[0510] 120. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with phenyl.

[0511] 121. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C2-6 alkynyl.

[0512] 122. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0513] 123. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0514] 124. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C1-4 alkyl.

[0515] 125. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C1-3 alkoxy.

[0516] 126. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof.

[0517] 127. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C1-4 haloalkyl.

[0518] 128. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with phenyl.

[0519] 129. The compound according to any one of the preceding items, wherein R3is C4 heteroaryl substituted with C2-6 alkynyl.

[0520] 130. The compound according to any one of the preceding items, C4 heteroaryl is furanyl.

[0521] 131. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0522] 132. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl. P7413PC00

[0523] 133. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl substituted with C1-4 alkyl.

[0524] 134. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl substituted with C1-3 alkoxy.

[0525] 135. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof.

[0526] 136. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl substituted with C1-4 haloalkyl.

[0527] 137. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl substituted with phenyl.

[0528] 138. The compound according to any one of the preceding items, wherein R3is Ca heteroaryl substituted with C2-6 alkynyl.

[0529] 139. The compound according to any one of the preceding items, Ca heteroaryl is benzofuranyl.

[0530] 140. The compound according to any one of the preceding items, wherein R3is pyridyl.

[0531] 141. The compound according to any one of the preceding items, wherein R3is 2- pyridyl.

[0532] 142. The compound according to any one of the preceding items, wherein R3is 3- pyridyl.

[0533] 143. The compound according to any one of the preceding items, wherein R3is 4- pyridyl.

[0534] 144. The compound according to any one of the preceding items, wherein R3is oxazolyl.

[0535] 145. The compound according to any one of the preceding items, wherein R3is furanyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0536] 146. The compound according to any one of the preceding items, wherein R3is furanyl, substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0537] 147. The compound according to any one of the preceding items, wherein R3is furanyl, substituted with C1-4 alkyl.

[0538] 148. The compound according to any one of the preceding items, wherein R3is furanyl, substituted with C1-3 alkoxy.

[0539] 149. The compound according to any one of the preceding items, wherein R3is furanyl, substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof. P7413PC00

[0540] 150. The compound according to any one of the preceding items, wherein R3is furanyl, substituted with C1-4 haloalkyl.

[0541] 151. The compound according to any one of the preceding items, wherein R3is furanyl, substituted with phenyl.

[0542] 152. The compound according to any one of the preceding items, wherein R3is furanyl, substituted with C2-6 alkynyl.

[0543] 153. The compound according to any one of the preceding items, wherein R3is furanyl.

[0544] 154. The compound according to any one of the preceding items, wherein R3is furan-2-yl.

[0545] 155. The compound according to any one of the preceding items, wherein R3is diazanaphthalenyl.

[0546] 156. The compound according to any one of the preceding items, wherein R3is indazolyl.

[0547] 157. The compound according to any one of the preceding items, wherein R3is benzothiazolyl.

[0548] 158. The compound according to any one of the preceding items, wherein R3is benzofuranyl, optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0549] 159. The compound according to any one of the preceding items, wherein R3is benzofuranyl, substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

[0550] 160. The compound according to any one of the preceding items, wherein R3is benzofuranyl, substituted with C1-4 alkyl.

[0551] 161. The compound according to any one of the preceding items, wherein R3is benzofuranyl, substituted with C1-3 alkoxy.

[0552] 162. The compound according to any one of the preceding items, wherein R3is benzofuranyl, substituted with halogen, such as one or more Cl, Br, or I, or a combination thereof.

[0553] 163. The compound according to any one of the preceding items, wherein R3is benzofuranyl, substituted with C1-4 haloalkyl.

[0554] 164. The compound according to any one of the preceding items, wherein R3is benzofuranyl, substituted with phenyl.

[0555] 165. The compound according to any one of the preceding items, wherein R3is benzofuranyl, substituted with C2-6 alkynyl.

[0556] 166. The compound according to any one of the preceding items, wherein R3is benzofuranyl.

[0557] 167. The compound according to any one of the preceding items, wherein R3is benzofuran-2-yl. P7413PC00

[0558] 168. The compound according to any one of the preceding items, wherein R3is an alkynyl group of Formula (A).

[0559] 169. The compound according to any one of the preceding items, wherein R4is H, halogen or C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted.

[0560] 170. The compound according to any one of the preceding items, wherein R4is H, halogen or C1-4 alkyl.

[0561] The compound according to any one of the preceding items, wherein R4is H.

[0562] 171. The compound according to any one of the preceding items, wherein R4is halogen.

[0563] 172. The compound according to any one of the preceding items, wherein R4is F. 173. The compound according to any one of the preceding items, wherein R4is Cl. 174. The compound according to any one of the preceding items, wherein R4is Br. 175. The compound according to any one of the preceding items, wherein R4is I. 176. The compound according to any one of the preceding items, wherein R4is C1-4 alkyl optionally substituted.

[0564] 177. The compound according to any one of the preceding items, wherein R4is methyl.

[0565] 178. The compound according to any one of the preceding items, wherein R5is H, C1-4 alkyl or C2-4 alkenyl.

[0566] 179. The compound according to any one of the preceding items, wherein R5is H. 180. The compound according to any one of the preceding items, wherein R5is C1-4 alkyl.

[0567] 181. The compound according to any one of the preceding items, wherein R5is C3 alkyl.

[0568] 182. The compound according to any one of the preceding items, wherein R5is methyl.

[0569] 183. The compound according to any one of the preceding items, wherein R5is C2-4 alkenyl.

[0570] 184. The compound according to any one of the preceding items, wherein R5is C2-4 alk-1 -en-1 -yl.

[0571] 185. The compound according to any one of the preceding items, wherein R5is vinyl.

[0572] 186. The compound according to any one of the preceding items, wherein R5is C3 alkenyl.

[0573] 187. The compound according to any one of the preceding items, wherein R5is prop- 1 -en-1 -yl.

[0574] 188. The compound according to any one of the preceding items, wherein R5is prop- 1-yl. P7413PC00

[0575] 189. The compound according to any one of the preceding items, wherein R5is c / s- prop-1-en-1-yl.

[0576] 190. The compound according to any one of the preceding items, wherein R5is trans- prop-1-en-1-yl.

[0577] 191. The compound according to any one of the preceding items, wherein A is an alkynyl group of Formula (A):

[0578]

[0579] wherein:

[0580] x is 0, 1, 2, 3, 4 or 5;

[0581] y is 0 or 1; and

[0582] z is 0, 1, 2, 3, 4 or 5.

[0583] 192. The compound according to any one of the preceding items, wherein A is the alkynyl group of Formula (A), wherein x = 0, 1, 2, 3, 4 or 5.

[0584] 193. The compound according to any one of the preceding items, wherein A is the alkynyl group of Formula (A), wherein y = 0 or 1.

[0585] 194. The compound according to any one of the preceding items, wherein A is the alkynyl group of Formula (A), wherein z = 0, 1, 2, 3, 4 or 5.

[0586] 195. The compound according to any one of the preceding items, wherein A is a group of Formula (A), wherein x + z = 1, 2, 3, 4, 5, or 6; and y = 0.

[0587] 196. The compound according to any one of the preceding items, wherein A is a group of Formula (A), wherein x + z = 4; and y = 0.

[0588] 197. The compound according to any one of the preceding items, wherein A is a group of Formula (A), wherein x = 4, y = 0, and z = 0.

[0589] 198. The compound according to any one of the preceding items, wherein A is a group of Formula (A), wherein x = 1, y = 0, and z = 0.

[0590] 199. The compound according to any one of the preceding items, wherein A is hexynyl.

[0591] 200. The compound according to any one of the preceding items, wherein A is propargyl.

[0592] 201. The compound according to any one of the preceding items, wherein the compound is of Formula (1 a) or (1 b): P7413PC00

[0593]

[0594] 202. The compound according to any one of the preceding items, wherein the compound is of Formula (1a-1), (1a-2), (1a-3), (1a-4), (1 b-1), (1b-2), (1b-3) or (1b-4):

[0595]

[0596] 203. The compound according to any one of the preceding items, wherein the compound is of Formula (1 a-1), (1a-4), (1 b-1), or (1b-4):

[0597]

[0598] , Formula (1 a-1 ),, Formula (1a-4), P7413PC00

[0599]

[0600] , Formula (1 b-1),, Formula (1b-4).

[0601] 204. The compound according to any one of the preceding items, wherein the dashed bond of Formula (1) is a double bond.

[0602] 205. The compound according to any one of the preceding items, wherein the compound is of Formula (2a) or (2b):

[0603]

[0604] 206. The compound according to any one of the preceding items, wherein the compound is of Formula (2a-1), (2a-2), (2a-3), (2a-4), (2b-1), (2b-2), (2b-3), or(2b-4):

[0605]

[0606] P7413PC00

[0607]

[0608] , Formula (2b-3),, Formula (2b-4).

[0609] 207. The compound according to any one of the preceding items, wherein the compound is of Formula (2a-1), (2a-4), (2b-1), or (2b-4):

[0610]

[0611] 208. The compound according to any one of the preceding items, wherein the dashed bond of Formula (1) is a single bond.

[0612] 209. The compound according to any one of the preceding items, wherein the compound is of Formula (3):

[0613]

[0614] , Formula (3)

[0615] 210. The compound according to any one of the preceding items, wherein the compound is of Formula (3a) or (3b): P7413PC00

[0616]

[0617] , Formula (3a),, Formula (3b).

[0618] 211. The compound according to any one of the preceding items, wherein the compound is of Formula (3a-1), (3a-2), (3a-3), (3a-4), (3b-1), (3b-2), (3b-3) or (3b-4):

[0619]

[0620] 212. The compound according to any one of the preceding items, wherein the compound is of Formula (3a-1), (3a-4), (3b-1), or (3b-4):

[0621]

[0622] , Formula (3a-1),, Formula (3a-4), P7413PC00

[0623]

[0624] , Formula (3b-1),, Formula (3b-4).

[0625] 213. The compound according to anyone of the preceding items, wherein the compound is of Formula (2), R4is Cl and R5is prop-1 -en-1yl.

[0626] 214. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is cyclopentyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0627] 215. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is cyclopentyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0628] 216. The compound according to any one of the preceding items, wherein the compound is of Formula (3), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is methyl, R4is H, and R5is H.

[0629] 217. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is phenyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0630] 218. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is phenyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0631] 219. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is 4-chlorophenyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0632] 220. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2- yl, R4is Cl, and R5is prop-1 -en-1-yl. P7413PC00

[0633] 221. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is furan-2-yl, R4is Cl, and R5is prop-1 -en-1-yl.

[0634] 222. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is cyclohexyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0635] 223. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is H, R2is n-hexan-1-yl, R3is benzofuran-2-yl, R4is Cl, and R5is prop-1 -en-1-yl.

[0636] 224. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2- yl, R4is Br, and R5is prop-1 -en-1-yl.

[0637] 225. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2- yl, R4is Cl, and R5is prop-1 -yl.

[0638] 226. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is 4-(methoxyl)benzyl, R2is n-hexan-1-yl, R3is furan-2- yl, R4is I, and R5is prop-1 -en-1-yl.

[0639] 227. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R1is H, R2is n-hex-1-yn-6-yl, R3is cyclopentyl, R4is Cl, and R5is prop-1 -en-1-yl.

[0640] 228. The compound according to any one of the preceding items, wherein the compound is

[0641]

[0642] P7413PC00

[0643]

[0644] 229. The compound according to any one of the preceding items, wherein the compound is

[0645]

[0646] P7413PC00

[0647]

[0648] , a stereoisomer thereof, or a combination of stereoisomers thereof.

[0649] 230. The compound according to any one of the preceding items, wherein the

[0650]

[0651] or a combination thereof.

[0652] 231. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0653]

[0654] 232. The compound according to any one of the preceding items, wherein the compound is a mixture of P7413PC00

[0655]

[0656] 233. The compound according to any one of the preceding items, wherein the compound is any one of

[0657]

[0658] or a combination thereof.

[0659] 234. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0660] Me Me

[0661]

[0662] 235. The compound according to any one of the preceding items, wherein the compound is a mixture of P7413PC00

[0663]

[0664] 236. The compound according to any one of the preceding items, wherein the compound is any one of

[0665]

[0666] combination thereof.

[0667] 237. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0668] Me Me

[0669]

[0670] 238. The compound according to any one of the preceding items, wherein the compound is a mixture of P7413PC00

[0671]

[0672] 239. The compound according to any one of the preceding items, wherein the compound is any one of

[0673]

[0674] combination thereof.

[0675] 240. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0676] Me Me

[0677]

[0678] 241. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0679]

[0680] P7413PC00

[0681] 242. The compound according to any one of the preceding items, wherein the

[0682]

[0683] combination thereof.

[0684] 243. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0685]

[0686] 244. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0687]

[0688] 245. The compound according to any one of the preceding items, wherein the compound is any one of P7413PC00

[0689]

[0690] combination thereof.

[0691] 246. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0692]

[0693] 247. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0694]

[0695] 248. The compound according to any one of the preceding items, wherein the compound is any one of P7413PC00

[0696]

[0697] combination thereof.

[0698] 249. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0699]

[0700] 250. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0701]

[0702] 251. The compound according to any one of the preceding items, wherein the compound is any one of P7413PC00

[0703]

[0704] 252. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0705]

[0706] 253. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0707]

[0708] 254. The compound according to any one of the preceding items, wherein the compound is any one of P7413PC00

[0709]

[0710] or a combination thereof.

[0711] 255. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0712]

[0713] 256. The compound according to any one of the preceding items, wherein the compound is a mixture of P7413PC00

[0714]

[0715] 257. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0716]

[0717] 258. The compound according to any one of the preceding items, wherein the compound is any one of

[0718]

[0719] or a combination thereof.

[0720] 259. The compound according to any one of the preceding items, wherein the compound is a mixture of P7413PC00

[0721]

[0722] 260. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0723]

[0724] 261. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0725]

[0726] 262. The compound according to any one of the preceding items, wherein the compound is any one of P7413PC00

[0727]

[0728] combination thereof.

[0729] 263. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0730]

[0731] 264. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0732]

[0733] 265. The compound according to any one of the preceding items, wherein the compound is any one of P7413PC00

[0734]

[0735] combination thereof.

[0736] 266. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0737]

[0738] 267. The compound according to any one of the preceding items, wherein the compound is a mixture of

[0739]

[0740] 268. The compound according to any one of the preceding items, wherein the mixture is a racemic mixture.

[0741] 269. The compound according to any one of the preceding items, wherein the compound is an anticancer agent.

[0742] 270. The compound according to any one of the preceding items, wherein the compound is a lymphangiogenesis inhibitor. P7413PC00

[0743] 271. The compound according to any one of the preceding items, wherein the compound is an NF-KB kinase modulator.

[0744] 272. The compound according to any one of the preceding items, wherein the compound is an NF-KB kinase inhibitor.

[0745] 273. A pharmaceutical composition comprising a compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0746] 274. The pharmaceutical composition according to item 273, comprising one or more compounds according to any one of items 1 to 272, including a mixture thereof.

[0747] 275. The compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for use as a medicament.

[0748] 276. A method of treating a disease, comprising administering a compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, to a subject in need thereof.

[0749] 277. The compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for use in the treatment of cancer.

[0750] 278. A method of treating cancer, comprising administering a compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, to a subject in need thereof.

[0751] 279. Use of a compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for the manufacture of a medicament for the treatment of cancer.

[0752] 280. The compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for use in inhibiting lymphangiogenesis and / or lymphatic metastasis. P7413PC00

[0753] 281. A method of inhibiting lymphangiogenesis and / or lymphatic metastasis, comprising administering a compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, to a subject in need thereof.

[0754] 282. Use of a compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of items 273 to 274, for the manufacture of a medicament for inhibiting lymphangiogenesis and / or lymphatic metastasis.

[0755] 283. The compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for use in the prevention of cancer progression.

[0756] 284. A method of prevention of cancer progression, comprising administering a compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, to a subject in need thereof.

[0757] 285. Use of a compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for the manufacture of a medicament for the prevention of cancer progression.

[0758] 286. The compound according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for use in the treatment or prevention of an NF-kB-related disease or disorder.

[0759] 287. A compound of Formula (1) according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for use in the treatment or prevention of an NF- kB-related disease or disorder.

[0760] 288. A method of treating or preventing an NF-kB-related disease or disorder, comprising administering a compound of Formula (1) according to any one of items 1 to 272, or a pharmaceutical composition according to any one of items 273 to 274, or a pharmaceutical composition thereof, to a subject in need thereof. P7413PC00

[0761] 289. Use of a compound of Formula (1) according to any one of items 1 to 272, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 273 to 274, for the manufacture of a medicament for the treatment or prevention of an NF-kB-related disease or disorder. P7413PC00

[0762] Items 2

[0763] 1. A compound of Formula (1):

[0764] R2R4

[0765] R1-N

[0766]

[0767] , Formula (1)

[0768] wherein:

[0769] R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, phenyl, benzyl, or 5- or 6-membered heteroaryl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl;

[0770] R2is H, C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, phenyl, or an alkynyl group A, wherein said C1-10 alkyl or phenyl is optionally substituted with C1-4 alkyl, phenyl or one or more halogen;

[0771] R3is C1-4 alkyl, C3-6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10aryl, or C3-9 heteroaryl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl;

[0772] R4is H, halogen or C1-4 alkyl;

[0773] R5is H, C1-4 alkyl or C2-4 alkenyl;

[0774] A is an alkynyl group of Formula (A):

[0775] CH2

[0776]

[0777] , Formula (A)

[0778] wherein:

[0779] x is 0, 1, 2, 3, 4 or 5;

[0780] y is 0 or 1; and

[0781] z is 0, 1, 2, 3, 4 or 5;

[0782] the dashed bond represents either a double bond or a single bond; or a tautomer or a pharmaceutically acceptable salt thereof.

[0783] 2. The compound according to item 1, wherein R1is H, methyl, phenyl, benzyl, 4- methoxybenzyl or pyridyl. P7413PC00

[0784] 3. The compound according to any one of the preceding items, wherein R1is H or 4- methoxybenzyl.

[0785] 4. The compound according to any one of the preceding items, wherein R2is H, methyl, ethyl, n-hexyl, 6,6,6-trifluorohexan-1-yl, n-decyl, -(CH2CH2O)2CH3, 4-(1-butyl)phen-1-yl, or 4-phenylbutan-1-yl.

[0786] 5. The compound according to any one of the preceding items, wherein R2is ethyl or n- hexyl.

[0787] 6. The compound according to any one of the preceding items, wherein R3is methyl, cyclopentyl, cyclopropyl, phenyl, naphthyl, pyridyl, diazanaphthalenyl, indazolyl, benzothiazolyl, oxazolyl, or oxetanyl.

[0788] 7. The compound according to any one of the preceding items, wherein R3is methyl or cyclopentyl.

[0789] 8. The compound according to any one of the preceding items, wherein R4is H, methyl, F, Cl, Br, or I.

