Phenoxy (hetero) aryl ethers with anti-proliferative activity

Abstract

The invention provides a phenoxy (hetero) aryl ether with anti-proliferative activity. The invention of the present application includes novel aromatic molecules useful in the treatment of pathological conditions, such as cancer, skin diseases, muscle disorders, and immune system-related disorders, such as disorders of the hematopoietic system, including the blood system, in human and veterinary medicine.

Description

[0001] This application is a divisional application of the Chinese application with the application date of August 23, 2019, the application number of 201980069893.6, and the invention title of "Phenoxy (hetero)aryl ethers with antiproliferative activity".

[0002] The present invention relates to novel compounds and their use as therapeutic agents in human and veterinary medicine. The compounds of the present invention are useful in the treatment of pathological conditions, including cancer, skin disorders, muscle disorders, lung disorders, disorders of the hematopoietic system, including blood system and immune system related disorders.

[0003] Invention description

[0004] The present invention encompasses novel molecules which show significant biological activity on cells of human and animal origin. It was found that the respective compounds influence the growth and survival of cancer cells and of primary non-cancer cells. In particular, molecules were identified which are capable of completely or partially inhibiting cell growth or leading to cell death.

[0005] The present invention thus relates to compounds with antiproliferative activity as defined herein, which are useful in the treatment of benign and malignant hyperproliferative disorders in human and veterinary medicine. In particular, the present invention relates to compounds as defined herein for use in the treatment of disorders of the hematopoietic system, including blood system and immune system related disorders, malignant tumors involving the myeloid and lymphoid line, malignant and non-malignant diseases of the skin and mucous membranes (e.g. keratosis), malignant and non-malignant diseases of the muscle, including muscle hyperproliferative diseases such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, hyperproliferative disorders, cancers and precancerous lesions of the skin and mucous membranes, such as non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), actinic keratosis, hyperproliferative diseases and cancers of the oral cavity and tongue, hyperproliferative disorders and cancers of the neuroendocrine system (such as medullary thyroid carcinoma), hyperproliferative diseases and cancers of the hematopoietic system (including the blood system) (such as leukemia and lymphoma), hyperproliferative disorders and cancers of the lung, breast, stomach, genitourinary tract, e.g. cervical cancer, including ovarian cancer, in human and veterinary medicine.

[0006] The compounds of the present invention relate to bis-aryl ether structures consisting of two six-membered aromatic rings, wherein one of the aromatic rings is an unsubstituted or substituted benzyl ring and the other aromatic ring is an unsubstituted or substituted aryl ring, which optionally comprises an N atom and thus optionally is a six-membered heteroaromatic ring. All such bis-aryl ether structures share the common feature that they contain substituents in both of the two positions which are para relative to the ether linkage, wherein such substituents on the benzyl ring which are not heteroaromatic rings are preferably selected from the group consisting of non-polar residues and / or residues with high steric requirements; and wherein such substituents on the aryl ring which are optionally heteroaromatic rings are selected from structural elements which preferably contain a high number of heteroatoms.

[0007] The first aspect of the present application relates to compounds of the general formula (I) and salts and solvates thereof:

[0008]

[0009] R 1 = C1-C 12 alkyl, preferably C4-C 12 alkyl, C2-C 12 alkenyl, preferably C4-C 12 alkenyl, C2-C 12 alkynyl, preferably C4-C 12 alkynyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, C5-C 12 dicycloalkyl, C7-C 12 dicycloalkenyl, C8-C 14 tricycloalkyl, -OC1-C 12 alkyl, preferably -OC3-C 12 alkyl, -OC2-C 12 alkenyl, preferably -OC3-C 12 alkenyl, -OC2-C 12 alkynyl, preferably -OC3-C 12 alkynyl, -OC3-C8cycloalkyl, -OC5-C8cycloalkenyl, -OC5-C 12 dicycloalkyl, -OC7-C 12 dicycloalkenyl, -OC8-C 14 tricycloalkyl, -SC1-C 12 alkyl, preferably -SC3-C 12 alkyl, -SC2-C 12 alkenyl, preferably -SC3-C 12 alkenyl, -SC2-C 12 alkynyl, preferably -SC3-C 12 alkynyl, -SC3-C8cycloalkyl, -SC5-C8cycloalkenyl, -SC5-C 12 dicycloalkyl, -SC7-C 12 dicycloalkenyl, -SC8-C 14 tricycloalkyl, -NHR 9 or -NR 9 R 10 wherein R 9 and R 10 are independently of each other selected from the group consisting of: C1-C 12 alkyl, preferably C3-C 12 alkyl, C2-C 12 alkenyl, preferably C3-C 12 alkenyl, C2-C 12 alkynyl, preferably C3-C 12alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Dicyclic alkenyl, C8-C 14 Tricycloalkyl, or R therein 9 Can be used with R 10 Together they form a ring structure, wherein the ring structure containing N atoms is selected from 3- to 8-membered ring structures or 5- to 12-membered bicyclic structures, and wherein all of the ring structures may additionally contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms contained in the ring structure, particularly wherein such substitution results in the residue containing at least twice the number of C atoms as the heteroatoms independently selected from O, S and N.

[0010] It includes in R 1 R 9 and R 10 All alkyl, alkenyl, and alkynyl residues in the definition are straight-chain or branched and are either unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Dicyclic alkenyl, C8-C 14 Tricyclic alkyl, straight or branched -OC1-C5 alkyl such as -OCH3, -OC3-C5 cycloalkyl such as -O (cyclopropyl), straight or branched -NH (C1-C5 alkyl), straight or branched -N (C1-C5 alkyl), -NH (C3-C5 cycloalkyl) such as -NH (cyclopropyl), -N (C3-C5 cycloalkyl), straight or branched -N (C1-C5 alkyl),

[0011] When included in R 1 R 9 and R 10 When the alkyl, alkenyl, and alkynyl residues in the definition are replaced by one or more =O substituents, such =O substitution cannot result in one of the groups selected from C=O, S=O, and N=O directly attaching to the aromatic ring;

[0012] It includes in R 1 R 9 and R 10all cyclic, bicyclic and tricyclic structures contained in the definition of R

[0013] wherein all alkyl, alkenyl and alkynyl residues contained in the definition of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms, and wherein such substitution results in the residue containing at least twice the number of C atoms than the number of heteroatoms independently selected from O, S and N, and wherein such substitution additionally cannot result in one of the groups selected from C=0, S=0 and N=0 being directly bound to an aromatic ring;

[0014] wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definition of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms, and wherein such substitution results in the residue containing at least the same number of carbon atoms as the number of heteroatoms independently selected from O, S and N;

[0015] wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definition of R 1 , R 9 and R 10 may be partially or completely halogenated, in particular fluorinated, more particularly perfluorinated;

[0016] wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;