[0790] 9. The compound according to any one of the preceding items, wherein R4is H or Cl.

[0791] 10. The compound according to any one of the preceding items, wherein R5is H, methyl, C1-4 alk-1 -en-1 -yl, prop-1 -en-1-yl.

[0792] 11. The compound according to any one of the preceding items, wherein R5is H or prop-1 - en-1-yl.

[0793] 12. The compound according to any one of the preceding items, wherein the compound is of Formula (2) or Formula (3):

[0794]

[0795] , Formula (3);

[0796] wherein

[0797] R1is H, methyl, phenyl, benzyl, 4-methoxybenzyl or pyridyl;

[0798] R2is H, methyl, ethyl, n-hexyl, 6,6,6-trifluorohexan-1-yl, n-decyl, -(CH₂CH₂O)₂CH₃, 4-(1- butyl)phen-1-yl, or 4-phenylbutan-1-y; P7413PC00

[0799] R3is methyl, cyclopentyl, cyclopropyl, phenyl, naphthyl, pyridyl, diazanaphthalenyl, indazolyl, benzothiazolyl, oxazolyl, or oxetanyl;

[0800] R4is H, methyl, F, Cl, Br, or I; and

[0801] R5is H, methyl, C1-4 alk-1 -en-1 -yl, prop-1 -en-1-yl.

[0802] 13. The compound according to any one of the preceding items, wherein the compound is of Formula (2), R4is Cl and R5is prop-1 -en-1 -yl.

[0803] 14. The compound according to any one of the preceding items, wherein the compound is:

[0804]

[0805] 15. A compound of Formula (1) according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. P7413PC00

[0806] Examples

[0807] Some of the compounds described in the examples were synthesized as a mixture of stereoisomers. For example, in Example 1 (Exemplification 2), the structures shown:

[0808] The first structure

[0809]

[0810] In some examples, at least two diastereoisomers were obtained. In some examples only one diastereoisomer was obtained. In some procedures, the diastereoisomers of said mixture were separated, e.g. by reverse phase C18 chromatography or by normal phase chromatography. In examples where diastereoisomers have been separated, the first diastereoisomer to elute from the column is designated by adding an ‘a’ to the end of its name (e.g., TTP652a, GW2366a, GW2377a, and others), while the second eluting diastereoisomer is designated by adding a ‘b’ (e.g., TTP652b, GW2366b, GW2377b, and others). The assignment of stereochemistry of the P7413PC00

[0811] separated diastereoisomers designated ‘a’ and ‘b’ is arbitrary, and thus, it is possible that the assigned stereochemistry is different, for example, opposite.

[0812] For example, in Example 1 (Exemplification 2), the first eluting diastereoisomer, designated rac- TTP652a, has been assigned arbitrarily to:

[0813]

[0814] , while the second eluting diastereoisomer, designated rac-TTP652b, has been assigned arbitrarily to:

[0815]

[0816] . Since the stereochemical assignment was made arbitrarily, it is possible that the absolute configuration is the reverse of that indicated here and in the examples.

[0817] In some examples, only one diastereoisomer was obtained which has been designated by adding an ‘a’ to the end of its name (e.g. rac-TTP757a and GW2365a). Since the stereochemical assignment was made arbitrarily, it is possible that the absolute configuration is the reverse of that indicated in the examples.

[0818] Example 1: Synthetic protocols

[0819] General methods

[0820] All reactions were conducted in flame-dried glassware under an atmosphere of argon unless otherwise stated. DCM, MeCN, THF and PhMe were dried over aluminium oxide via an MBraun SPS-800 solvent purification system and further stored over preactivated molecular sieves (3 A or 4 A). MeOH, 1,4-dioxane, DMSO and DMA were purchased as anhydrous. iPrOH was purchased as HPLC grade. Et2O, TBME and benzene were purchased as anhydrous and then transferred to a flask containing preactivated molecular sieves (3 A or 4 A). Pyridine was purchased anhydrous and distilled onto preactivated molecular sieves (4 A). Hexane and P7413PC00

[0821] acetone were distilled onto preactivated molecular sieves (3 A or 4 A). AcOH was purchased as absolute and used without further purification. The dryness of solvents was controlled via Karl Fischer titration. Reagents were used as received from commercial suppliers unless otherwise stated (Sigma Aldrich, Merck, AK Scientific, Fluorochem, BLD Pharm and TCI). Et3N, DIPEA, DBU and HMPA were dried by stirring for at least 30 minutes over CaH2followed by distillation onto preactivated molecular sieves (3 A or 4 A). DMF was dried by stirring overnight with preactivated molecular sieves (4 A) and then distilled under vacuum onto molecular sieves (4 A). Concentration in vacuo was performed using a rotary evaporator with the water bath temperature at 35 °C, followed by further concentration using a high vacuum pump unless otherwise stated. TLC analysis was carried out on silica coated aluminium foil plates (Merck Kieselgel 60 F254). The TLC plates were visualized by UV irradiation and / or by staining with KMnO4stain (KMnO4(5.0 g), 5 % aq. NaOH (8.3 mL) and K2CO3 (33.3 g) in H2O (500 mL)). Molecular sieves were activated by drying in the oven at 120 °C for at least 24 h, before they were heated in a microwave at maximum power for 2 minutes, followed by evaporation of the formed vapor under high vacuum. This was repeated 3-4 times and finished by gently flamedrying the flask containing the molecular sieves. Automated flash column chromatography (AFCC) was carried out with Interchim PuriFlash 420 or 5.050 using 30 μm prepacked columns unless otherwise stated. Infrared spectra (IR) were acquired on a PerkinElmer Spectrum Two™ UATR. Mass spectra (HRMS) were recorded on a Bruker Daltonics MicrOTOF time-of-flight spectrometer with positive electrospray ionization, or negative ionization when stated. Nuclear magnetic resonance (NMR) spectra were recorded on a Varian Mercury 400 MHz spectrometer or a Bruker BioSpin GmbH 400 MHz spectrometer, running at 400 and 101 MHz for1H and13C, respectively. Chemical shifts (6) are reported in ppm relative to the residual solvent signals (chloroform-d: 7.26 ppm1H NMR, 77.16 ppm13C NMR; methanol-d4: 3.31 ppm1H NMR, 49.00 ppm13C NMR; and benzene-d6: 7.16 ppm1H NMR, 128.06 ppm13C NMR). Multiplicities are indicated using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br = broad.

[0822] All GWXXXXa or GWXXXXb refers to the order by which the isomer elute from reverse phase C18 using MeCN / MQ water system where ‘a’ elutes before ‘b’.

[0823] For GW2366a and GW2366b, GW2377a and GW2377b, GW2387a and GW2387b, and GW2486a and GW2486b, the ‘a’ and ‘b’ refers to the order by which the diastereoisomers elute by C18 reverse phase chromatography, ‘a’ elutes before ‘b’.

[0824] For TTP652a and TTP652b, TTP814a and TTP814b, TTP821a and TTP821b, and TTP757a and TTP757b, the ‘a’ and ‘b’ refers to the order by which the diastereoisomers elute by normal phase chromatography, ‘a’ elutes before ‘b’. P7413PC00

[0825] Stereochemical assignment of diastereoisomers designated ‘a’ and ‘b’ is arbitrary, and thus, it is possible that the assigned stereochemistry is the reverse of that indicated.

[0826] Exemplification 1: Compound 79

[0827] Intermediate 59 (3, 4 -di bromofuran -2, 5-dione):

[0828] O

[0829]

[0830] o

[0831] Maleic anhydride (10.715 g, 109.27 mmol, 1.0 equiv.), AlCh (218 mg, 1.64 mmol, 1.5 mol%) and bromine (11.2 mL, 219 mmol, 2.0 equiv.) was charged to a PTFE insert fitting in a stainless-steel autoclave. The autoclave was heated gradually from 60 °C to 120 °C. After 17 h at 120 °C the autoclave was allowed to cool slowly, which caused it to release pressure. The autoclave was opened and the resulting orange solid was transferred to a flask and the PTFE fitting was washed with benzene. The benzene was removed by nitrogen flow and the resulting solid material was heated to reflux in heptane (250 mL) and filtered while hot. The remaining solid in the flask was heated to reflux in another portion of heptane (100 mL) which too was filtered while hot. The liquid phase was heated to reflux to yield a homogeneous light-yellow solution which was allowed to cool slowly during which large crystals formed. The flask was cooled to -24 °C in a freezer and left for 5 days to ensure complete crystallization. The crystals were collected by filtration and washed with pentane. Residual solvent was removed under high vacuum to afford 3, 4-dibromofuran-2, 5-dione as large light-yellow needles (23.326 g, 91.17 mmol, 83%).13C NMR (101 MHz, CDCl3) 6c (ppm) 158.7, 131.5. The obtained data are in accordance with the literature (Jones et al, 2012) P7413PC00

[0832] Intermediate 60 (3, 4-diiodo-1H-pyrrole-2, 5-dione):

[0833] O

[0834]

[0835] o

[0836] 3, 4-dibromofuran-2, 5-dione (59) (23.294 g, 91.04 mmol, 1.0 equiv.) was charged to a flask containing MeCN (260 mL) followed by addition of HMDS (29.0 mL, 137 mmol, 1.5 equiv.) and lastly Nal (40.948 g, 271.1 mmol, 3.0 equiv.). The flask was purged with argon and the mixture was heated to reflux. After 1 h at reflux, the reaction mixture was cooled to rt and then diluted with water (500 mL) which induced precipitation. After 1 day at -24 °C, the resulting ice was melted and the solid material was collected by filtration and washed with plenty of water. The yellow solid was transferred to a new flask and dried under high vacuum. The material was recrystallized from refluxing PhMe / / PrOH (240 mL, 5:1). Upon identifying crystal formation, the flask was cooled to -24 °C. The next day, the crystals formed were collected by filtration and washed with pentane. The resulting crystals were dried under high vacuum to afford the product as orange crystals (15.333 g, 43.95 mmol, 48%, crop 1). The liquid phase from the filtration was concentrated in vacuo and redissolved in refluxing PhMe / / PrOH (14:1, 150 mL). Upon obtaining a homogeneous solution, heptane (50 mL) was added and the solution was allowed to cool to room temperature. Upon identifying crystals, the solution was further cooled to -24 °C in a freezer overnight. The following morning, a new crop was isolated by filtration and the resulting orange crystals were washed with pentane and dried under high vacuum (4.243 g, 12.16 mmol, 13%, crop 2). Combined yield of 3, 4-diiodo-1 / 7-pyrrole-2, 5-dione: 19.576 g, 56.11 mmol, 62%. Rf(2:1 Heptane / EtOAc) 0.5.1H NMR (400 MHz, DMSO-d6) δH(ppm) 11.48 (s, 1H).13C NMR (101 MHz, DMSO-d6) δc(ppm) 168.7, 120.1.

[0837] Intermediate 61 (3,4-diiodo-1 -(4-methoxybenzyl)-1 H-pyrrole-2, 5-dione):

[0838] O

[0839] jT N-PMB

[0840] O

[0841] To a suspension of 3, 4-diiodo-1 / 7-pyrrole-2, 5-dione (60) (1746 mg, 5.00 mmol, 1.0 equiv.) and K2CO3 (830 mg, 6.01 mmol, 1.2 equiv.) in acetone (50 mL) was added 4-methoxybenzyl chloride (1.46 mL, 10 mmol, 2.0 equiv.). The reaction was heated to 50 °C for 3 hours before the reaction was allowed to cool to rt. Sat. aq. NH4CI was added (15 mL), the mixture was diluted with water (55 mL) and extracted with EtOAc (3 x 75 mL). The combined organic phases were dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a reddish brown solid. The crude material was recrystallized from heptane / EtOAc (5:1, 180 mL) and the solution was stored at -24 °C. The next day yellow crystals had formed. They were isolated by P7413PC00

[0842] filtration, washed with heptane and dried on the filter. They were collected and further dried under high vacuum yielding 3, 4-diiodo-1-(4-methoxybenzyl)-1 / 7-pyrrole-2, 5-dione as yellow crystals (1.710 g, 3.65 mmol, 73%). Rf(2:1 Heptane / EtOAc) 0.55.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.32 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.71 (s, 2H), 3.78 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 166.2, 159.7, 130.5, 127.9, 117.51, 114.3, 55.4, 43.3. The obtained data are in accordance with the literature (Dubernet et al, 2005).

[0843] Intermediate 62 (3-ethyl-4-iodo-1-(4-methoxybenzyl)-1H-pyrrole- 2,5-dione):

[0844]

[0845] A solution of 3, 4-diiodo-1-(4-methoxybenzyl)-1 / 7-pyrrole-2, 5-dione (61) (2001 mg, 4.27 mmol, I.0 equiv) and Cui (81 mg, 0.43 mmol, 0.1) in 4:1 anhydrous THF / HMPA (40 mL) was stirred at 0 °C for 20 min. The solution was cooled to -78 °C and diethylzinc (0.87 M in hexanes, titrated as mentioned below, 4.9 mL, 4.27 mmol, 1.0 equiv.) was added dropwise. After stirring 1 h at -78 °C, the reaction mixture was allowed to heat to rt. After 5 min at rt, the mixture was quenched with saturated aqueous NH4CI (25 mL). The mixture was further diluted with water (60 mL) and extracted with EtOAc (3 x 75 mL). The combined organic layers were washed four times with water (4 x 70 mL) and once with brine (70 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a brown oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 85:15) yielding as a light yellow solid (1228 mg, 3.31 mmol, 78%). Titration of diethylzinc: To a flamedried 10 mL round-bottomed flask was added iodine (261 mg, 1.03 mmol). A saturated solution of LiCI in THF (0.5 M, 4 mL) was added. After the iodine had completely dissolved, the brown solution was cooled to 0 °C and Et2Zn was added drop-wise until the brown color disappeared. 0.59 mL was used corresponding to a concentration of diethylzinc of 0.87 M (Krasovskiy and Knochel, 2006) Rf (2:1 Heptane / EtOAc) 0.66.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.31 (d, J= 8.7 Hz, 2H), 6.83 (d, J= 8.6 Hz, 2H), 4.63 (s, 2H), 3.78 (s, 3H), 2.47 (q, J= 7.6 Hz, 2H), 1.15 (t, J= 7.6 Hz, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 169.2, 166.5, 159.5, 154.3, 130.3, 130.3, 128.4, 114.2, 102.0, 55.4, 42.2, 21.6, 11.8. HRMS (ESI) Calc, for Ci4Hi5INO3+372.0091; found 372.0086.

[0846] Intermediate 65 (3-ethy 1-1 -(4-methoxybenzyl)-4-(tributylstannyl)-1 H-pyrrole-2, 5-dione):

[0847]

[0848] P7413PC00

[0849] To a stirred solution of 3-ethyl-4-iodo-1-(4-methoxybenzyl)-1 / - / -pyrrole- 2,5-dione (62) (367 mg, 0.990 mmol, 1.0 equiv.) and tris(dibenzyli-deneacetone) dipalladium (46.9 mg, 0.0512 mmol, 5.2 mol%) in / PrOH (10 mL) at rt was added bis(tributyltin) (1.25 mL, 2.47 mmol, 2.5 equiv.) and anhydrous A / , / V-diisopropylethylamine (430 pL, 2.47 mmol, 2.5 equiv.). After being stirred at rt for 2.5 h, the reaction mixture was diluted with water (40 mL) and EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with 0.1 M aq. HCI (40 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a light brown oil. The crude was purified by AFCC (Heptane / EtOAc 100:0 —> 94:6) yielding 3-ethyl-1-(4-methoxybenzyl)-4-(tribu-tylstannyl)-1 / 7-pyrrole-2, 5-dione as a clear oil (434 mg, 0.812 mmol, 82%). Rf (4:1 Heptane / EtOAc) 0.63.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.29 (d, J= 8.7 Hz, 2H), 6.83 (d, J= 8.7 Hz, 2H), 4.56 (s, 2H), 3.77 (s, 3H), 2.43 (q, J= 7.5 Hz, 2H), 1.56 - 1.45 (m, 6H), 1.37 - 1.26 (m, 6H), 1.18 - 1.08 (m, 9H), 0.88 (t, J= 7.3 Hz, 9H).13C NMR (101 MHz, CDCl3) 6c (ppm) 175.6, 171.6, 160.3, 159.1, 144.7, 130.0, 129.4, 114.0, 55.4, 41.3, 29.1, 27.3, 21.2, 14.4, 13.8, 10.6. HRMS (ESI) Calc, for C26H40NO3120Sn+536.2181; found 536.2186.

[0850] Reagent - Copper(l) diphenylphosphinate (CuDPP):

[0851]

[0852] Diphenylphosphinic acid (1006 mg, 4.61 mmol, 1.0 equiv.) and CU2O (330 mg, 2.31 mmol, 0.5 equiv.) were refluxed in degassed toluene (12.5 mL) using a Dean-Stark apparatus under an argon atmosphere. After 18 h, the mixture was allowed to cool, and the suspension was filtered with exclusion of air. The solid was washed with degassed anhydrous toluene (10 mL), degassed anhydrous Et2O (5 mL) and degassed distilled hexane (10 mL) and then dried under reduced pressure to a light tan solid (1.119 g, 3.99 mmol, 87%). Toluene used in reaction was degassed by three cycles of freeze-pump-thaw, while solvents used for washings were degassed by sparging with argon for 20 min. vmax (ATR) 1590, 1484, 1437, 1126, 1069, 1038, 1016, 996, 750, 728, 691, 574, 560, 530, 515, 436. The obtained data are in accordance with the literature (Saito et al, 2011).

[0853] Intermediate 66 (3-Acetyl-4-ethyl-1 -(4-methoxybenzyl)-1 H-pyrrole-2, 5-dione):

[0854] O

[0855] | N-PMB

[0856]

[0857] O

[0858] O P7413PC00

[0859] To a suspension of S-phenyl thioacetate (27 pL, 0.199 mmol, 5.0 equiv.), CuDPP (55.8 mg, 0.199 mmol, 5.0 equiv.), tri-2-furylphoshine (3.7 mg, 0.0159 mmol, 0.40 equiv.), and PdCh(PPh3)2 (5.5 mg, 0.0078 mmol, 0.20 equiv.) in anhydrous degassed n-hexane (300 pL) in a flame-dried reaction tube was added anhydrous degassed THF (100 pL). The solution was stirred for 30 min, before a solution of 3-ethyl-1-(4-methoxybenzyl)-4-(tributylstannyl)-1 / 7-pyrrole-2, 5-dione (65) (21.2 mg, 0.0397 mmol, 1.0 equiv.) in a 3:1 mixture of anhydrous degassed n-hexane and anhydrous degassed THF (400 pL) was added. The tube was sealed with teflon tape and parafilm and heated to 60 °C. After 30 min, the solution was cooled, and the mixture was diluted with EtOAc (15 mL) and water (15 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (25 mL), sat. aq. NaHCOs (25 mL) and brine (25 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to an orange oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 85:15) yielding as a yellow oil (5.2 mg, 0.0181 mmol, 46%). Rf (2:1 Heptane / EtOAc) 0.52.1H NMR (400 MHz, CDCl3) 6H 7.31 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.62 (s, 2H), 3.78 (s, 3H), 2.75 (q, J= 7.5 Hz, 2H), 2.57 (s, 3H), 1.17 (t, J = 7.5 Hz, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 194.4, 169.7, 169.3, 159.5, 155.3, 132.0, 130.3, 128.3, 114.2, 55.4, 41.5, 31.3, 18.4, 12.8. HRMS (ESI) Calc, for CI6HI8NO4+288.1230; found 288.1225.

[0860] Compound 79:

[0861]

[0862] Na2CO3 (2.0 mg, 0.0189 mmol, 1.2 equiv.) and 2-bromo-3-hydroxycyclo-pent-2-en-1-one (8.5 mg, 0.048 mmol, 3.1 equiv.) were charged to a flame-dried reaction tube. 3-Acetyl-4-ethyl-1-(4-methoxybenzyl)-1 / - / -pyrrole- 2,5-dione (66) (4.4 mg, 0.0153 mmol, 1.0 equiv.) dissolved in anhydrous THF (1 mL) was added at 0 °C. After the addition, the mixture was allowed to warm to rt, and it was stirred for 25 h. The reaction mixture was diluted with water (15 mL) and EtOAc (15 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a white solid. The crude material was purified by AFCC (Heptane / EtOAc 80:20 —> 60:40) yielding 1-acetyl-5-ethyl-3-(4-methoxybenzyl)-3-azaspiro[bicyclo[3.1,0]hexane-6,1'- cyclopentane]-2,2',4,5'-tetraone as a white film (3.0 mg, 0.00782 mmol, 51%). Rf(2:1 Heptane / EtOAc) 0.17.1H NMR (400 MHz, CDCl3) 6H 7.29 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.54 (s, 2H), 3.79 (s, 3H), 2.92 (s, 4H), 2.36 (s, 3H), 2.14 (q, J = 7.3 Hz, 2H), 1.14 (t, J = 7.3 Hz, 3H).13C NMR (101 MHz, CDCl3) P7413PC00

[0863] 6c (ppm) 205.3, 203.8, 193.7, 170.2, 167.7, 159.5, 130.4, 127.4, 114.2, 56.2, 55.4, 55.2, 51.6, 43.3, 36.3, 35.8, 31.3, 29.9, 15.2, 11.9. Note: One carbon signal too much is seen in the aliphatic region. HRMS (ESI) Calc, for C2iH22NO6+384.1442; found 384.1438.

[0864] Exemplification 2: rac-TTP652a and rac-TTP652b

[0865] Intermediate 31 (4-hydroxycyclopent-2-en-1-one):

[0866]

[0867] HO

[0868] A 1 L flask was charged with furfuryl alcohol (25.0 g, 0.255 mol, 1.00 equiv.) and 740 mL of MilliQ water. To the solution was added KH2PO4 (1.262 g, 9.27 mmol, 0.037 equiv.) and the pH was adjusted to 4.10 (pH meter) by addition of phosphoric acid (0.5 M, 4 drops). The solution was heated to reflux for 40 h before being cooled to rt and washed with DCM (2 x 100 mL). The combined organic layers were extracted with MilliQ water (2 x 100 mL) and the combined aqueous layers were concentrated in vacuo (rot. evap., 70 °C, 125 mbar) to give an orange oil. The oil was dissolved in DCM (200 mL) and the resulting solution was dried over Na2SO4, filtered and concentrated in vacuo to a dark brown oil (11.087 g). Rf (3:1 EtOAc / Heptane) 0.24.

[0869] 1H NMR (400 MHz, CDCl3) 6H (ppm) 7.57 (dd, J=5.7, 2.4 Hz, 1H), 6.24 (dd, J=5.6, 1.4 Hz, 1H), 5.07 (m, 1H), 2.79 (dd, J=18.4, 6.1 Hz, 1H), 2.29 (dd, J=18.4, 2.0 Hz, 1H).13C NMR (101 MHz, CDCl3) 6c (ppm) 206.7, 163.4, 135.3, 70.6, 44.4. vmax(ATR) 3406, 2928, 1710, 1673, 1586, 1404, 1341, 1103, 1043, 947, 796, 659. HRMS (ESI) Calc. for C5H7O2+99.0441; found 99.0434. P7413PC00

[0870] Intermediate 32 (4-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-1 -one):

[0871] O

[0872] T

[0873]

[0874] BSO

[0875] The resulting oil from above containing 4-hydroxycyclopent-2-en-1-one (31) (11.087 g, assumed 111.1 mmol, 1.00 equiv.) was dissolved in anhydrous THF (57 mL) and anhydrous triethylamine (24.5 mL, 175.8 mmol, 1.58 equiv.) was added followed by DMAP (272 mg, 2.23 mmol, 0.02 equiv.). The solution was cooled to 0 °C and TBSCI (15.045 g, 105.8 mmol, 0.95 equiv.) was added portion wise. After 10 min, the ice bath was removed and the resulting mixture was stirred for 16 h. The solution was poured into aq. HCI (0.5 M, 57 mL), the phases were separated and the aqueous phase was extracted with heptane (2 x 60 mL). The organic layers were combined and washed with HCI (0.5 M, 2 x 30 mL), 5% NaHCO3h solution (30 mL) and brine (30 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo. The crude material was azeotroped twice with PhMe (2 x 100 mL) to remove TBS-OH yielding a brown oil (20.211 g). The residual oil was distilled in a Kugelrohr apparatus (2 mbar, 115 °C) yielding 4-((tert-butyldimethylsilyl)oxy)cyclopent-2-en-1-one as a light yellow oil (14.891 g, 70.12 mmol, 28% over 2 steps). Rf(4:1 Heptane / EtOAc) 0.44.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.47 (dd, J=5.7, 2.3 Hz, 1 H), 6.18 (d, J=5.7 Hz, 1 H), 4.99 (m, 1 H), 2.71 (dd, J=18.1, 6.0 Hz, 1 H), 2.25 (dd, J=18.1, 2.1 Hz, 1 H), 0.91 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 206.6, 164.0, 134.6, 71.0, 45.1, 25.9, 18.2, -4.6, -4.6. vmax(ATR) 2955, 2930, 2886, 2858, 1723, 1472, 1355, 1253, 1183, 1108, 1072, 900, 836, 778, 670. HRMS (ESI) Calc, for C11H21O2SF 213.1305; found 213.1316. The obtained data are in accordance with the literature (Curran et al, 1997).

[0876] Intermediate 33 (4-((tert-butyldimethylsilyl)oxy)-2 -chlorocyclopent-2 -en-1 -one):

[0877]

[0878] TBSO

[0879] To a solution of 4-((te / Y-butyldimethylsilyl)oxy)cyclopent-2-en-1-one (32) (1540 mg, 7.26 mmol, 1.0 equiv.) in anhydrous DCM (60 mL) was added a solution of Et4NCb (2580 mg, 10.9 mmol, 1.5 equiv.) in anhydrous DCM (10 mL) over 5 min at 0 °C. The mixture was stirred at this temperature for 30 min. Then anhydrous triethylamine (1.51 mL, 10.8 mmol, 1.5 equiv.) was added dropwise. The reaction mixture was then stirred for another 30 min at 0 °C. The reaction was quenched by addition of sat. aq. NaHCO3(30 mL). The layers were separated, and the aqueous layer extracted with Et2O (3 x 25 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a dark brown oil (1.781 g). The crude material was used directly. Rf (4:1 Heptane / EtOAc) 0.62.

[0880] 1H NMR (400 MHz, CDCl3) 6H (ppm) 7.34 (d, J=2.7 Hz, 1H), 4.95 (m, 1 H), 2.87 (dd, J=18.4, 6.1 P7413PC00

[0881] Hz, 1H), 2.37 (d, J=18.4 Hz, 1H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 197.8, 156.6, 137.4, 67.9, 44.3, 25.8, 18.2, -4.6, -4.6. vmax(ATR) 2954, 2930, 2886, 2858, 1736, 1667, 1602, 1362, 1349, 1283, 1257, 1173, 1086, 1006, 968, 950, 900, 832, 779, 669, 556. HRMS (ESI) Calc, for C11H2035CIO2Si+247.0916; found 247.0909, calc, for C11H2037CI02Si+249.0887; found 249.0891.

[0882] Intermediate 44 ((E)-tert-butyl((3-chloro-2-(prop-1-en-1-yl)-4 ((triethylsilyl)oxy)-cyclopent-3-en-1 -yl)oxy)dimethylsilane):

[0883]

[0884] Ni(acac)2(18.5 mg, 0.072 mmol, 1 mol%), neocuproine (15.4 mg, 0.074 mmol, 1 mol%) and Mn powder (795 mg, 14.5 mmol, 2.0 equiv.) were charged to a flame-dried round bottomed flask. A solution of crude 4-((te / Y-butyldimethylsilyl)oxy)-2-chlorocyclopent-2-en-1-one (33) (1781 mg, presumed 7.22 mmol, 1.0 equiv.) in anhydrous DMA (21.5 mL) was added followed by 1-bromopropene (0.62 mL, 7.22 mmol, 1 equiv.) and TESCI (2.42 mL, 14.4 mmol, 2 equiv.). The mixture was heated to 40 °C. After 3 h, the mixture was diluted with pentane (100 mL) washed with water (3 x 30 mL). The organic layer was dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to an orange oil (3.132 g). The crude material was used directly. Rf(9:1 Heptane / EtOAc) 0.79.1H NMR (400 MHz, CDCl3) 6H (ppm) 5.58 (dqd, J = 15.2, 6.5, 0.8 Hz, 1H), 5.23 (ddq, J = 15.1, 8.8, 1.6 Hz, 1H), 4.00 (dt, J = 7.2, 4.2 Hz, 1H), 3.03 (dd, J = 9.2, 3.7 Hz, 1H), 2.58 (ddd, J = 15.4, 7.2, 1.7 Hz, 1 H), 2.23 (ddd, J = 15.3, 4.4, 1.6 Hz, 1H), 1.70 (dd, J = 6.4, 1.6 Hz, 4H), 1.00 (t, J = 7.9 Hz, 9H), 0.87 (s, 9H), 0.70 (q, J = 7.8 Hz, 6H), 0.03 (s, 3H), 0.03 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 145.3, 130.5, 128.3, 107.4, 74.4, 58.2, 41.9, 25.9, 18.2, 18.1, 6.7, 5.5, -4.4, -4.7. HRMS (ESI) Calc, for C20H4035CIO2Si2+403.2250; found 403.2239, calc, for C20H4037CIO2Si2+405.2221; found 405.2214.

[0885] Intermediate 39 ((E)-4-((tert-butyldimethylsilyl)oxy)-2-chloro-3-(prop-1 -en-1 -yl)cyclopent-2-en-1 -one):

[0886]

[0887] To a solution of crude (E)-te / Y-butyl((3-chloro-2-(prop-1-en-1-yl)-4-((triethylsilyl)oxy)cyclopent-3-en-1-yl)oxy)dimethylsilane (44) (3.132 g, assumed 7.22 mmol, 1.0 equiv) in anhydrous DCM (230 mL) was added DDQ (3288 mg, 14.5 mmol, 2.0 equiv.) at rt. The solution was stirred for 18 P7413PC00

[0888] h, before sat. aq. NaHCO3(50 mL), H2O (50 mL) and Et2O (100 mL) were added. The layers were separated and the aqueous layer was extracted with Et2O (2 x 50 mL). The combined organic layers were washed with sat. aq. NaHCO3(50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered through sand and celite and concentrated in vacuo to a dark red oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 92:8) yielding (E)-4-((tert-butyldimethylsilyl)oxy)-2-chloro-3-(prop-1-en-1-yl)cyclopent-2-en-1-one as a yellow oil (683 mg, 2.38 mmol, 33% over 3 steps). Rf(9:1 Heptane / EtOAc) 0.37.1H NMR (400 MHz, CDCl3) 6H (ppm) 6.71 (dq, J = 15.9, 6.8 Hz, 1H), 6.52 (dq, J = 15.8, 0.6 Hz, 1 H), 5.10 (dd, J = 6.0, 1.6 Hz, 1 H), 2.86 (dd, J = 18.2, 6.2 Hz, 1 H), 2.40 (dd, J = 18.2, 1.9 Hz, 1 H), 1.98 (dd, J = 6.8, 1.6 Hz, 3H), 0.89 (s, 8H), 0.17 (s, 3H), 0.12 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 197.3, 162.7, 140.2, 130.4, 123.4, 68.3, 44.1, 25.8, 19.8, 18.0, -3.7, -4.8. vmax(ATR) 2954, 2930, 2858, 1720, 1640, 1581, 1471, 1253, 1084, 967, 925, 893, 832, 777. HRMS (ESI) Calc, for C14H2435ClO2Si+287.1229; found 287.1248, calc, for C14H2437ClO2Si+289.1200; found 289.1213.

[0889] Intermediate 46 (rac-(4R,5S)-4-((tert-butyldimethylsilyl)oxy)-2,5-dichloro-3-((E)-prop-1 -en-1 -yl)cyclopent-2-en-1 -one):

[0890] O

[0891]

[0892] Me

[0893] To a solution of LiHMDS (1 M in THF, 765 pL, 0.763 mmol, 1.0 equiv.) in anhydrous THF (3.8 mL) at -78 °C was added a solution of (E)-4-((te / Y-butyldimethylsilyl)oxy)-2-chloro-3-(prop-1-en-1-yl)cyclopent-2-en-1-one (39) (218.9 mg, 0.763 mmol, 1.0 equiv.) in anhydrous THF (3.0 mL) dropwise. The mixture was stirred at -78 °C for 30 min. Trifluoromethanesulfonyl chloride (89 pL, 0.84 mmol, 1.1 equiv.) was then added at -78 °C in one portion. The mixture was stirred for 15 min at -78 °C, then allowed to warm to rt. After 1 h at rt, the reaction was quenched by addition of sat. aq. NH4CI (10 mL), diluted with water (5 mL) and extracted with DCM (3x15 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo. The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 97:3) yielding rac-(4R,5S)-4-((te / Y-butyldimethylsilyl)oxy)-2,5-dichloro-3-((E)-prop-1-en-1-yl)cyclopent-2-en-1-one as a light yellow oil (180.0 mg, 0.560 mmol, 73%).

[0894] Rf(9:1 Heptane / EtOAc) 0.58.1H NMR (400 MHz, CDCl3) 6H (ppm) 6.75 (dq, J = 15.9, 6.9 Hz, 1H), 6.51 (dq, J = 15.9, 0.8 Hz, 1H), 5.01 (d, J = 1.0 Hz, 1H), 4.15 (d, J = 1.8 Hz, 1 H), 2.00 (dd, J = 6.9, 1.7 Hz, 3H), 0.90 (s, 9H), 0.24 (s, 3H), 0.24 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 190.7, 160.9, 143.3, 128.7, 122.9, 78.2, 61.2, 25.8, 19.9, 18.0, -3.6, -5.2. vmax(ATR) 2954, 2930, 2886, 2858, 1732, 1636, 1576, 1471, 1255, 1095, 964, 863, 830, 778, 737. HRMS (ESI) Calc, for C14H2335Cl2O2Si+321.0839; found 321.0845 calc, for C14H2335Cl37ClO2Si+323.0810; found 323.0816, Calc, for C14H2335Cl2O2Si+325.0781; found 325.0786. P7413PC00

[0895] Intermediate 48 (rac-(4R,5S)-2,5-dichloro-4-hydroxy-3-((E)-prop-1 -en-1 -yl)cyclopent-2-en-1-one):

[0896]

[0897] Me

[0898] To a solution of / 'ac-(4 / ?,5S)-4-((te / Y-butyldimethylsilyl)oxy)-2,5-dichloro-3-((E)-prop-1-en-1-yl)cyclopent-2-en-1-one (46) (62.0 mg, 0.193 mmol, 1.0 equiv.) in MeOH (2 mL) was added acetyl chloride (55 pL, 0.77 mmol, 4.0 equiv.) at 0 °C. The mixture was stirred at 0 °C for 15 min, after which it was heated to rt and stirred for 25 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a clear oil. The crude material was purified by AFCC (Heptane / EtOAc 95:5 —> 75:25) yielding / 'ac-(4R,5S)-2,5-dichloro-4-hydroxy-3-((E)-prop-1-en-1-yl)cyclopent-2-en-1-one as a clear oil (29.3 mg, 0.143 mmol, 73%). Rf(2:1 Heptane / EtOAc) 0.43.1H NMR (400 MHz, CDCl3) 6H (ppm) 6.95 (dq, J = 15.9, 6.9 Hz, 1H), 6.61 (dq, J = 16.0, 0.9 Hz, 1 H), 5.11 (dd, J = 6.5, 2.0 Hz, 1 H), 4.32 (d, J = 2.0 Hz, 1 H), 3.04 (d, J = 6.6 Hz, 1 H), 2.04 (dd, J = 6.9, 1.7 Hz, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 190.9, 160.1, 144.5, 128.9, 122.8, 77.3, 61.3, 20.3. HRMS (ESI) Calc, for C8H935CI2O2+206.9974; found 206.9977, Calc, for C8H935CI37CIO2+208.9945; found 208.9947, Calc, for C8H937CI2O2+210.9916; found 210.9915.

[0899] Intermediate 49 ((E)-2,4-dichloro-5-(prop-1 -en-1 -yl)cyclopent-4-ene-1,3-dione):

[0900] o

[0901]

[0902] Me

[0903] Pyridinium chlorochromate (22.6 mg, 0.105 mmol, 2.2 equiv.) and Celite (32.7 mg) were suspended in anhydrous DCM (0.5 mL) at rt. A solution of 2,5-dichloro-4-hydroxy-3-((E)-prop-1-en-1-yl)cyclopent-2-en-1-one (48) (10.0 mg, 0.048 mmol, 1.0 equiv.) in anhydrous DCM (0.5 mL) was added to the mixture. After 24 h, the solution was diluted with Et2O (15 mL) and was filtered through a pad of Celite. The pad was washed with heptane / Et2O (1:1, 20 mL) and the filtrate was concentrated in vacuo io yield (E)-2,4-dichloro-5-(prop-1-en-1-yl)cyclopent-4-ene-1,3-dione as a brown oil (9.1 mg, purity unknown). The crude material was used directly.