[0017] and wherein R 1Preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, tert-butyl, tert-pentyl, tert-octyl, 3-pentyl, -CF3, -CF2CF3, -(CF2)2CF3, -CH(CF3)2, -CH2SCH3, -CH2CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH2CH3, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, dimethyl-aminomethyl, dimethyl-aminoethyl, diethyl-aminomethyl, ethyl-methyl- Aminomethyl, cyclopropyl, methyl-cyclopropyl, ethyl-cyclopropyl, trifluoromethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dicyclopentyl, dicyclohexyl, dicycloheptyl (preferably norbornel), dicyclooctyl, dicyclooctenyl, dicyclononyl, methyldicyclononyl, adamantyl, tricyclodecyl, ethylene oxide, oxacyclobutyl, tetrahydrofuranyl, methyltetrahydrofuranyl, trimethyltetrahydrofuranyl, tetrahydropyranyl, aziridinyl, N-methylaziridinyl, aziridine, N-methylaziridine, aziridine, N-methylaziridine, difluoroaziridine, pyrrolidinyl, N-methyl Pyrroloalkyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thiiranyl, thietanyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethylpiperazinyl, dithianly, morpholinyl, N-methylmorpholinyl, thiomorpholinyl, N-methylthiomorpholinyl, oxazaspiroheptyl, N-methyloxazaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl Thiazaspiroheptyl, N-methylthiaazaspiroheptyl, difluorothiaazaspiroheptyl, azaspiroctyl, N-methylazaspiroctyl, oxaazaspiroctyl, N-methyloxaazaspiroctyl, oxaazaspironyl, N-methyloxaazaspironyl, azaspironyl, N-methylazaspironyl, oxaazaspirodecyl, N-methyloxaazaspirodecyl, azaspirodecyl, N-methylazaspirodecyl, dihydro-oxazinyl, N-methyldihydro-oxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxopentyl, imidazoalkyl, N-methylimidazoalkyl, N,N-methylazepanyl, N-methylazaspirohexanyl, oxa-azaspirodecanyl, N-methyloxa-azaspirodecanyl, azaspirodecanyl, N-methylazaspirodecanyl, oxa-azabicyclooctanyl, N-methyloxa-azabicyclooctanyl, azabicyclooctanyl, N-methylazabicyclooctanyl, azabicycloheptanyl, N-methylazabicycloheptanyl, azabicyclononanyl, N-methylazabicyclononanyl, azadamantyl, -O(adamantyl), oxa-azabicyclononanyl, N-methyloxa-azabicyclononanyl, oxa-azabicycloheptanyl, N-methyloxa-azabicycloheptanyl, diazabicyclooctanyl, N-methyldiazabicyclooctanyl, N,N-dimethyldiazabicyclooctanyl, diazabicycloheptanyl, N-methyldiazabicycloheptanyl, N,N-dimethyldiazabicycloheptanyl; 4-oxocyclohexyl, 3-oxocyclopentyl; 2-oxocyclobutyl, 4-oxobicyclo[4.1.0]hept-1-yl;,

[0018] and wherein R 1 is even more preferably selected from C4-C 12 alkyl, C4-C 12 alkenyl, C4-C 12 alkynyl, cyclic, bicyclic and tricyclic residues, wherein the alkyl, alkenyl and alkynyl residues are preferably branched, including:

[0019]

[0020] R 2 -R 5 are independently of each other selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, linear or branched C2-C4 alkynyl, C3-C6 cycloalkyl, -CH2(C3-C6 cycloalkyl), linear or branched -OC1-C3 alkyl, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl);

[0021] wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R 2 -R 5 are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2;

[0022] wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R2 -R 5 All alkyl, alkenyl, ynyl, and cycloalkyl residues in the definition may include one or more heteroatoms independently selected from O, S, and N in the substitution of a carbon atom, wherein such substitution does not result in the direct attachment of one of the groups selected from C=O and S=O to the aromatic ring;

[0023] Where R 2 -R 3 Each is preferably -H, R 4 Preferably -H or -F, R 5 Preferably, the following groups are used: -H, -F, -Cl, -Br, -CH3, -CF3, -CH=CH2, -C≡CH, -CH2OH, -CH2NHCH3, -OH, -OCH3, -OCF3, cyclopropyl, ethylene oxide, -CH2-N-morpholinyl, -C(CH3)3, -CH2OCH3, -NO2, -CN, -NH2, -N(CH3)2, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2;

[0024] Wherein, the substituent R is defined in general formula (I) 1 To R 5 The hexacyclic aromatic rings that are bonded are preferably selected from:

[0025]

[0026] X 1 -X 4 They are selected independently from N and CR. 11 CR 12 CR 13 CR 14 ;

[0027] R 11 -R 14 The compounds are independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C4 alkyl, straight-chain or branched C2-C4 alkenyl, straight-chain or branched C2-C4 alkynyl, C3-C6 cycloalkyl, -CH2 (C3-C6 cycloalkyl), straight-chain or branched -OC1-C3 alkyl, -O (cyclopropyl), straight-chain or branched -NH (C1-C3 alkyl), straight-chain or branched -N (C1-C3 alkyl)(C1-C3 alkyl), -NH (cyclopropyl), -N (cyclopropyl)2, straight-chain or branched -N (C1-C3 alkyl)(cyclopropyl);