[0904] 1H NMR (400 MHz, CDCl3) 6H (ppm) 7.61 (dq, J = 15.9, 7.0 Hz, 1H), 6.50 (dq, J = 15.8, 1.7 Hz, 1H), 4.61 (s, 1H), 2.07 (dd, J = 7.0, 1.7 Hz, 3H). P7413PC00

[0905] Intermediate 64 (3-hexyl-4-iodo-1 -(4-methoxybenzyl)-1 H-pyrrole-2, 5-dione):

[0906] _0

[0907] JT N-PMB

[0908]

[0909] 1O

[0910] A pear-shaped flask was charged with a stirring bar and zinc chloride (2322 mg, 17.1 mmol, 2.0 equiv.) which was put under high vacuum after which the solid ZnCb was melted using a flamegun and subsequently allowed to cool to solidify, before being dissolved in THF (20 mL) and cooled to 0 °C followed by addition of hexyllithium (2.3 M in hexane, 14.8 mL, 34.2 mmol, 4.0 equiv.). The solution was allowed to heat to rt. After 1 h at rt, the white suspension was allowed to settle and the supernatant was used for both the titration (see below) and the reaction.

[0911] 3, 4-diiodo-1-(4-methoxybenzyl)-1 / 7-pyrrole-2, 5-dione (61) (4006 mg, 8.54 mmol, 1.0 equiv.) and Cui (167 mg, 0.85 mmol, 0.1 equiv.) were charged to a flask followed by addition of THF (64 mL) and HMPA (16 mL). The mixture was stirred at rt for 10 min before being cooled to -40 °C after which the prepared dihexylzinc (0.52 M, 20 mL, 10.2 mmol, 1.2 equiv.) was added dropwise over 5 min. After 2 h at -40 °C, the reaction was quenched by the addition of sat. aq. NH4CI (10 mL) and the mixture was allowed to warm to rt slowly. Then it was further diluted with Et2O (600 mL), and the organic phase was washed once with 1 M aq. HCI (150 mL) and twice with water (2 x 150 mL). The organic phase was dried over Na2SO4, filtered through sand and celite and concentrated in vacuo. The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 88:12) to isolate 3-hexyl-4-iodo-1-(4-methoxybenzyl)-1 / 7-pyrrole-2, 5-dione (1748 mg, 4.09 mmol, 48%) as a yellow oil. Titration of dihexylzinc: To a flamedried 10 mL round-bottomed flask was added iodine (253.5 mg, 1.00 mmol). A saturated solution of LiCI in THF (0.5 M, 4 mL) was added. After the iodine had completely dissolved, the brown solution was cooled to 0 °C and Hex2Zn was added dropwise until the brown color disappeared. 0.96 mL was used corresponding to a concentration of dihexylzinc of 0.52 M (Krasovskiy and Knochel, 2006). Rf (2:1 Heptane / EtOAc) 0.68.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.30 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.63 (s, 2H), 3.78 (s, 3H), 2.47 - 2.40 (m, 2H), 1.56 (p, J = 7.2 Hz, 2H), 1.40 - 1.24 (m, 6H), 0.92 - 0.83 (m, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 169.3, 166.5, 159.4, 153.6, 130.3, 128.5, 114.2, 102.5, 55.4, 42.2, 31.5, 29.3, 28.0, 27.4, 22.6, 14.2.

[0912] Intermediate 70 (3-hexyl-1 -(4-methoxybenzyl)-4-(tributylstannyl)-1 H-pyrrole-2, 5-dione):

[0913] O

[0914] If N—PMB

[0915] BujSn^"^^

[0916]

[0917] O

[0918] To a stirred solution of 3-hexyl-4-iodo-1-(4-methoxybenzyl)-1 / 7-pyrrole-2, 5-dione (64) (815 mg, 1.91 mmol, 1.0 equiv.) and tris(dibenzylideneacetone) dipalladium (87.3 mg, 0.0953 mmol, 5.0 mol%) in / PrOH (17 mL) at rt was added bis(tributyltin) (2.40 mL, 4.77 mmol, 2.5 equiv.) and P7413PC00

[0919] anhydrous A / , / V-diisopropylethylamine (830 pL, 4.77 mmol, 2.5 equiv.). After being stirred at rt for 3 h, the reaction mixture was diluted with heptane (approximately 20 mL) and concentrated in vacuo. The residue was redissolved in heptane (30 mL) and concentrated in vacuo to a black oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 92:8) yielding 3-hexyl-1-(4-methoxybenzyl)-4-(tributylstannyl)-1 / 7-pyrrole-2, 5-dione as a light-yellow oil (1066 mg, 1.81 mmol, 95%). Rf(4:1 Heptane / EtOAc).1H NMR (400 MHz, CDCl3) 6H (ppm) 7.28 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.7 Hz, 2H), 4.56 (s, 2H), 3.77 (s, 3H), 2.43 - 2.34 (m, 2H), 1.53 - 1.44 (m, 8H), 1.37 - 1.24 (m, 14H), 1.15 - 1.08 (m, 4H), 0.88 (t, J = 7.3 Hz, 12H).13C NMR (101 MHz, CDCl3) 6c (ppm) 175.6, 171.8, 159.3, 159.1, 145.0, 130.0, 129.4, 114.0, 55.4, 41.3, 31.7, 30.0, 29.7, 29.2, 27.9, 27.4, 22.7, 14.2, 13.8, 10.6.

[0920] Intermediate 71 (3-(cyclopentanecarbonyl)-4-hexyl-1-(4-methoxybenzyl)-1H-pyrrole-2,5-dione):

[0921] -PMB

[0922]

[0923] A flask was charged with CuDPP (17.0 mg, 0.0524 mmol, 2.0 equiv.), PdCb(PPh3)2 (4.0 mg, 0.0052 mmol, 0.20 equiv.), tri-2-furylphoshine (2.7 mg, 0.010 mmol, 0.40 equiv.) and lastly S-(p-tolyl) cyclopentanecarbothioate (5.6 mg, 0.026 mmol, 1.0 equiv.) followed by addition of 3:1 n-hexane / THF (0.5 mL) at rt. After 30 min at rt, 3-hexyl-1-(4-methoxybenzyl)-4-(tributylstannyl)-1 / 7-pyrrole-2, 5-dione (70) (42.9 mg, 0.0776 mmol, 3.0 equiv.) was dissolved in 3:1 n-hexane / THF (0.5 mL) and added to the suspension. The setup was sealed and heated to 60 °. After 2 h at 60 °C, the reaction mixture was diluted with heptane (2 mL) and filtered through a pad of celite. The resulting homogeneous yellow solution was concentrated in vacuo and directly subjected to purification by AFCC (Heptane / EtOAc 100:0 —> 80:20) yielding 3-(cyclopentanecarbonyl)-4-hexyl-1-(4-methoxybenzyl)-1 H-pyrrole-2, 5-dione (4.2 mg, 0.011 mmol, 41%). Rf(4:1 Heptane / EtOAc) 0.52.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.30 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 4.61 (s, 2H), 3.78 (s, 3H), 3.70 (tt, J = 8.6, 6.9 Hz, 1 H), 2.70 -2.63 (m, 2H), 1.90 - 1.80 (m, 2H), 1.80 - 1.70 (m, 2H), 1.67 - 1.57 (m, 4H), 1.56 - 1.46 (m, 2H), 1.40 - 1.22 (m, 6H), 0.87 (t, J = 5.7 Hz, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 199.6, 169.8, 169.0, 159.3, 153.6, 132.9, 130.0, 128.3, 114.1, 55.3, 50.9, 41.3, 31.4, 29.5, 28.7, 28.7, 26.1, 24.8, 22.5, 14.0. P7413PC00

[0924] Intermediates 81 and 82:

[0925]

[0926] Me

[0927] To a flamedried reaction tube containing 3-(cyclopentanecarbonyl)-4-hexyl-1-(4-methoxybenzyl)-1 / 7-pyrrole-2, 5-dione (71) (5.0 mg, 0.013 mmol, 1.0 equiv.) was added Na2CO3(1.9 mg, 0.018 mmol, 1.4 equiv.) followed by a solution of crude (E)-2,4-dichloro-5-(prop-1-en-1-yl)cyclopent-4-ene-1,3-dione (49) (approximately 4 mg, 0.020 mmol, 1.6 equiv.) in anhydrous THF (1 mL). The mixture was stirred at room temperature. After 20 min, the mixture was filtered through cotton and concentrated in vacuo to a brown oil (10.6 mg) The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 90:10) yielding a mixture of the two diastereoisomers as a light-yellow oil (approximately 4.0 mg, 0.0071 mmol, 56%). Rf (4:1 Heptane / EtOAc) 0.51.1H NMR (400 MHz, C6D6) 6H (ppm) 7.44 (2 xd, 4H), 7.24 (dq, 1 H), 7.09 (dq, 1 H), 6.70 (2 x d, 4H), 6.08 (dq, 1 H), 5.96 (dq, 1 H), 4.85 (s, 3H), 4.81 (s, 3H), 3.20 (s, 2H), 3.20 (s, 2H), 2.98 (p, 2H), 2.40 - 2.22 (m, 4H), 2.16 - 2.00 (m, 4H), 1.89 - 1.75 (m, 4H), 1.73 -1.62 (m, 2H), 1.53 - 1.37 (m, 6H), 1.34 (2 x dd, 6H), 1.29 - 1.09 (m, 16H), 0.84 - 0.76 (2 x t, 6H). Note: Number of protons should total 72 as both diastereomers are reported as each proton being equal to 1 even though the diastereomeric ratio is approx. 0.7:1. Coupling constants are not reported due to small amount of compound and overlap of signals. HRMS (ESI) Calc, for C32H3735ClNO6+566.2304; found 566.2315, calc, for C32H3737ClNO6+568.2275; found 568.2298.

[0928] rac-TTP652a and rac-TTP652b:

[0929]

[0930] To a solution of the mixture of 81 and 82 (approximately 4 mg in total, 0.0071 mmol, 1.0 equiv.) in MeCN (0.5 mL) at 0 °C was added a solution of Ce(NH4)2(NO3)6(12.7 mg, 0.0224 mmol, 3.2 equiv.) in MeCN / H2O (4:1, 0.5 mL). The solution was stirred at 0 °C for 1 h, and then allowed to warm to room temperature. After a total of 4 h, the temperature was increased to 50 °C (during the next hour the solution lost its vibrant yellow color and became opaque pale yellow). After a P7413PC00

[0931] total of 5 h, another portion of CAN (17.3 mg, 0.0316 mmol, 4.5 equiv.) was added. After a total of 7.5 h, the mixture was diluted with EtOAc (15 mL) and half saturated aq. NaCI (15 mL). The phases were separated, and the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a clear oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 —> 80:20) to yield the two diastereomers as clear films.

[0932] rac-TTP652a (Isomer 1: elutes first from column):

[0933] Me, Me

[0934] , CI

[0935]

[0936] Rf(4:1 Heptane / EtOAc) 0.27.

[0937] 1H NMR (400 MHz, C6D6) 6H (ppm): 7.52 (dq, J = 16.1, 7.0 Hz, 1H), 6.49 (dq, J= 15.8, 1.8 Hz, 1H), 3.03 (p, J= 8.0 Hz, 1H), 2.14 (td, J= 10.8, 4.9 Hz, 2H), 2.05 (dd, J= 7.0, 1.7 Hz, 3H), 2.00 - 1.76 (m, 4H), 1.76 - 1.63 (m, 2H), 1.63 - 1.52 (m, 2H), 1.39 - 1.13 (m, 8H), 0.86 (t, J = 6.8 Hz, 3H).

[0938] 1H NMR (400 MHz, CDCl3) 6H (ppm): 7.80 (s, 1H), 7.50 (dq, J= 15.9, 7.0 Hz, 1H), 6.48 (dq, J = 15.9, 1.6 Hz, 1H), 3.03 (p, J= 8.0 Hz, 1H), 2.21 -2.08 (m, 2H), 2.05 (dd, J= 7.0, 1.7 Hz, 3H), 1.97 - 1.76 (m, 4H), 1.76 - 1.63 (m, 3H), 1.59 - 1.53 (m, 2H), 1.36 - 1.15 (m, 7H), 0.86 (t, J = 6.8 Hz, 3H).

[0939] 13C NMR (101 MHz, CDCl3) 6c (ppm): 199.7, 189.9, 187.4, 170.3, 167.0, 148.2, 148.1, 146.4, 119.2, 55.0, 52.9, 50.2, 46.2, 31.4, 30.8, 29.5, 29.5, 27.5, 26.2, 25.9, 22.6, 22.2, 21.0, 14.1. Vmax (ATR) 2955, 2930, 1789, 1709, 1631, 1563, 1338, 1312, 1210, 1210, 1210, 1083, 969 cm'

[0940] HRMS (ESI+) Calc, for C24H2935CINO5+446.1729; found 446.1735, calc, for C24H2937CINO5+448.1700; found 448.1712.

[0941] rac-TTP652b (Isomer 2: elutes second from column): P7413PC00

[0942] Me Me

[0943]

[0944] Rf(4:1 Heptane / EtOAc) 0.24.

[0945] 1H NMR (400 MHz, C6D6) 6H (ppm): 7.50 (dq, J= 15.8, 6.9 Hz, 1H), 6.48 (dq, J= 15.9, 1.8 Hz, 1H), 3.02 (p, J= 7.9 Hz, 1H), 2.14 (td, J= 11.7, 4.7 Hz, 2H), 2.04 (dd, J= 7.0, 1.7 Hz, 3H), 1.96 - 1.75 (m, 4H), 1.75 - 1.62 (m, 2H), 1.61 - 1.52 (m, 2H), 1.36 - 1.18 (m, 8H), 0.86 (t, J = 6.6 Hz, 3H).

[0946] 1H NMR (400 MHz, CDCl3) 6H (ppm): 7.74 (s, 1H), 7.50 (dq, J= 15.9, 7.0 Hz, 1H), 6.48 (dq, J = 15.9, 1.6 Hz, 1H), 3.01 (p, J= 8.0 Hz, 1H), 2.22 -2.06 (m, 2H), 2.04 (dd, J= 7.0, 1.7 Hz, 3H), 1.95 - 1.75 (m, 4H), 1.75 - 1.62 (m, 3H), 1.59 - 1.50 (m, 2H), 1.37 - 1.16 (m, 7H), 0.86 (t, J = 6.6 Hz, 3H).

[0947] 13C NMR (101 MHz, CDCl3) 6c (ppm): 199.4, 191.5, 185.9, 170.5, 167.2, 149.1, 148.5, 145.6, 119.3, 54.9, 52.9, 50.1, 46.4, 31.5, 30.6, 29.5, 29.4, 27.3, 26.2, 25.8, 22.6, 22.3, 21.1, 14.1. Vmax (ATR) 2955, 2930, 1788, 1709, 1631, 1561, 1338, 1308, 1216, 1115, 969 cm1.

[0948] HRMS (ESI) Calc, for C24H2935ClNO5+446.1729; found 446.1737, calc, for C24H2937ClNO5+448.1700; found 448.1716. P7413PC00

[0949] Exemplification 3: GW2361, GW2366a, GW2366b, GW2365a, GW2374, GW2377a, GW2377b, GW2387a, GW2387b, GW2486a, GW2486b, TTP652a, TTP652b, TTP806a, TTP806b, TTP814a, TTP814b, TTP821a, TTP821b, and TTP757a

[0950] The compounds TTP806a, TTP806b, TTP814a, TTP814b, TTP821a and TTP821b were obtained in an analogous way to TTP652a and TTP652b. The required cyclopent-4-ene-1,3-diones analogous to intermediate 49 were obtained by the following procedures. The intermediates 84, 86 and 87 were elaborated to the required cyclopent-4-ene-1,3-diones by the same sequence as 39 -> 49.

[0951] Intermediate 83 (Z)-2-bromo-4-((tert-butyldimethylsilyl)oxy)-3-(prop-1 -en-1 -yl)cyclopent-2-en-1 -one:

[0952]

[0953] To a solution of CuBr. SMe2 (4237 mg, 20.6 mmol, 2.00 equiv.) in anhydrous THF (5 mL) at -78 °C was added 1 -propenylmagnesium bromide dropwise (0.5 M in THF, 82.5 mL, 41.2 mmol, 4.00 equiv.). The mixture was stirred for 30 min at -78 °C, before TMEDA (6.2 mL, 41.2 mmol, 4.00 equiv.) and TMSCI (6.6 mL, 51.5 mmol. 5.00 equiv.) were added followed by dropwise addition of a solution of known compound 2-bromo-4-((te / Y-butyldimethylsilyl)oxy)cyclopent-2-en-1-one (3001 mg, 10.30 mmol, 1.00 equiv.) in anhydrous THF (10 mL). The mixture was stirred at -78 °C for 15 min, then allowed to warm to room temperature. After 1 h at rt, the solution was diluted with pentane (400 mL) and the organic phase was washed with water (5x100mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a greenish opaque oil.

[0954] To a solution of the crude silyl enol ether in anhydrous CH2CI2 (100 mL) at rt was added DDQ (4677 mg, 20.6 mmol, 2.00 equiv.). After 17 h at rt, sat. aq. NaHCO3h (200 mL) was added. The layers were separated and aqueous layer was extracted with Et2O (3x75 mL). The combined organic layers were washed with sat. aq. NaHCO3h (150 mL) and brine (150 mL), dried over anhydrous Na2SO4, filtered through sand and celite and concentrated in vacuo to a dark red oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 -> 92:8) yielding the title compound as a yellow oil (2411 mg, 7.277 mmol, 71% over 2 steps).

[0955] Rf(9:1 Heptane / EtOAc) 0.32.1H NMR (400 MHz, CDCl3) 6H (ppm) 6.14 -6.01 (m, 2H), 4.96 (dd, J= 6.1, 2.0 Hz, 1H), 2.91 (dd, J= 18.2, 6.1 Hz, 1H), 2.46 (dd, J= 18.2, 2.0 Hz, 1H), 1.84 - 1.79 (m, 3H), 0.88 (s, 11 H), 0.11 (s, 3H), 0.09 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 197.9, 169.4, 135.3, 125.1, 122.5, 71.8, 44.1, 32.0, 25.8, 18.2, 17.1, -4.2, -4.6. vmax(ATR) 2954, 2929, P7413PC00

[0956] 2886, 2857, 1724, 1642, 1603, 1252, 1091, 1007, 904, 833, 777 cm1. HRMS (ESI) Calc, for C14H2479BrO2Si+331.0723; found 331.0732, calc, for C14H2481BrO2Si+333.0703; found 333.0714.

[0957] Intermediate 84 (E)-2-bromo-4-((tert-butyldimethylsilyl)oxy)-3-(prop-1 -en-1 -yl)cyclopent-2-en-1 -one:

[0958]

[0959] To a solution of (Z)-2-bromo-4-((te / Y-butyldimethylsilyl)oxy)-3-(prop-1-en-1-yl)cyclopent-2-en-1-one (83) (2411 mg, 7.277 mmol, 1.00 equiv.) in anhydrous CH2CI2(73 mL) at rt was added iodine (93.3 mg, 0.368 mmol, 0.05 equiv.) The mixture was stirred for 1.5 h at rt. The mixture was then washed with 10 w / w% aq. Na2S2O3(20 mL) and the organic layer was dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a yellow oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 -> 92:8) yielding the title compound as a yellow oil (2366 mg, 7.141 mmol, 98%).

[0960] Rf(9:1 Heptane / EtOAc) 0.28.1H NMR (400 MHz, CDCl3) 6H (ppm) 6.73 (dq, J = 15.9, 6.8 Hz, 1H), 6.53 (dq, J = 15.9, 0.8 Hz, 1H), 2.88 (dd, J= 18.2, 6.2 Hz, 1H), 2.43 (dd, J = 18.1, 1.9 Hz, 1H), 1.97 (dd, J = 6.9, 1.6 Hz, 3H), 0.88 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 197.8, 166.1, 141.3, 124.9, 122.7, 69.6, 44.1, 25.8, 19.8, 18.0, -3.7, -4.8. vmax(ATR) 2955, 2930, 2886, 2857, 1716, 1639, 1576, 1472, 1274, 1254, 1083, 966, 883, 837, 776 cm1. HRMS (ESI) Calc, for C14H2479BrO2Si+331.0723; found 331.0734, calc, for C14H2481BrO2Si+333.0703; found 333.0717.

[0961] Intermediate 85 (Z)-2-iodo-4-((tert-butyldimethylsilyl)oxy)-3-(prop-1 -en-1 -yl)cyclopent-2-en-1 -one:

[0962]

[0963] To a solution of CuBr. SMe2(4234 mg, 20.6 mmol, 2.00 equiv.) in anhydrous THF (5 mL) at -78 °C was added 1 -propenylmagnesium bromide dropwise (0.5 M in THF, 82.5 mL, 41.2 mmol, 4.00 equiv.). The mixture was stirred for 30 min at -78 °C, before TMEDA (6.2 mL, 41.2 mmol, 4.00 equiv.) and TMSCI (6.6 mL, 51.5 mmol, 5.00 equiv.) were added followed by dropwise addition of known compound 2-iodo-4-((te / Y-butyldimethylsilyl)oxy)cyclopent-2-en-1-one (3486 mg, 10.30 mmol, 1.00 equiv.) in anhydrous THF (10 mL). The mixture was stirred at -78 °C for 15 min, then allowed to warm to room temperature. After 1 h at rt, the solution was diluted with P7413PC00

[0964] pentane (400 mL) and the organic phase was washed with water (5x100mL), dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a yellow opaque oil. To a solution of the crude silyl enol ether in anhydrous CH2CI2 (100 mL) at rt was added DDQ (4683 mg, 20.6 mmol, 2.00 equiv.). After 17 h at rt, sat. aq. NaHCO3h (200 mL) was added. The layers were separated and aqueous layer was extracted with Et2O (3x75 mL). The combined organic layers were washed with sat. aq. NaHCO3h (150 mL) and brine (150 mL), dried over anhydrous Na2SO4, filtered through sand and celite and concentrated in vacuo to a dark red oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 -> 92:8) yielding the title compound as a yellow oil (2873 mg, 7.594 mmol, 74% over 2 steps).

[0965] Rf(9:1 Heptane / EtOAc) 0.37.1H NMR (400 MHz, CDCl3) 6H (ppm) 6.12 (dq, J = 11.8, 1.3 Hz, 1 H), 6.03 (dq, J = 11.8, 6.8 Hz, 1 H), 5.01 (ddd, J = 6.1, 2.1, 0.9 Hz, 1 H), 2.95 (dd, J = 18.1, 6.2 Hz, 1H), 2.49 (dd, J = 18.1, 2.1 Hz, 1H), 1.83 (dd, J= 6.9, 1.4 Hz, 3H), 0.88 (s, 11 H), 0.10 (s, 3H), 0.09 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 199.7, 176.3, 134.3, 124.8, 105.9, 73.6, 43.4, 25.8, 18.2, 17.1, -4.2, -4.6. vmax(ATR) 2953, 2929, 2885, 2856, 1716, 1638, 1590, 1471, 1252, 1169, 1089, 1006, 890, 831, 776 cm1. HRMS (ESI) Calc, for C14H24IO2Si+ 379.0585; found 379.0584.

[0966] Intermediate 86 (E)-2-bromo-4-((tert-butyldimethylsilyl)oxy)-3-(prop-1 -en-1 -yl)cyclopent-2-en-1 -one:

[0967]

[0968] To a solution of (Z)-2-iodo-4-((te / Y-butyldimethylsilyl)oxy)-3-(prop-1 -en-1 -yl)cyclopent-2-en-1 -one (85) (2873 mg, 7.594 mmol, 1.00 equiv.) in anhydrous CH2CI2 (76 mL) at rt was added iodine (96.4 mg, 0.380 mmol, 0.05 equiv.) The mixture was stirred for 1.5 h at rt. The mixture was then washed with 10 w / w% aq. Na2S2Os (20 mL) and the organic layer was dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a yellow oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 -> 92:8) yielding the title compound as a yellow oil (2781 mg, 7.351 mmol, 97%).

[0969] Rf(9:1 Heptane / EtOAc) 0.31.1H NMR (400 MHz, CDCl3) 6H (ppm) 6.72 (dq, J = 15.9, 6.8 Hz, 1H), 6.50 (dq, J = 15.9, 1.0 Hz, 1H), 5.16 (dd, J= 6.4, 1.9 Hz, 1H), 2.92 (dd, J= 18.1, 6.3 Hz, 1H), 2.47 (dd, J = 18.1, 2.0 Hz, 1H), 1.98 (dd, J= 6.9, 1.6 Hz, 3H), 0.88 (s, 9H), 0.16 (s, 3H), 0.11 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm) 199.7, 171.9, 141.7, 127.8, 103.5, 71.2, 43.7, 25.8, 19.7, 18.0, -3.7, -4.7. vmax(ATR) 2954, 2929, 2885, 2857, 1709, 1637, 1562, 1472, 1254, 1180, 1082, 964, 875, 837, 806, 776 cm1. HRMS (ESI) Calc, for C14H24IO2Si+ 379.0585; found 379.0587. P7413PC00

[0970] Intermediate 874-((tert-butyldimethylsilyl)oxy)-2-chloro-3-propylcyclopent-2-en-1 -one:

[0971]

[0972] Me

[0973] (E)-4-((te / Y-butyldimethylsilyl)oxy)-2-chloro-3-(prop-1 -en-1 -yl)cyclopent-2-en-1 -one (39) (600 mg, 2.09 mmol, 1.00 equiv.) was charged to a flamedried flask flushed with argon followed by anhydrous EtOAc (20 mL). The solution was stirred for 5 min before Pd / C (10 wt% Pd, 248 mg, 0.209 mmol, 0.1 equiv.) was added under argon atmosphere. Then the argon atmosphere was then exchanged for a H2 atmosphere and the reaction was for stirred for 2 hours. The atmosphere was then exchanged for argon again and the resulting mixture was filtered through sand and celite and concentrated in vacuo to a yellow oil. The crude material was purified by AFCC (Heptane / EtOAc 100:0 -> 92:8) yielding the title compound as a light yellow oil (505.4 mg, 1.749 mmol, 84%).

[0974] Rf(9:1 Heptane / EtOAc) 0.49.1H NMR (400 MHz, CDCl3) 6H (ppm) 4.82 (dd, J = 5.9, 2.0 Hz, 1H), 2.83 (dd, J = 18.0, 6.0 Hz, 1H), 2.50 (t, J = 7.8 Hz, 2H), 2.33 (dd, J = 18.1, 2.1 Hz, 1 H), 1.70 - 1.49 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H), 0.89 (s, 9H), 0.13 (s, 3H), 0.10 (s, 3H).13C NMR (101 MHz, CDCl3) 6c (ppm)13C NMR (101 MHz, CDCl3) 6 197.2, 172.4, 133.0, 69.3, 44.3, 29.9, 25.7, 20.3, 18.1, 14.4, -4.4, -5.0. Vmax (ATR) 2957, 2931, 2858, 1727, 1627, 1472, 1464, 1347, 1253, 1079, 970, 917, 836, 827, 775, 669 cm1. HRMS (ESI) Calc, for Ci4H2635CIO2Si+289.1385; found 289.1385, calc, for Ci4H2637CIO2Si+291.1359; found 291.1356.

[0975] TTP806a - Racemic, pure diastereoisomer:

[0976] Me Me

[0977]

[0978] TTP806a (Isomer 1: elutes first from column):

[0979] Rf (2:1 Heptane / EtOAc) 0.38.

[0980] 1H NMR (400 MHz, CDCl3) 6H (ppm): 7.66 (s, 1 H), 7.52 (d, J= 1.6 Hz, 1H), 7.43 (dq, J = 15.8, 7.0 Hz, 1H), 7.31 (d, J= 3.7 Hz, 1H), 6.58 (dd, J = 3.7, 1.7 Hz, 1 H), 6.46 (dq, J = 15.7, 1.6 Hz, 1H), 2.21 - 2.02 (m, 2H), 1.99 (dd, J = 7.0, 1.7 Hz, 3H), 1.97 - 1.88 (m, 1H), 1.32 - 1.17 (m, 7H), 0.85 (t, J = 6.5 Hz, 3H). P7413PC00

[0981] HRMS (ESI) Calc, for C23H2379BrNO6+488.0704; found 488.0712, calc, for C23H2281BrNO6+490.0683; found 490.0695.

[0982] TTP806b - Racemic, pure diastereoisomer:

[0983] Me Me

[0984]

[0985] TTP806b (Isomer 2: elutes second from column):

[0986] Rf (2:1 Heptane / EtOAc) 0.36.

[0987] 1H NMR (400 MHz, CDCl3) 6H (ppm): 7.60 (s, 1H), 7.59 (dq, J= 15.8, 7.0 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.30 (d, J= 3.7 Hz, 1H), 6.58 (dd, J= 3.7, 1.7 Hz, 1H), 6.51 (dq, J= 15.8, 1.8 Hz, 1H), 2.22 -2.07 (m, 2H), 2.05 (dd, J= 7.0, 1.7 Hz, 3H), 1.99 - 1.87 (m, 1H), 1.31 - 1.17 (m, 7H), 0.88 - 0.82 (m, 3H).

[0988] HRMS (ESI) Calc, for C23H2379BrNO6+488.0704; found 488.0702, calc, for C23H2281BrNO6+490.0683; found 490.0685.

[0989] TTP814a - Racemic, pure diastereoisomer:

[0990] Me Me

[0991]

[0992] TTP814a (Isomer 1: elutes first from column):

[0993] Rf(4:1 Heptane / EtOAc) 0.18.

[0994] 1H NMR (400 MHz, CDCl3) 6H (ppm): 8.13 (s, 1H), 7.53 (d, J= 2.1 Hz, 1H), 7.31 (d, J= 3.7 Hz, 1 H), 6.58 (dd, J = 3.7, 1.7 Hz, 1 H), 2.53 (t, J = 7.6 Hz, 2H), 2.21 - 2.01 (m, 2H), 2.01 - 1.87 (m, 1H), 1.52 (h, J = 7.5 Hz, 2H), 1.33 - 1.19 (m, 6H), 1.19- 1.06 (m, 1H), 0.93 (t, J= 7.4 Hz, 3H), 0.84 (t, J = 6.8 Hz, 3H).

[0995] 13C NMR (101 MHz, CDCl3) 6c (ppm): 190.1, 187.8, 173.9, 170.6, 166.8, 159.3, 152.1, 151.9, 147.7, 119.6, 113.6, 52.2, 49.8, 45.1, 31.4, 29.5, 27.4, 26.7, 22.6, 22.3, 20.5, 14.1, 14.1. P7413PC00

[0996] Vmax (ATR) 3272, 2961, 2932, 2872, 1790, 1711, 1675, 1569, 1463, 1343, 1290, 1213, 1106, 1067, 1016, 766 cm1.

[0997] HRMS (ESI) Calc, for C23H2535CINO6+446.1365; found 446.1378, calc, for C23H2537CINO6+448.1336; found 448.1352.

[0998] TTP814b - Racemic, pure diastereoisomer:

[0999] Me Me

[1000]

[1001] TTP814b (Isomer 2: elutes second from column):

[1002] Rf(4:1 Heptane / EtOAc) 0.14.

[1003] 1H NMR (400 MHz, CDCl3) 6H (ppm): 8.09 (s, 1 H), 7.50 (d, J= 1.7 Hz, 1H), 7.32 (d, J= 3.7 Hz, 1 H), 6.59 (dd, J = 3.7, 1.7 Hz, 1 H), 2.63 (t, J = 7.4 Hz, 2H), 2.22 - 2.02 (m, 2H), 1.98 - 1.83 (m, 1 H), 1.67 (h, J = 7.4 Hz, 2H), 1.33 - 1.15 (m, 7H), 0.99 (t, J = 7.4 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H).

[1004] 13C NMR (101 MHz, CDCl3) 6c (ppm): 191.9, 186.0, 173.8, 170.7, 167.0, 160.1, 152.1, 151.5, 147.7, 119.6, 113.7, 52.1, 49.6, 45.3, 31.4, 29.4, 27.1, 26.9, 22.6, 22.1, 20.6, 14.1 (2C).

[1005] Vmax (ATR) 3278, 2960, 2931, 1872, 1790, 1709, 1673, 1609, 1568, 1462, 1609, 1568, 1462, 1341, 1287, 1211, 1112, 1016, 764, 731 cm1.

[1006] HRMS (ESI) Calc, for C23H2535CINO6+446.1365; found 446.1375, calc, for C23H2537CINO6+448.1336; found 448.1348.

[1007] TTP821a - Racemic, pure diastereoisomer:

[1008]

[1009] TTP821a (Isomer 1: elutes first from column): P7413PC00

[1010] Rf(2:1 Heptane / EtOAc) 0.45.

[1011] 1H NMR (400 MHz, CDCl3) 6H (ppm): 8.02 (s, 1H), 7.52 (d, J= 1.8 Hz, 1H), 7.41 (dq, J= 15.7, 7.0 Hz, 1H), 7.29 (d, J= 3.7 Hz, 1H), 6.57 (dd, J= 3.7, 1.7 Hz, 1H), 6.40 (dq, J= 15.8, 1.6 Hz, 1H), 2.21 -2.02 (m, 2H), 1.98 (dd, J= 7.0, 1.7 Hz, 3H), 1.96 - 1.87 (m, 1H), 1.32 - 1.17 (m, 7H), 0.84 (t, J = 6.6 Hz, 3H).

[1012] 13C NMR (101 MHz, CDCl3) 6c (ppm): 189.9, 189.4, 174.2, 170.6, 166.9, 157.5, 152.1, 148.9, 147.8, 124.0, 122.5, 119.6, 113.5, 52.4, 50.1, 46.5, 31.4, 29.5, 27.3, 22.6, 22.2, 20.9, 14.1. Vmax (ATR) 3278, 2929, 2858, 1789, 1721, 1703, 1672, 1627, 1568, 1538, 1462, 1301, 1203, 1107, 1021, 768, 732 cm1.

[1013] HRMS (ESI) Calc, for C23H23INC 536.0565; found 536.0571.

[1014] TTP821b - Racemic, pure diastereoisomer:

[1015] Me Me

[1016]

[1017] TTP821b (Isomer 2: elutes second from column):

[1018] Rf(2:1 Heptane / EtOAc) 0.43.

[1019] 1H NMR (400 MHz, CDCl3) 6H (ppm): 7.93 (s, 1H), 7.59 (dq, J= 15.8, 7.0 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.29 (d, J= 3.7 Hz, 1H), 6.57 (dd, J= 3.7, 1.7 Hz, 1H), 6.45 (dq, J= 15.8, 1.6 Hz, 1H), 2.23 -2.06 (m, 2H), 2.04 (dd, J= 7.0, 1.7 Hz, 3H), 1.96 - 1.85 (m, 1H), 1.32 - 1.14 (m, 7H), 0.90 - 0.80 (m, 3H).

[1020] 13C NMR (101 MHz, CDCl3) 6c (ppm): 191.9, 187.9, 174.0, 170.8, 167.2, 158.2, 152.1, 149.2, 147.7, 124.1, 121.8, 119.6, 113.5, 52.0, 49.8, 46.7, 31.4, 29.5, 27.1, 22.6, 22.4, 21.0, 14.2. Vmax (ATR) 3276, 2931, 1788, 1703, 1672, 1628, 1568, 1537, 1462, 1339, 1298, 1208, 1109, 1017, 967, 767, 731 cm1.

[1021] HRMS (ESI) Calc, for C23H23lNO6+536.0565; found 536.0571. P7413PC00

[1022]

[1023] Intermediate 883-iodo-4-(6-(trimethylsilyl)hex-5-yn-1 -y I )-1 H-pyrrole-2, 5-dione:

[1024] O

[1025]

[1026] To a solution of the known compound (6-iodohex-1-yn-1-yl)trimethylsilane (60, 3358 mg, 12 mmol, 2.4 equiv.) in a mixture of anhydrous pentane and anhydrous diethyl ether (3:2, 50 mL) was added te / Y-butyllithium (1.7 M in pentane, 14 mL, 24 mmol, 4.8 equiv.) dropwise at -78 °C. The mixture was stirred at this temperature for 90 min. ZnCh (1.0 M in THF, 15 mL, 15 mmol, 3.0 equiv.) was then added at -78 °C and the mixture was allowed to slowly warm to rt. After 45 min at rt, the reaction mixture was heated to 45 °C followed by addition of known compound 3, 4-diiodo-1 / 7-pyrrole-2, 5-dione (1739 mg, 5.0 mmol, 1.0 equiv.) dissolved in anhydrous THF (3x10 mL). After 2.5 h at 45 °C, the reaction was cooled to 0 °C followed by dropwise addition of sat. aq. NH4CI (15 mL). The resulting solution was further diluted with water (35 mL), the layers were separated and the aqueous layer was extracted with diethyl ether (3x50 mL) and the combined organics were dried over Na2SO4, filtered through sand and celite and concentrated in vacuo. The resulting orange solid was triturated with CH2CI2 (5x10 mL) and the combined CH2CI2 layers were concentrated in vacuo to a mixture of yellow solid and oil). The crude material was purified by AFCC (Heptane / EtOAc 100:0 -> 85:15) yielding the title compound as a yellow solid (222.9 mg, 0.594 mmol, 12%). P7413PC00

[1027] Rf(4:1 Heptane / EtOAc) 0.37.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.59 (s, 1H), 2.53 - 2.42 (m, 2H), 2.28 (t, J = 6.9 Hz, 2H), 1.76 - 1.67 (m, 2H), 1.65 - 1.53 (m, 2H), 0.14 (s, 9H).13C NMR (101 MHz, CDCl3) 6c (ppm) 169.1, 166.1, 154.1, 106.5, 103.9, 85.4, 28.3, 27.4, 26.5, 19.6, 0.3. vmax(ATR) 3247, 2956, 2172, 1781, 1761, 1730, 1700, 1329, 1249, 840 cm1. HRMS (ESI) Calc, for Ci3Hi9lO2Si+376.0224; found 376.0228.