[0028] It includes in R 11 -R 14All alkyl, alkenyl, alkynyl, and cycloalkyl residues in the definition are either unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2;

[0029] It includes in R 11 -R 14 All alkyl, alkenyl, ynyl, and cycloalkyl residues in the definition may include one or more heteroatoms independently selected from O, S, and N in the substitution of a carbon atom, wherein such substitution does not result in the direct attachment of one of the groups selected from C=O and S=O to the aromatic ring;

[0030] Where R 11 -R 14 Preferably selected from -H, -F, -Cl, -Br, -CH3, -CF3, -OH, -OCH3, -OCF3, cyclopropyl, ethylene oxide, -C(CH3)3, -N(CH3)2, -NH2, -CN, -CH2OCH3, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2OH, -NO2, -CH2-N-morpholinyl;

[0031] And the general formula (I) defines X as... 1 -X 4 The six-membered aromatic rings are preferably selected from:

[0032]

[0033] R 6 and R 7 Independently selected from -H, -F, -CH3; or R 6 and R 7 Together they form a cyclic residue containing the carbon atoms to which they are bonded, and wherein the cyclic residue is a C3 cycloalkyl group;

[0034] R 8 Selected from -H, C1-C3 alkyl (preferably -CH3), C2-C3 alkenyl, C2-C3 alkynyl, -F, -CF3, and aromatic and heteroaromatic residues (preferably six-membered aromatic rings and five- to six-membered heteroaromatic rings);

[0035] It includes in R 8 The aromatic and heteroaromatic residues described in the definition may optionally be connected to R via a C1 alkylene or C2 alkylene linker. 8 The bonded carbon atoms are connected;

[0036] It includes in R 8all aromatic and heteroaromatic residues in the definition of R are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -N02, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl);

[0037] wherein R 8 all heteroaromatic residues in the definition of R are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -N02, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl);

[0038] wherein R 8 all alkyl, alkenyl, alkynyl residues in the definition of R are linear or branched and unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CN, -NCO, -NCS, -OH and -NH2;

[0039] wherein R 8 is preferably -H, -F, -CH3, -CH2CH3, -CF3, -C6H5;

[0040] wherein R 2 -R 8 and R 11 -R 14 all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definition of R are partially or fully halogenated, in particular fluorinated, more particularly perfluorinated;

[0041] Z 1 and Z 2 are selected from the following group:

[0042]

[0043] wherein Z 1 is selected from the group consisting of -H, linear or branched C1-C3 alkyl (preferably -CH3), cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -N3, -CF3, -CF2CF3, and wherein Z 2 is independently selected from the group consisting of linear or branched C1-C3 alkyl, preferably -CH3, -CF3, -CF2CF3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3, -CN and -OR15 (Gen Ia), wherein R 15 is selected from the group consisting of -H, C1-C8 alkyl, preferably C1-C4 alkyl, C2-C8 alkenyl, preferably C2-C4 alkenyl, C2-C8 alkynyl, preferably C2-C4 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, C5-C 12 dicycloalkyl, C7-C 12 dicycloalkenyl, C8-C 14 tricycloalkyl, and aromatic and heteroaromatic residues, preferably five- to six-membered aromatic and five- to six-membered heteroaromatic rings;

[0044] and wherein the dicycloalkyl and tricycloalkyl residues include fused, bridged and spirocyclic systems;

[0045] wherein the residues comprised in the definition of R 15 are optionally linked via a C1 alkylene or C2 alkylene or C3 alkylene linker to the O to which R 15 is bound;

[0046] wherein all aromatic and heteroaromatic residues comprised in the definition of R 15 are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl);

[0047] wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, dicycloalkyl, dicycloalkenyl and tricycloalkyl residues and alkylene linkers comprised in the definition of R 15 are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, =0, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl);

[0048] all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaromatic residues and alkylene linkers comprised in the definition of R 15 may comprise one or more heteroatoms independently selected from O, S and N in place of carbon atoms;

[0049] all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaromatic residues and alkylene linkers comprised in the definition of R 15 may be partially or fully halogenated, in particular fluorinated, more particularly perfluorinated

[0050] R 15 is preferably -H, -CH3, -CH2CH3, n-propyl, i-propyl, cyclopropyl, benzyl;

[0051] Z 1 is preferably -H, -CH3, -CF3 and cyclopropyl; and / or wherein Z 2 is preferably -OH, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2-C6H4-Me and -CN; for example:

[0052]

[0053] or wherein Z 1 and Z 2 together are =O, =S, =NR 16 or the zwitterionic =N [+] R 17 O [-] (Generic formula Ib); wherein R 16 is selected from -H, -OH, -OCH3, -CN, -S(O)CH3, -S(O)CF3, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, straight or branched C1-C3 alkyl (preferably -CH3), cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5 and -CH2C6H5; wherein R 17 is selected from straight or branched C1-C3 alkyl (preferably -CH3), cyclopropyl, -C6H5 and -CH2C6H5;

[0054] Z 1 and Z 2 together are preferably =O, =NR 16 or the zwitterionic =N [+] R 17 O [-] ; wherein R 16 is preferably selected from -H, -OH, -OCH3, -CH3, cyclopropyl and -CH2C6H5; wherein R17 Preferably, -CH3, -C(CH3)3 and -CH2C6H5 are preferred:

[0055]

[0056] Or Z 1 and Z 2 Together they form a cyclic residue (general formula Ic) containing the carbon atom to which they are bonded; wherein the cyclic residue is selected from three-membered rings, four-membered rings, five-membered rings and six-membered rings, wherein all rings may optionally contain one or more heteroatoms independently selected from O, S and N to replace the carbon atom; wherein all rings are either unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3;

[0057] Z 1 and Z 2 Preferably, they form ternary, quaternary, or quinary cyclic residues, the cyclic residues comprising the carbon atoms to which they are bonded; wherein the cyclic residues are preferably selected from cyclopropyl, cyclobutyl, ethylene oxide, oxazolidinyl, aziridinyl, aziridinyl, thiohexacyclobutane, thiazolidine, methylthiazolidine, thiazolidine-dionyl, methylthiazolidine-dionyl, and oxazolidinyl, methyloxazolidinyl, oxazolidinyl-dionyl, and methyloxazolidinyl-dionyl; and wherein the cyclic residues are optionally preferably substituted with -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3, and -CF3;

[0058]

[0059] It includes Z 1 and Z 2 All alkyl and cyclic residues in the definition may be partially or completely halogenated, particularly fluorinated, and even more particularly perfluorinated.

[0060] R 1 -R 17 X 1 -X 4 Z 1 and Z 2 The following preferred definitions may optionally be applied independently and / or in combination to all aspects, including preferred and specific aspects, all embodiments, including preferred and specific embodiments, and all subgenus defined in this invention:

[0061] 1)R 1preferably six or more, even more preferably seven or more carbon atoms;

[0062] 2) R 1 preferably selected from the group consisting of branched alkyl, alkenyl and alkynyl residues;

[0063] 3) R 1 preferably selected from the group consisting of cyclic, bicyclic and tricyclic structures, wherein the bicyclic and tricyclic residues include fused, bridged and spirocyclic systems;

[0064] 4) R 1 preferably free of heteroatoms;

[0065] 5) R 1 preferably selected from the group consisting of cyclohexyl, norbornyl, dicyclooctyl, dicyclononyl, methyl dicyclononyl, tricyclodecanyl, most preferably adamantyl, such as 1-adamantyl and 2-adamantyl;