[1028] Intermediate 893-iodo-1 -(4-methoxybenzyl)-4-(6-(trimethylsilyl)hex-5-yn-1 -y I )-1 H-pyrrole-2, 5-dione:

[1029]

[1030] TMS

[1031] To a suspension of 3-iodo-4-(6-(trimethylsilyl)hex-5-yn-1-yl)-1 / 7-pyrrole-2, 5-dione (88, 184.3 mg, 0.491 mmol, 1.00 equiv.) and K2CO3 (83.7 mg, 0.606 mmol, 1.2 equiv.) in acetone (5 mL) was added 4-methoxybenzyl chloride (145 uL, 155 mg, 0.993 mmol, 2.00 equiv.). The reaction mixture was heated to 50 °C.

[1032] After 16 hours the reaction was allowed to cool to rt before sat. aq. NH4CI (1 mL) was added. The mixture was diluted with water (30 mL) and extracted with EtOAc (3x30 mL). The combined organic phases were dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to an orange oil. The crude material was purified by AFCC (heptane / EtOAc 100:0 -> 88:12) yielding the title compound as a yellow oil (131.2 mg, 0.265 mmol, 53%).

[1033] Rf(4:1 Heptane / EtOAc) 0.51.1H NMR (400 MHz, CDCl3) 6H (ppm) 7.30 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.63 (s, 2H), 3.78 (s, 3H), 2.46 (t, J = 7.6 Hz, 2H), 2.26 (t, J = 6.9 Hz, 2H), 1.74 - 1.62 (m, 2H), 1.62 - 1.51 (m, 2H), 0.14 (s, 9H).13C NMR (101 MHz, CDCl3) 6c (ppm) 169.2, 166.4, 159.4, 153.0, 130.3, 128.4, 114.2, 106.6, 103.0, 85.2, 55.4, 42.2, 28.4, 27.5, 26.5, 19.6, 0.3. Vmax (ATR) 2954, 2172, 1774, 1707, 1613, 1513, 1432, 1394, 1344, 1247, 1177, 1035, 840, 760 cm1. HRMS (ESI) Calc, for C2iH27lO3Si+496.0799; found 496.0799.

[1034] Intermediate 89 was elaborated to intermediate 90 using the same sequence as 64 -> 81 / 82

[1035] TTP757a - Racemic, pure diastereoisomer:

[1036]

[1037] P7413PC00

[1038] To a solution of 90 (4.9 mg, 0.0095 mmol, 1.0 equiv.) in 7:4:1 mixture of CH2Cl2 / acetone / H20 (0.96 mL) was added one crystal of AgNCh at rt. After 19 h, another portion of AgNCh (5.0 mg, 0.029 mmol, 3.1 equiv.) was added. After a total of 43 h, the reaction was quenched by addition of sat. aq. NH4CI (1 mL). Water (15 mL) and CH2CI2 (15 mL) were added. The layers were separated and the aqueous layer was extracted with CH2CI2 (2x15 mL). The combined organic layers were dried over Na2SO4, filtered through sand and celite and concentrated in vacuo to a light-yellow film. The crude material was purified by AFCC (Heptane / EtOAc 100:0 -> 85:15) yielding the title compound as a white film (1.08 mg, 0.0024 mmol, 26%).

[1039] Rf (2:1 Heptane / EtOAc) 0.55

[1040] 1H NMR (400 MHz, CDCl3) 6H (ppm): 7.55 (s, 1H), 7.51 (dq, J= 15.7, 7.0 Hz) 1H), 6.49 (dq, J = 15.9, 1.7 Hz, 1H), 3.04 (p, J = 7.9 Hz, 1H), 2.24 - 2.13 (m, 4H), 2.05 (dd, J = 7.0, 1.7 Hz, 3H), 1.90 (t, J = 2.6 Hz, 1 H), 1.74 - 1.62 (m, 4H), 1.62 - 1.45 (m, 6H), 1.40 - 1.27 (m, 2H).

[1041] HRMS (ESI) Calc, for C24H2535CINO5+442.1416; found 442.1403, calc, for C24H2535CINO5+444.1387; found 444.1481.

[1042] Representative protocol for thioester formation:

[1043] EDCI (3.6761 g, 19.176 mmol, 1.2 equiv.) was charged to a flask which was dissolved in CH2CI2 (50 mL, HPLC grade, non-anhydrous), cooled to 0 °C followed by addition of the cyclopentanecarboxylic acid (1.9 mL, 17.52 mmol, 1.1 equiv.). After a 2 min at 0 °C, either p-thiocresol or2-Mercaptopyridine (1.0 equiv.) was added in one portion and after 5 min at 0 °C, the reaction was allowed to warm to r.t. After 2 h at r.t., the reaction was diluted with Et2O (100 mL) and washed once with 1 M aq. HCI (50 mL) and twice with water (2x50 mL). The resulting organic phase was dried over Na2sC>4, filtered through sand and celite and concentrated in vacuo. The crude material was purified by AFCC (heptane to 9:1 heptane / EtOAc) to isolate the product. P7413PC00

[1044] Thioester 91 was prepared according to “Representative protocol for thioester formation”:

[1045]

[1046] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.31 - 7.27 (m, 2H), 7.23 - 7.19 (m, 2H), 3.08 (p, J = 7.7 Hz, 1 H), 2.37 (s, 3H), 2.00 - 1.84 (m, 4H), 1.78 - 1.67 (m, 2H), 1.66 - 1.57 (m, 2H).

[1047] Thioester 92 was prepared according to “Representative protocol for thioester formation”:

[1048]

[1049] 'H NMR (400 MHz, CDCl3-d) 5H(ppm) 7.29 - 7.26 (m, 2H), 7.22 - 7.19 (m, 2H), 2.59 (tt, J = 11.5, 3.6 Hz, 1 H), 2.37 (s, 3H), 2.03 - 1.95 (m, 2H), 1.86 - 1.77 (m, 2H), 1.71 - 1.63 (m, 1 H), 1.51 (qd, J = 12.3, 3.4 Hz, 2H), 1.38 - 1.16 (m, 3H).

[1050] Thioester 93 was prepared according to “Representative protocol for thioester formation”:

[1051]

[1052] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.62 (dd, J = 1.7, 0.8 Hz, 1 H), 7.40 - 7.37 (m, 2H), 7.28 - 7.24 (m, 3H), 6.57 (dd, J = 3.6, 1.7 Hz, 1 H), 2.40 (s, 3H).

[1053] Thioester 94 was prepared according to “Representative protocol for thioester formation”:

[1054]

[1055] P7413PC00

[1056] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 8.05 - 8.01 (m, 2H), 7.63 - 7.58 (m, 1H), 7.51 - 7.46 (m, 2H), 7.42 - 7.37 (m, 2H), 7.29 - 7.26 (m, 2H), 2.41 (s, 3H).

[1057] Thioester 95 was prepared according to “Representative protocol for thioester formation”:

[1058]

[1059] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.99 - 7.95 (m, 2H), 7.49 - 7.44 (m, 2H), 7.41 - 7.36 (m, 2H), 7.29 - 7.26 (m, 2H), 2.41 (s, 3H).

[1060] Thioester 96 was prepared according to “Representative protocol for thioester formation”:

[1061]

[1062] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 8.69 (ddd, J = 4.8, 1.9, 1.0 Hz, 1 H), 7.81 (ddd, J = 7.9, 7.2, 1.9 Hz, 1 H), 7.79 - 7.75 (m, 1 H), 7.75 - 7.72 (m, 1 H), 7.65 - 7.61 (m, 2H), 7.52 (ddd, J = 8.4, 7.2, 1.2 Hz, 1 H), 7.38 - 7.32 (m, 2H).

[1063] Representative Liebeskind-Srogl coupling of PMB protected stannanes:

[1064] CuTC (148.0 mg, 0.776 mmol, 3.0 equiv.), Pd2dba3 (45.9 mg, 0.0501 mmol, 0.2 equiv.) and thioester (112.0 mg, 0.511 mmol, 2.0 equiv.) were charged to a flask which was purged with argon for several minutes. Then solvent (3:1 hexane / THF, 5 mL) and P(O / -Pr)3 (25 pL, 0.101 mmol, 0.4 equiv.) were added and the mixture was stirred at r.t. for 10 min after which stannane (151.1 mg, 0.2559 mmol, 1.0 equiv.) was added and the system was heated to 60 °C in a sealed round-bottom flask. After 2 h at 60 °C, the reaction mixture was filtered through a plug of silica eluting with 2:1 heptane / EtOAc and the resulting solution was concentrated in vacuo. The material was purified by AFCC (heptane to 7:3 heptane / EtOAc) to isolate the product (50.6 mg, 50%) as a yellow oil / solid.

[1065] Representative Liebeskind-Srogl coupling of PMB protected stannanes:

[1066] CuTC (148.0 mg, 0.776 mmol, 3.0 equiv.), Pd2dba3 (45.9 mg, 0.0501 mmol, 0.2 equiv.) and thioester (112.0 mg, 0.511 mmol, 2.0 equiv.) were charged to a flask which was purged with argon for several minutes. Then solvent (3:1 hexane / THF, 5 mL) and P(O / -Pr)3 (25 pL, 0.101 P7413PC00

[1067] mmol, 0.4 equiv.) were added and the mixture was stirred at r.t. for 10 min after which stannane (151.1 mg, 0.2559 mmol, 1.0 equiv.) was added and the system was heated to 60 °C in a sealed round-bottom flask. After 2 h at 60 °C, the reaction mixture was filtered through a plug of silica eluting with 2:1 heptane / EtOAc and the resulting solution was concentrated in vacuo. The material was purified by AFCC (heptane to 7:3 heptane / EtOAc) to isolate the product (50.6 mg, 50%) as a yellow oil / solid.

[1068] Liebeskind Srogl product 97 was prepared according to “Representative Liebeskind- Srogl coupling of PMB protected stannanes” using thioester 91 and stannane 70:

[1069] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.32 - 7.28 (m, 2H), 6.87 - 6.82 (m, 2H), 4.61 (s, 2H), 3.78 (s, 3H), 3.70 (tt, J = 8.7, 6.9 Hz, 1 H), 2.70 - 2.65 (m, 2H), 1.91 - 1.70 (m, 4H), 1.68 - 1.58 (m, 4H), 1.54 - 1.46 (m, 2H), 1.39 - 1.24 (m, 6H), 0.89 - 0.84 (m, 3H).

[1070] Liebeskind Srogl product 98 was prepared according to “Representative Liebeskind- Srogl coupling of PMB protected stannanes” using thioester 93 and stannane 70:

[1071] OMe

[1072]

[1073] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.68 (dd, J = 1.7, 0.7 Hz, 1 H), 7.35 - 7.30 (m, 2H), 7.26 (m, 1H)[1]6.87 - 6.83 (m, 2H), 6.62 (dd, J = 3.7, 1.7 Hz, 1 H), 4.65 (s, 2H), 3.79 (s, 3H), 2.57 - 2.49 (m, 2H), 1.59 - 1.49 (m, 2H), 1.32 - 1.17 (m, 6H), 0.85 - 0.80 (m, 3H). ’Hides under residual CHCb signal.

[1074] Liebeskind Srogl product 99 was prepared according to “Representative Liebeskind- Srogl coupling of PMB protected stannanes” using thioester 94 and stannane 70:

[1075] OMe

[1076]

[1077] P7413PC00

[1078] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.84 - 7.80 (m, 2H), 7.67 - 7.62 (m, 1H), 7.52 - 7.47 (m, 2H), 7.35 - 7.31 (m, 2H), 6.88 - 6.82 (m, 2H), 4.65 (s, 2H), 3.79 (s, 3H), 2.47 - 2.42 (m, 2H), 1.56 - 1.43 (m, 2H), 1.28 - 1.11 (m, 6H), 0.82 - 0.77 (m, 3H).

[1079] Liebeskind Srogl product 100 was prepared according to “Representative Liebeskind-Srogl coupling of free stannanes” using thioester 96 and PMB deprotected stannane 70:

[1080] 'H NMR (400 MHz, CDCl3-d) 5H(ppm) 7.77 - 7.74 (m, 1H), 7.62 - 7.58 (m, 2H), 7.57 - 7.51 (m, 1 H), 7.36 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H), 7.30 (s, 1 H), 2.61 - 2.56 (m, 2H), 1.64 - 1.56 (m, 2H), 1.31 - 1.18 (m, 6H), 0.83 - 0.78 (m, 3H).

[1081] Liebeskind Srogl product 100 was prepared according to “Representative Liebeskind-Srogl coupling of free stannanes” using thioester 92 and PMB deprotected stannane 70:

[1082]

[1083] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 3.21 - 3.13 (m, 1H), 2.68 - 2.60 (m, 2H), 1.90 - 1.83 (m, 2H), 1.82 - 1.75 (m, 2H), 1.72 - 1.65 (m, 1 H), 1.56 - 1.48 (m, 2H), 1.40 - 1.23 (m, 11 H), 0.90 -0.85 (m, 3H).

[1084] Representative spirocyclopropanation using intermediate 48:

[1085] A vial containing intermediate 48 (48.8 mg, 0.236 mmol, 1.9 equiv.) was further charged with PCC (105.2 mg, 0.485 mmol, 3.8 equiv.) and celite (150.3 mg) followed by addition of wet CH2CI2 (2.4 mL) at r.t. After 15 h at r.t., the reaction mixture was diluted with heptane (approx. 1 mL) and poured onto a pad of celite wetted with heptane. The mixture was filtered through the pad of celite and the filter cake was washed with additional 1:1 heptane / CH2Cl2 (8 mL). The resulting mixture was concentrated by nitrogen flow and subsequently in vacuo.

[1086] A vial containing Liebeskind-Srogl product (50.5 mg, 0.128 mmol, 1.0 equiv) was further charged with Na2COs (32.4 mg, 0.306 mmol, 2.4 equiv.) and a magnet. The mixture was suspended in THF (0.5 mL) after which the crude 1,3-diketone (dissolved in 0.5 mL THF, rinse flask with additional 0.5 mL THF) was added at r.t. After 2 h at r.t., the reaction mixture was poured onto a pad of silica gel which was wetted with Et2O. The mixture was filtered through and the filter cake was washed with Et2O (approx. 8 mL). The resulting solution was concentrated in vacuo. The crude material was purified by AFCC (prep. SIHP puriflash column, P7413PC00

[1087] 5 micron, 100 x21.2 mm, flow = 20 mL / min, start 100% heptane, increase to 85:15 heptane / EtOAc over 30 min, then increase to 7:3 heptane / EtOAc over 5 min) to isolate the product (45.8 mg, 64%) as a sticky yellow material.

[1088] Representative PMB deprotection:

[1089] A vial containing PMB protected spirocyclopropane (34.3 mg, 0.0608 mmol, 1.0 equiv.) was charged with CAN (269.4 mg, 0.4914 mmol, 8.1 equiv.) after which a 4:1 mixture of MeCN / mq water (1.2 mL) was added. The system was allowed to fully dissolve after which it was heated to 50 °C. After 30 min at 50 °C, the reaction mixture was diluted with Et2O (30 mL), water (15 mL) and brine (15 mL). The mixture was extracted (3x30 mL) with Et2O and the combined organics were dried over Na2SO4, filtered through sand and celite and concentrated in vacuo. The crude material was purified by AFCC (prep. SIHP puriflash column, 5 micron, 100 x 21.2 mm, flow = 20 mL / min, start 100% heptane, increase to 75:25 heptane / EtOAc over 30 min) which separated the two diastereoisomers. The separated diastereoisomers were concentrated in vacuo and subjected to lyophilization in mq water / MeCN (approx. 1:1, 7 mL in total). This yielded the products as a white fluffy solid.

[1090] GW2361 - Racemic and mixture of diastereoisomers at C1:

[1091] GW2361 was prepared according to “Representative spirocyclopropanation using intermediate 48”.

[1092]

[1093] Rf (4:1 heptane / EtOAc, UV active, KMnO4 stain) 0.26. P7413PC00

[1094] Note, integrals of NMR signals are normalized to accommodate the diastereomeric ratio and NMR is reported as a mixture of diastereoisomers.

[1095] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.78-7.73 (m, 2H), 7.59-7.54 (m, 1H), 7.52-7.47 (m, 1 H), 7.44-7.37 (m, 2H), 7.36-7.28 (m, 2H), 6.87-6.84 (m, 2H), (6.48 (dq, J = 15.9, 1.7 Hz), 6.39 (dq, J = 15.9, 1.7 Hz), 1H), 4.65 (s, 2H), (3.80 (s), 3.79 (s), 3H), (2.15-2.04 (m), 2.06 (dd, J = 7.0, 1.7 Hz), 1.95 (dd, J = 7.0, 1.7 Hz), 6H)[1], 1.32-1.15 (m, 7H), 0.86-0.78 (m, 3H). ^This signal underintegrates.

[1096] GW2366a and GW2366b:

[1097] GW2366a and GW2366b were prepared according to “Representative PMB deprotection

[1098] GW2366a - Racemic, pure diastereoisomer:

[1099]

[1100] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.43.

[1101] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.81 - 7.76 (m, 2H), 7.64 (s, 1 H), 7.62 - 7.51 (m, 2H), 7.47-7.42 (m, 2H), 6.50 (dq, J = 15.8, 1.7 Hz, 1H), 2.21 - 1.91 (m, 6H), 1.35-1.11 (m, 7H), 0.89 - 0.81 (m, 3H).

[1102] HRMS (ESI): Calc. for C25H25ClNO4+454.1416; found 454.1412.

[1103] GW2366b - Racemic, pure diastereoisomer:

[1104] Me Me

[1105]

[1106] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.48. P7413PC00

[1107] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.83 - 7.78 (m, 2H), 7.67 (s, 1 H), 7.62 - 7.56 (m, 1 H), 7.48 - 7.42 (m, 2H), 7.33 - 7.22 (m, 1 H), 6.39 (dq, J = 15.8, 1.6 Hz, 1H), 2.21 - 1.92 (m, 6H)[1], 1.36-1.08 (m, 7H), 0.89 - 0.81 (m, 3H).[1]This signal underintegrates.

[1108] HRMS (ESI): Calc. for C25H25ClNO4+454.1416; found 454.1424.

[1109] GW2365a - Racemic, pure diastereoisomer:

[1110] The Liebeskind-Srogl product was prepared according to “Representative Liebeskind-Srogl coupling of PMB protected stannanes” using thioester 95 and stannane 70 and advanced directly to spirocyclopropanation according to “Representative spirocyclopropanation using intermediate 48” and finally subjected to PMB deprotection according to “Representative PMB deprotection".

[1111]

[1112] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.55.

[1113] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.76 - 7.72 (m, 2H), 7.62 (bs, 1H), 7.47 - 7.39 (m, 2H), 7.34 - 7.24 (m, 1 H), 6.40 (dq, J = 16.0, 1.6 Hz, 1H), 2.19 - 1.94 (m, 3H), 1.97 (dd, J = 7.0, 1.7 Hz, 3H), 1.34 - 1.10 (m, 7H)[1], 0.88 - 0.83 (m, 3H).[1]This signal underintegrates.

[1114] HRMS (ESI): Calc. for C25H24O5NCl2+488.1026; found 488.1020. P7413PC00

[1115] GW2374 - Racemic and mixture of diastereoisomers at C1:

[1116] GW2374 was prepared according to “Representative spirocyclopropanation using intermediate 48”.

[1117] Rf (2:1 heptane / EtOAc, UV active, KMnCM stain) 0.43. Note, integrals of NMR signals are normalized to accommodate the diastereomeric ratio and NMR is reported as a mixture of diastereoisomers.

[1118] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.75 - 7.35 (m, 2H), 7.35 - 7.25 (m, 3H), 6.88 - 6.82 (m, 2H), 6.56 (dd, J = 3.7, 1.7 Hz, 1 H), 6.52 - 6.42 (m, 1 H), 4.67 - 4.58 (m, 2H), (3.80 (s), 3.80 (s),

[1119]

[1120] 3H), 2.12 (dt, J= 10.8, 5.3 Hz, 2H), (2.05 (dd, J = 7.0, 1.7 Hz), 2.00 (dd, J = 7.0, 1.7 Hz), 3H), 1.97 - 1.84 (m, 1 H), 1.29 - 1.08 (m, 7H)[10.86 - 0.80 (m, 3H). ’This signal underintegrates.

[1121] HRMS (ESI): Calc. for C31H31NClO4+564.1784; found 564.1786. P7413PC00

[1122] GW2377a and GW2377b:

[1123] GW2377a and GW2377b were prepared according to “Representative PMB deprotection”.

[1124] GW2377a - Racemic, pure diastereoisomer:

[1125]

[1126] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.37.

[1127] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.78 (s, 1H), 7.53 (d, J= 1.9 Hz, 1H), 7.39 (dq, J= 15.9, 7.0 Hz, 1H), 7.31 (d, J= 3.7 Hz, 1H), 6.58 (dd, J= 3.7, 1.7 Hz, 1H), 6.46 (dq, J= 15.7, 1.6 Hz, 1H), 2.16 (ddd, J= 14.0, 11.3, 4.6 Hz, 1H), 2.07 (ddd, J= 13.9, 11.7, 4.4 Hz, 1H), 2.00 (dd, J = 7.0, 1.7 Hz, 3H), 1.97 - 1.86 (m, 1 H), 1.33 - 1.11 (m, 7H), 0.86 - 0.83 (m, 3H).

[1128] HRMS (ESI): Calc, for C23H23NO6Cl+444.1208; found 444.1258.

[1129] GW2377b - Racemic, pure diastereoisomer:

[1130]

[1131] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.31.

[1132] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.66 (s, 1 H), 7.60 - 7.49 (m, 2H), 7.31 (d, J = 3.7 Hz, 1H), 6.59 (dd, J= 3.7, 1.7 Hz, 1H), 6.51 (dq, J= 15.9, 1.7 Hz, 1H), 2.17 (ddd, J= 15.6, 11.4, 4.6 Hz, 1H), 2.12 -2.03 (m, 4H), 1.98 - 1.88 (m, 1H), 1.33- 1.17 (m, 7H), 0.87 - 0.82 (m, 3H). HRMS (ESI): Calc, for C23H23NO6Cl+444.1208; found 444.1201.

[1133] GW2387a and GW2387b:

[1134] GW2387a and GW2387b were prepared according to “Representative spirocyclopropanation using intermediate 48“. P7413PC00

[1135] GW2387a - Racemic, pure diastereoisomer (with minor impurities):

[1136]

[1137] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.53.

[1138] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.55 - 7.43 (m, 2H), 6.48 (dq, J = 16.0, 1.4 Hz, 1H), 2.61 - 2.52 (m, 1H), 2.16 (dt, J = 10.6, 5.2 Hz, 2H), 2.04 (dd, J = 7.0, 1.7 Hz, 3H), 2.01 - 1.99 (m, 1H), 1.90 - 1.74 (m, 3H), 1.72 - 1.61 (m, 1H), 1.41 - 1.14 (m, 11H), 0.92 - 0.80 (m, 5H).

[1139] HRMS (ESI): Calc, for C25H31NO5Cl+460.1885; found 460.1875.

[1140] GW2387b - Racemic, pure diastereoisomer (with minor impurities):

[1141]

[1142] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.50.

[1143] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.55 - 7.44 (m, 2H), 6.48 (dq, J = 15.7, 1.4 Hz, 1H), 2.55 (tt, J = 11.3, 3.4 Hz, 1 H), 2.23 - 2.11 (m, 2H), 2.04 (dd, J = 7.0, 1.7 Hz, 3H), 2.02 - 1.98 (m, 1H), 1.89 - 1.74 (m, 3H), 1.70 - 1.62 (m, 1H), 1.41 - 1.14 (m, 11H)[1], 0.89 - 0.82 (m, 5H).

[1144] [1]This signal underintegrates.

[1145] HRMS (ESI): Calc, for C25H31NO5Cl+460.1885; found 460.1879.

[1146] GW2486a and GW2486b:

[1147] GW2486a and GW2486b were prepared according to “Representative spirocyclopropanation using intermediate 48“. P7413PC00

[1148] GW2486a - Racemic, pure diastereoisomer:

[1149] Me Me

[1150]

[1151] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.43.

[1152] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.72 (dt, J= 7.6, 1.0 Hz, 1H), 7.61 (bs, 1H), 7.60 (d, J = 0.9 Hz, 1 H), 7.49 (ddd, J = 8.5, 7.1, 1.3 Hz, 1 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.35 - 7.27 (m, 2H), 6.43 (dq, J= 15.9, 1.5 Hz, 1H), 2.21 (ddd, J= 15.3, 11.0, 4.4 Hz, 1H), 2.16 -2.07 (m, 1H), 2.04 - 1.93 (m, 1 H), 1.92 (dd, J = 7.0, 1.7 Hz, 3H), 1.39 - 1.14 (m, 7H)[1], 0.86 - 0.81 (m, 3H). ^This signal overintegrates.

[1153] HRMS (ESI): Calc, for C27H25NO6Cl+494.1365; found 494.1353.

[1154] GW2486b - Racemic, pure diastereoisomer:

[1155] Me Me

[1156]

[1157] Rf (2:1 heptane / EtOAc, UV active, KMnC stain) 0.38.

[1158] 1H NMR (400 MHz, CDCl3-d) 6H (ppm) 7.72 (dt, J = 7.9, 1.0 Hz, 1 H), 7.65 - 7.55 (m, 3H), 7.49 (ddd, J = 8.5, 7.1, 1.3 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.32 (ddd, J = 8.1, 7.2, 1.0 Hz, 1 H), 6.56 (dq, J= 15.8, 1.6 Hz, 1H), 2.28 -2.12 (m, 2H), 2.10 (dd, J= 7.0, 1.7 Hz, 3H), 2.01 - 1.85 (m, 1H), 1.35 - 1.17 (m, 7H), 0.86 - 0.82 (m, 3H).

[1159] HRMS (ESI): Calc, for C27H25NO6Cl+494.1365; found 494.1359. P7413PC00

[1160] Example 2: Cytotoxicity studies

[1161] Experimental information

[1162] The effects of the compounds on cell viability have been examined in two mammalian cancer cell lines, namely U-2OS bone cancer (Osteosarcoma) cells and 786-0 kidney cancer (renal, adenocarcinoma) cells. Cells were cultured in vented T75 flasks (Thermo Scientific, cat. no. 130190) under a humidified atmosphere at 37 °C containing 5% CO2, with passaging to new flask approximately every third day depending on the cell line. During passaging, the cells were washed twice with warm DPBS (Sigma-Aldrich, cat. no. D8537) and dissociated from the flask through incubation with a 0.25% trypsin / EDTA mixture (Sigma-Aldrich, cat. no. T4049).

[1163] Subsequently, the trypsin mixture was diluted with medium, and one fifth to one twelfth of the resulting solution was transferred to a new flask containing additional fresh culture medium. U-2OS (ATCC HTB-96, human osteosarcoma) cells were cultured in McCoy’s 5A Medium (Sigma-Aldrich, cat. no. M9309) supplemented with 10% FBS (Gibco, cat. no. A3160801) and 1% penicillin / streptomycin (Gibco, cat. no. 15150-022). 786-0 cells (ATCC CRL-1932, human renal carcinoma) were cultured in RPMI-1640 medium supplemented with 10% FBS, 1% penicillin / streptomycin, and 1% Ala-Gin (Sigma-Aldrich, cat. no. G8541).

[1164] Cells were seeded in 75 pL full growth medium into the inner 60 wells of black-bottomed 96-well plates (Thermo Scientific, cat. no. 137101), at a cell density of 2000 cells / well, and allowed to adhere through overnight incubation (37 °C, 5 % CO2, humid). The following day, the examined compounds were prepared as 4X solutions in a four-fold dilution series, through 50-fold dilution of 200X stock solutions in DMSO into full growth medium. The cells were then treated, in technical triplicates, through addition of 25 pL 4X solution to the wells, yielding the desired compound concentrations at a final DMSO concentration of 0.5 %, followed by 46.5 hours of incubation (37 °C, 5 % CO2, humid). Next, 20 pL CellTiter-Blue reagent (Promega, cat. no. G8081) was added to each well, and the plates were returned to the incubator for an additional 1.5 hours of incubation. Finally, the resorufin fluorescence (excitation at 552 ±10 nm and emission at 598 ±10 nm) was measured on a Tecan Spark 10M multimode plate reader. Data treatment consisted of subtraction of background fluorescence (the average fluorescence measured in wells containing medium and CellTiter-Blue reagent but no cells), followed by normalization to the average fluorescence measured from DMSO-treated cells. Finally, the data was plotted and fitted to a 4-parameter nonlinear regression in GraphPad Prism 10.2.3 for Windows, GraphPad Software, Boston, Massachusetts USA, www.graphpad.com. All IC50-values presented with a standard deviation represent the mean of three biological replicates.

[1165] Table 1. The biological data (inhibition of cancer cell viability) for rac-TTP652a, rac-TTP652b, GW2361, GW2366a, GW2366b, GW2365a, GW2374, GW2377a, GW2377b, GW2387a, GW2387b, GW2486a, GW2486b, TTP806a, TTP806b, TTP814a, TTP814b, TTP821a, P7413PC00

[1166] TTP821b, and TTP757a. Values of IC50 for which standard deviations are presented are derived from three biological replicate experiments. Figure 1 and 2 are representative of the graphs obtained for rac-TTP652a and rac-TTP652b. The remaining IC50-values are derived from the graphs presented as Figures 3 through 11.

[1167] U2OS cells 786-0 cells

[1168] IC50 / µM IC50 / µM

[1169] rac-TTP652a 3.2 ± 0.8 13 ± 1.3

[1170] rac-TTP652b 2.2 ± 0.2 5.6 ± 2.6 GW2361 - Racemic and 5.11 - mixture of

[1171] diastereoisomers at C1.

[1172] GW2366a - Racemic, pure 1.06 - diastereoisomer

[1173] GW2366b - Racemic, pure 1.45 - diastereoisomer

[1174] GW2365a - Racemic, pure 5.37 - diastereoisomer

[1175] GW2374 - Racemic and 2.17 - mixture of

[1176] diastereoisomers at C1

[1177] GW2377a - Racemic, pure 0.862 - diastereoisomer

[1178] GW2377b - Racemic, pure 1.36 - diastereoisomer

[1179] GW2387a - Racemic, pure 1.51 - diastereoisomer

[1180] GW2387b - Racemic, pure 1.99 - diastereoisomer

[1181] GW2486a - Racemic, pure 0.86 - diastereoisomer

[1182] GW2486b - Racemic, pure 2.18 - diastereoisomer.

[1183] TTP806a - Racemic, pure 1.67 - diastereoisomer

[1184] TTP806b - Racemic, pure 1.76 - diastereoisomer

[1185] TTP814a - Racemic, pure 1.16 - diastereoisomer

[1186] TTP814b - Racemic, pure 1.15 - diastereoisomer

[1187] TTP821a - Racemic, pure 1.45 - diastereoisomer

[1188] TTP821b - Racemic, pure 1.09 - diastereoisomer

[1189] TTP757a - Racemic, pure 1.93 ± 0.436 4.24 and 6.22 diastereoisomer,

[1190]

[1191] corresponding to TTP652a P7413PC00

[1192] Example 3: NMR comparison ofAD0157 and Compound 1 (Cyclohelminthol X)

[1193]

[1194] Table 2. NMR shifts for AD0157 and Compound 1 (Cyclohelminthol X). N MR data reported in CD3OD. All chemical shifts are reported in ppm and tabulated with the lowest13C signal and the associated1H signal to the highest13C signal and the associated1H signal.

[1195] Garcia-Caballero et al, WO 2015 / 004149 WO 2020 / 109297 2014

[1196] AD0157 AD0157 Compound 1

[1197] 13C NMR1H NMR13C NMR1H NMR13C NMR1H NMR 1 13.2 0.92, t (7.1 Hz, 13.2 0.92, t (7.1 Hz, 13.2 0.92, t (7.1 Hz,

[1198] 3H) 3H) 3H)

[1199] 2 17.6 1.90, dd (6.8, 17.6 1.90, dd (6.8, 17.6 1.90, dd (6.8,

[1200] 1.6 Hz, 3H) 1.6 Hz, 3H) 1.6 Hz, 3H) 3 19.6 2.02, dd (7.0, 19.6 2.02, dd (7.0, 19.6 2.02, dd (7.0,

[1201] 1.7 Hz, 3H) 1.7 Hz, 3H) 1.7 Hz, 3H) 4 20.8 0.81, d (6.6 Hz, 20.8 0.81, d (6.6 Hz, 20.8 0.81, d (6.6

[1202] 3H) 3H) Hz, 3H) 5 21.7 2.06 (1H), 2.27, 21.7 2.06 (1H), 21.7 2.06 (1H), ddd (13.8, 11.7, 2.27, ddd 2.27, ddd 4.2 Hz, 1H) (13.8, 11.7, 4.2 (13.8, 11.7, 4.2

[1203] Hz, 1 H) Hz, 1 H) 6 22.3 1.28 (2H) 22.3 1.28 (2H) 22.3 1.28 (2H) 7 27.3 1.05 (1H), 1.71 27.3 1.05 (1H), 1.71 27.3 1.05 (1H), 1.71

[1204] (1 H) (1 H) (1 H)

[1205] 8 29.1 1.28 (2H) 29.1 1.28 (2H) 29.1 1.28 (2H) 9 31.2 1.26 (2H) 31.2 1.26 (2H) 31.2 1.26 (2H) 10 33.4 1.20 (1H), 2.06 33.4 1.20 (1H), 2.06 33.4 1.20 (1H), 2.06

[1206] (1H) (1H) (1H)

[1207] 11 36.8 1.48 (1H) 36.8 1.48, d (1H)* 36.8 1.48, d (1H)* 12 38.3 1.22 (1H), 1.93 38.3 1.22 (1H), 1.93 38.3 1.22 (1H), 1.93

[1208] (1H) (1H) (1H)

[1209] 13 41.8 1.42 (1H) 41.8 1.42 (1H) 41.8 1.42 (1H) 14 43.3 2.40 (1H) 43.3 2.40 (1H) 43.3 2.40 (1H) 15 45.4 1.46 (1H), 2.05 45.4 1.46 (1H), 2.05 45.4 1.46 (1H), 2.05

[1210] (1H) (1H) (1H)

[1211] 16 48.0 48.0 48.0

[1212] 17 49.7 49.7 49.7

[1213] 18 51.4 1.83, d (10.5 51.4 1.83, d (10.5 51.4 1.83, d (10.5

[1214]

[1215] Hz, 1 H) Hz, 1 H) Hz, 1 H) P7413PC00

[1216] 19 53.9 53.9 53.9

[1217] 20 61.2 4.10, d (10.5 61.2 4.10, d (10.5 61.2 4.10, d (10.5

[1218] Hz, 1 H) Hz, 1 H) Hz, 1 H) 21 86.2 86.2 86.2

[1219] 22 119.0 6.52, dq (16.0, 119.0 6.52, dq (16.0, 119.0 6.52, dq (16.0,

[1220] 1.7 Hz, 1 H) 1.7 Hz, 1 H) 1.7 Hz, 1 H) 23 125.0 6.68, dq (15.4, 125.0 6.68, dq (15.4, 125.0 6.68, dq (15.4,

[1221] 1.6 Hz, 1 H) 1.6 Hz, 1 H) 1.6 Hz, 1 H) 24 145.4 145.4 145.4

[1222] 25 145.7 6.92, dq (15.4, 145.7 6.92, dq (15.4, 145.7 6.92, dq (15.4,

[1223] 6.8 Hz, 1 H) 6.8 Hz, 1 H) 6.8 Hz, 1 H) 26 147.2 7.48, dq (16.0, 147.2 7.48, dq (16.0, 147.2 7.48, dq (16.0,

[1224] 7.0 Hz, 1 H) 7.0 Hz, 1 H) 7.0 Hz, 1 H) 27 148.2 148.2 148.2

[1225] 28 168.6 168.6 168.6

[1226] 29 171.9 171.9 171.9

[1227] 30 178.3 178.3 178.3

[1228] 31 186.4 186.4 186.4

[1229] 32 191.1 191.1 191.1

[1230] 33 195.7 195.7 195.7

[1231]

[1232] 34 201.6 201.6 201.6

[1233] *a dublet has been assigned to this signal but there is no coupling constant reported

[1234] It is clear from the tabulated data that the compound referred to as “AD0157” isolated in the publication by Garcia-Caballero et al, 2014 and described in patent applications WO 2015 / 004149 is identical to “Compound 1” reported in patent “WO 2020 / 109297”.

[1235] Example 4: Studies of inhibition of Akt phosphorylation and cytotoxicity in human dermal lymphatic endothelial cells (HDLEC).

[1236] A) Inhibition of VEGF-C induced Akt-phosphorylation by GW2377a in HDLEC

[1237] Treatment with 10 pM GW2377a prior to induction of Akt-phosphorylation with VEGF-C (final concentration of 100 ng / mL) was found to inhibit the phosphorylation to a similar extent as observed for CHM-X (AD0157). Additionally, an effect on total Akt levels was also observed. Figure 13A presents representative western blots for pAkt, Akt, and p-actin from an experiment with two hours of treatment prior to 30 minutes of VEGF-C treatment. Figures 13B and 13C contain plots of the DMSO-normalised (non-VEGF-C induced control) pAkt and Akt signals, respectively, from two biological replicate experiments using the same incubation times as in 13A.

[1238] Experimental

[1239] Human dermal lymphatic endothelial cells (HDLEC) were purchased from PromoCell GmbH (cat. no. C-12216) and cultured according to their recommendations. For investigations of Akt-phosphorylation, HDLEC were seeded in 1 mL full-growth medium 12-well plates (Thermo Scientific, cat. no. 150628) at a cell density of 4000 cells / well, and allowed to adhere and grow to 70-80 % confluence over two days. Next, the cells were serum-starved as the full-growth medium was exchanged for low serum medium (0.5 % FCS, no other additives) followed by P7413PC00

[1240] overnight incubation (37 °C, 5 % CO2, humid). The next day, the medium was exchanged for fresh low-serum medium containing the examined compounds at the desired concentrations, followed by incubation. At the end of the incubation, recombinant human VEGF-C (Bio-Techne, cat. no. 9199-VC-025 / CF) in medium (or just medium for the non-induced controls) was spiked into the wells at a final concentration of 100 ng / mL, prior to another 30 minutes of incubation. Subsequently, the medium was aspirated and the cells were washed once with ice-cold DPBS (Sigma-Aldrich, cat. no. D8537), before being lysed in the plate through addition of 50 pL RIPA lysis buffer (150 mM NaCI, 5 mM EDTA, 50 mM Tris HCI, 0.5 % (m / v) sodium deoxycholate, 1 % (v / v) NP-40, 0.1 % (m / v) SDS), containing both protease (Thermo Scientific, cat. no. A32955) and phosphatase inhibitors (Thermo Scientific, cat. no. A32957), and 10 minutes of incubation on ice with occasional shaking of the plate. The resulting lysates were collected in 1.5 mL tubes (Corning, cat. no. MCT-150-C), subjected to tip-sonication (2x10 pulses / sample using a Branson Sonifier 250 with an attached microtip) to shear DNA, and cleared through centrifugation (16,000 g, 4 °C, 10 min). The concentration of the lysates was determined through a commercial BCA-assay (Thermo Scientific, cat. no. 23225) and samples containing 8 pg protein in 25 pL were prepared through addition of suitable volumes lysate, PBS, and 4X sample buffer (Bio-Rad, cat. no. 1610747, with 10 % (v / v) added p-mercaptoethanol). The samples were then heated to 95 °C for 5 minutes before 19 pL (6 pg protein) was loaded onto a 12-well 4-15 % Mini-PROTEAN TGX gel (Bio-Rad, cat. no. 4561086). Electrophoresis was conducted at 200 V for 26-30 minutes using 3 pL Precision Plus Protein All Blue Standards (Bio Rad, cat. no. 1610373) solution as molecular mass marker, and a 1X Tris / SDS / Glycine solution as the running buffer (Bio-Rad, cat. no. 1610732, diluted 10-fold with MQ-H2O).

[1241] After SDS-PAGE, the proteins were transferred to a PVDF membrane (Bio-Rad, cat. No.

[1242] 1704156), which was subsequently blocked through one hour of incubation in a 5 % (m / v) BSA solution in TBST (20 mM Tris-base, 150 mM NaCI, 0.1 % (v / v) Tween-20, pH = 7.6) for one hour at room temperature, prior to overnight incubation with an anti-pAkt (Ser473) primary antibody at 4 °C (Cell Signalling Technology, cat. no. 9271 S, from rabbit, 1:1000 in blocking buffer). Next day, the membrane was washed thrice with TBST (5-10 minutes / wash) and incubated with an HRP-conjugated secondary anti-rabbit antibody (Goat Anti-Rabbit IgG H& L (HRP), Abeam, cat. no. ab6721) in TBST for one hour at room temperature. The membrane was then washed thrice with TBST and developed using SuperSignal West Femto detection reagent (Thermo Fischer, cat. no. 34094) on an ImageQuant LAS 4000 system. Subsequently, the membrane was stripped through incubation in stripping buffer (0.1 % SDS, 1 % Tween-20, 200 mM glycine, pH = 2.2, 2x10 minutes of incubation) and three washes with TBST (5 minutes each), before being re-blocked as described above. Next, the membrane was incubated at 4 °C overnight with an anti-Akt antibody (Cell Signalling Technology, cat. no. 9272S, from rabbit, 1:1000 in blocking buffer), and the procedure was repeated with the minor change that reblocking was conducted using 5 % skimmed milk solution in TBST rather than a BSA solution. Finally, the membrane was re-probed for p-actin through the same workflow utilising the P7413PC00

[1243] following primary and secondary antibodies: Anti-p-actin (monoclonal from mouse, 1:5000 in 5 % milk solution in TBST, Sigma-Aldrich, cat. no. A5441) and Sheep anti-mouse (1:10,000 in TBST, Cytiva, NA931).

[1244] Signal quantification was conducted in ImageQuant v.8.2.0 using the p-actin signals as loading controls. The data was normalised to the non-VEGF-C-treated DMSO control samples and plotted in GraphPad Prism 10.4.2 for Windows, GraphPad Software, Boston, Massachusetts USA, www.graphpad.com. Image analysis was performed using Fiji (Imaged) 2.3.0, and the final membrane-based figures were prepared in Affinity Designer 2.6.4.

[1245] B) Cytotoxicity of GW2377a in HDLEC

[1246] The effect of GW2377a on HDLEC cell viability has been examined in three biological replicate experiments, from which a mean IC50-value of 1.76 ± 0.11 pM was calculated. A representative graph is included as Figure 12.

[1247] Experimental

[1248] Cells were seeded in 75 pL full growth medium into the inner 60 wells of black-bottomed 96-well plates (Thermo Scientific, cat. no. 137101), at a cell density of 4000 cells / well, and allowed to adhere through overnight incubation (37 °C, 5 % CO2, humid). The following day, the examined compounds were prepared as 4X solutions in a four-fold dilution series, through 50-fold dilution of 200X stock solutions in DMSO into full growth medium. The cells were then treated, in technical triplicates, through addition of 25 pL 4X solution to the wells, yielding the desired compound concentrations at a final DMSO concentration of 0.5 %, followed by 46.5 hours of incubation (37 °C, 5 % CO2, humid). Next, 20 pL CellTiter-Blue reagent (Promega, cat. no. G8081) was added to each well, and the plates were returned to the incubator for an additional 1.5 hours of incubation. Finally, the resorufin fluorescence (excitation at 552 ±10 nm and emission at 598 ±10 nm) was measured on a Tecan Spark 10M multimode plate reader. Data treatment consisted of subtraction of background fluorescence (the average fluorescence measured in wells containing medium and CellTiter-Blue reagent but no cells), followed by normalization to the average fluorescence measured from DMSO-treated cells. Finally, the data was plotted and fitted to a 4-parameter nonlinear regression in GraphPad Prism 10.4.2 for Windows, GraphPad Software, Boston, Massachusetts USA, www.graphpad.com.

[1249] In conclusion, Example 4 demonstrates that compounds of the present invention inhibits key lymphangiogenic signaling pathways in lymphatic endothelial cells. Lymphangiogenesis plays a pivotal role in cancer progression by facilitating both metastatic dissemination and modulation of the immune microenvironment. The compounds can therefore be used to treat cancer, for example, by inhibiting cancer progression and / or by increasing anti-tumor immunity. P7413PC00

[1250] References

[1251] T. T. Curran, D. A. Hay, C. P. Koegel, J. C. Evans. The preparation of optically active 2-cyclopenten-1,4-diol derivatives from furfuryl alcohol. Tetrahedron 1997, 53, 1983-2004.

[1252] M. Dubernet, V. Caubert, J. Guillard, M.-C. Viaud-Massuard. Synthesis of substituted bis(heteroaryl)maleimides. Tetrahedron 2005, 61, 4585-4593.

[1253] Garcia-Caballero, M.; Canedo, L.; Fernandez-Medarde, A.; Medina, M. A.; Quesada, A. R. The Marine Fungal Metabolite, AD0157, Inhibits Angiogenesis by Targeting the Akt Signaling Pathway. Mar. Drugs 2014, 12, 279-299.

[1254] Garcia-Caballero, M.; Paupert, J.; Blacher, S.; Van De Velde, M.; Quesada, A. R.; Medina, M. A.; Noel, A. Targeting VEGFR-3 / -2 signaling pathways with AD0157: A potential strategy against tumor-associated lymphangiogenesis and lymphatic metastases. J. Hematol. Oncol. 2017, 10, 122.

[1255] M. W. Jones, R. A. Strickland, F. F. Schumacher, S. Caddick, James. R. Baker, M. I. Gibson, D. M. Haddleton. Polymeric Dibromomaleimides As Extremely Efficient Disulfide Bridging Bioconjugation and Pegylation Agents. J. Am. Chem. Soc. 2012, 134, 1847-1852.

[1256] Joukov, V.: Pajusola, K.; Kaipainen, A.; Chilov, D.; Lahtinen, I.,; Kukk, E. et al. A Novel Vascular Endothelial Growth Factor, VEGF-C, is a Ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) Receptor Tyrosine Kinases. EMBO J. 1996, 15, 290-298.

[1257] A. Krasovskiy, P. Knochel, Synthesis 2006, 890-891.

[1258] T. Saito, H. Fuwa, M. Sasaki. Synthetic studies on goniodomin A: convergent assembly of the C15-C36 segment via palladium-catalyzed organostannane-thioester coupling. Tetrahedron 2011, 67, 429-445.

[1259] Oliver, G.; Kipnis, J.; Randolph, G. J.; Harvey, N. L. The Lymphatic Vasculature in the 21 (st) Century: Novel Functional Roles in Homeostasis and Disease. Cell. 2020,182, 270-296.

[1260] Paduch R. The role of lymphangiogenesis and angiogenesis in tumor metastasis. Cell Oncol.

[1261] 2016, 39, 397-410.

[1262] Parker, A. L.; Benguigui, M.; Fornetti, J.; Goddard, E.; Lucotti, S.; Insua-Rodriguez, J.; Wiegmans, A. P. Current challenges in metastasis research and future innovation for clinical translation, Clin. Exp. Metastasis, 2022, 39, 263-277.

[1263] Yamada, Y.; Nezu, J.; Shimane, M.; Hirata, Y. Molecular Cloning of a Novel Vascular Endothelial Growth Factor, VEGF-D. Genomics, 1997, 42, 483-488. P7413PC00

[1264] Brown, M.; Assen, F. P.; Leithner, A.; Abe, J.; Schachner, H.; Asfour, G.; Bago-Horvath, Z.; Stein, J. V.; Uhrin, P.; Sixt, M.; et al. Lymph node blood vessels provide exit routes for metastatic tumor cell dissemination in mice. Science, 359, 1408-1411 (2018).

[1265] Pereira, E. R.; Kedrin, D.; Seano, G.; Gautier, O.; Meijer, E. F. J.; Jones, D.; Chin, S. M.;

[1266] Kitahara, S.; Bouta, E. M.; Chang, J.; et al. Lymph node metastases can invade local blood vessels, exit the node, and colonize distant organs in mice. Science, 359, 1403-1407 (2018).

[1267] Reticker-Flynn, N. E.; Zhang, W.; Belk, J. A.; Basto, P. A.; Escalante, N. K.; Pilarowski, G. O. W.; Bejnood, A.; Martins, M. M.; Kenkel, J. A.; Linde, I. L., et al. Lymph node colonization induces tumor-immune tolerance to promote distant metastasis. Cell, 185, 1924-1942 (2022).

[1268] Deng, H.; Zhang, J.; Wu, F.; Wei, F.; Han, W.; Xu, X.; Zhang Y. Current Status of Lymphangiogenesis: Molecular Mechanism, Immune Tolerance, and Application Prospect, Cancers, 15, 1169 (2023).

[1269] Sun, M., Angelillo, J., Hugues, S. Lymphatic transport in anti-tumor immunity and metastasis, J. Exp. Med. 222, e20231954 (2025).

[1270] Joukov, V.: Pajusola, K.; Kaipainen, A.; Chilov, D.; Lahtinen, I.,; Kukk, E. et al. A Novel Vascular Endothelial Growth Factor, VEGF-C, is a Ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) Receptor Tyrosine Kinases. EMBO J. 15, 290-298 (1996).

[1271] Kuonqui, K. G. et al. Regulation of VEGFR3 signaling in lymphatic endothelial cells, Front. Cell Dev. Biol. 13, doi: 10.3389 / fcell.2025.1527971 (2025).

[1272] Oliver, G.; Kipnis, J.; Randolph, G. J.; Harvey, N. L. The Lymphatic Vasculature in the 21 (st) Century: Novel Functional Roles in Homeostasis and Disease. Cell, 182, 270-296 (2020).

[1273] Sainz-Jaspeado, M.; Claesson-Welsh, L. Cytokines regulating lymphangiogenesis. Curr. Opin. Immunol. 53, 58-63 (2018).

[1274] Tacconi, C. et al. Activation of the VEGFCA / EGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer, Cancer Res. 79, 4196-4210 (2019).

Claims

P7413PC00Claims1. A compound of Formula (1):R2R4R1-NR5, Formula (1)wherein:R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, phenyl, benzyl, or 5- or 6-membered heteroaryl is optionally substituted;R2is H, C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, phenyl, benzyl or an alkynyl group A, wherein said C1-10 alkyl, phenyl or benzyl is optionally substituted;R3is C1-4 alkyl, C3-6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or an alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10aryl, or Cs-9 heteroaryl is optionally substituted;R4is H, halogen or C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted; R5is H, C1-4 alkyl or C2-4 alkenyl;A is an alkynyl group of Formula (A):CH2, Formula (A)wherein:x is 0, 1, 2, 3, 4 or 5;y is 0 or 1; andz is 0, 1, 2, 3, 4 or 5;the dashed bond represents either a double bond or a single bond; or a tautomer or a pharmaceutically acceptable salt thereof.

2. The compound according to any one of the preceding claims, wherein R1is H, methyl, phenyl, benzyl, 4-methoxybenzyl or pyridyl.

3. The compound according to any one of the preceding claims, wherein R2is H, methyl, ethyl, n-hexyl, 6,6,6-trifluorohexan-1-yl, n-decyl, -(CH₂CH₂O)₂CH₃, or 4-(1-butyl)phen-1- yl, 4-phenylbutan-1-yl, or the alkynyl group A of formula (A) according to claim 1.P7413PC004. The compound according to any one of the preceding claims, wherein R3is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, halophenyl, furanyl, benzofuranyl, naphthyl, pyridyl, diazanaphthalenyl, indazolyl, benzothiazolyl, oxazolyl, or oxetanyl.

5. The compound according to any one of the preceding claims, wherein R4is H, methyl, F, Cl, Br, or I.

6. The compound according to any one of the preceding claims, wherein R5is H, methyl, C2-4 alk-1 -en-1 -yl or C1-4 alk-1-yl.

7. The compound according to any one of the preceding claims, wherein A is ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, or octynyl.

8. The compound according to any one of the preceding claims, wherein the compound is of Formula (2) or Formula (3):

9. The compound according to claim 8, wherein the compound is of Formula (2):wherein:R1is H or benzyl, optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;R2is C1-10 alkyl, C2-10 alkynyl or an alkynyl group A;R3is C1-4 alkyl, C5-6 cycloalkyl, C5-6 heterocycloalkyl, Ce aryl or a 5-10 membered heteroaryl, each optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;R4is H or a halogen;R5is C1- alkyl or C2-4 alkenyl; andA is an alkynyl group according to formula (A) of claim 1, wherein x = 0, 1, 2, 3, or 4, y = 0 or 1, and z = 0, 1, 2, or 3.P7413PC0010. The compound according to any one of the preceding claims,wherein:R1is H or 4-methoxybenzyl;R2is C1-10 alkyl, C2-10 alkynyl or an alkynyl group A;R3is methyl, cyclopentyl, cyclohexyl, phenyl, furanyl, or benzofuranyl optionally substituted with one or more C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C1-4 alkoxy, halogen, or a combination thereof;R4is Cl, Br, or I;R5is C1- alkyl or C2-4 alkenyl; andA is an alkynyl group according to formula (A) of claim 1, wherein x = 0, 1, 2, 3 or 4, y = 0 or 1, and z = 0.

11. The compound according to any one of the preceding claims, wherein R4is Cl, Br, or I, and R5is C3 alkyl or C3 alkenyl.

12. The compound according to any one of the preceding claims, wherein R4is Cl, Br, or I, and R5is prop-1 -en-1-yl or prop-1 -yl.

13. The compound according to any one of the preceding claims, wherein R1is H, R4is Cl, Br, or I, and R5is C3 alkyl or C3 alkenyl.

14. The compound according to any one of the preceding claims, wherein R1is H, R4is Cl, Br, or I, and R5is prop-1 -en-1-yl or prop-1 -yl.

15. The compound according to any one of the preceding claims, wherein R1is H, C1-6 alkyl, phenyl, benzyl, a 5- or 6-membered heteroaryl or alkynyl group A, wherein said C1- alkyl, phenyl, benzyl, 5- or 6-membered heteroaryl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

16. The compound according to any one of the preceding claims, wherein R2is H, C1-10 alkyl wherein one or more methylene unit(s) is optionally and individually replaced with - O-, phenyl, benzyl or alkynyl group A, wherein said C1-10 alkyl, phenyl or benzyl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl, or C2-6 alkynyl.

17. The compound according to any one of the preceding claims, wherein R2is an alkynyl group of Formula (A), wherein x + z = 1, 2, 3, 4, 5, or 6, and y = 0.P7413PC0018. The compound according to any one of the preceding claims, wherein R3is C1-4 alkyl, C3-6 cycloalkyl wherein one or more methylene unit(s) is optionally and individually replaced with -O-, C6-10 aryl, C3-9 heteroaryl, or alkynyl group A, wherein said C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, or C3-9 heteroaryl is optionally substituted with C1-4 alkyl, C1-3 alkoxy, halogen, C1-4 haloalkyl, phenyl or C2-6 alkynyl.

19. The compound according to any one of the preceding claims, wherein R4is H, halogen or C1-4 alkyl, wherein said C1-4 alkyl is optionally substituted.

20. The compound according to any one of the preceding claims, wherein R4is H, halogen or C1- alkyl.

21. The compound according to any one of the preceding claims, wherein A is the alkynyl group of Formula (A), wherein x = 0, 1, 2, 3, 4 or 5.

22. The compound according to any one of the preceding claims, wherein the compound isP7413PC00stereoisomers thereof.

23. The compound according to any one of the preceding claims, wherein the compound is any one of133P7413PC00P7413PC00MeOor a combination or a mixture thereof.

24. The compound according to any one of the preceding claims, wherein the mixture is a racemic mixture.

25. The compound according to any one of the preceding claims, wherein the compound is an anticancer agent and / or a lymphangiogenesis inhibitor.P7413PC0026. The compound according to any one of the preceding claims, wherein the compound is an NF-KB kinase modulator and / or an inhibitor.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

28. The compound according to any one of claims 1 to 26, ora pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use as a medicament.

29. The compound according to any one of claims 1 to 26, ora pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the treatment of cancer.

30. The compound according to any one of claims 1 to 26, ora pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in inhibiting lymphangiogenesis and / or lymphatic metastasis.

31. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the prevention of cancer progression.

32. The compound according to any one of claims 1 to 26, ora pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the treatment or prevention of an NF-kB-related disease or disorder.

Images