[0066] 6) R 1 preferably contains one or more heteroatoms, preferably one, two or three heteroatoms independently selected from the group consisting of O, S and N, to replace R 1 the carbon atoms comprised in R

[0067] 7) R 1 preferably selected from the group consisting of tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azadamantyl and -O(adamantyl);

[0068] 8) preferably two, or more preferably three substituents independently selected from the group consisting of R 2 -R 5 one of the substituents R 2 -R 5 is different from -H;

[0069] 9) in case both substituents independently selected from the group consisting of R 2 -R 5 are different from -H and are in ortho position relative to the ether linkage, both substituents are preferably different from -F, -Cl, -Br, -I and -NO2, more preferably different from each other;

[0070] 10) the composition of the ring atoms defined by X 1 -X 4 is preferably selected from the following cases: all X 1 -X 4 are independently selected from the group consisting of CR 11 , CR12 , CR 13 , CR 14 , or X 1 -X 4 one of which is N and the other three are independently selected from CR 11 , CR 12 , CR 13 , CR 14 , or X 1 -X 4 two of which are N and the other two are independently selected from CR 11 , CR 12 , CR 13 , CR 14 ; i.e. the aromatic or heteroaromatic ring is selected from the group consisting of benzene, pyridine, pyrimidine, pyridazine and pyrazine;

[0071] 11) preferably two, or more preferably three, substituents independently selected from R 11 -R 14 one of which is -H, i.e. preferably two substituents independently selected from R 11 -R 14 , more preferably one of said substituents is different from -H;

[0072] 12) in case two substituents independently selected from R 11 -R 14 are different from -H and are in ortho position relative to the ether linkage, these two substituents are preferably different from -F, -Cl, -Br, -I and -NO2, more preferably from each other;

[0073] 13) R 6 , R 7 and R 8 are each preferably -F;

[0074] 14) R 6 and R 7 preferably together form a cyclic residue comprising the carbon atom to which they are bound, and wherein said cyclic residue is cyclopropyl.

[0075] A preferred aspect of the present application relates to compounds of general formula (I) and salts and solvates thereof, wherein R 6 , R 7 and R 8 are each -F,

[0076] and R 1 -R 5 , R 9 -R 17 , X 1 -X 4 , Z 1 and Z 2as defined in general formula (I), including the substituents and preferred definitions.

[0077] A further preferred aspect of the present application relates to compounds of general formula (Ia) and salts and solvates thereof, wherein R 6 , R 7 and R 8 are each -F or are each -H, and wherein Z 2 is -OH or -OS(O)2CH3,

[0078] and R 1 is -R 5 , R 9 is -R 14 , X 1 is -X 4 and Z 1 is as defined in general formula (I), including the substituents and preferred definitions.

[0079] A further preferred aspect of the present application relates to compounds of general formula (Ia) and salts and solvates thereof, wherein R 6 and R 7 together form a cyclic residue comprising the carbon atoms to which they are bound, and wherein said cyclic residue is cyclopropyl, and wherein R 8 is -H,

[0080] and wherein Z 1 is selected from -H, -CH3and -CF3, and wherein Z 2 is -OH or -OS(O)2CH3,

[0081] and R 1 is -R 5 , R 9 is -R 14 and X 1 is -X 4 as defined in general formula (I), including the substituents and preferred definitions.

[0082] A further preferred aspect of the present application relates to compounds of general formula (I) and salts and solvates thereof, wherein R 1 is selected from residues comprised in the general definition of R 1 comprising four or more, preferably six or more, even more preferably seven or more carbon atoms,

[0083] and wherein R 1 is free of heteroatoms,

[0084] and wherein R 1 is more preferably selected from cyclic, bicyclic and tricyclic structures,

[0085] and wherein R 1even more preferably selected from the group consisting of cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecanyl and adamantyl,

[0086] and wherein R 1 is most preferably adamantyl,

[0087] and R 2 -R 8 , R 11 -R 17 , X 1 -X 4 , Z 1 and Z 2 are as defined in general formula (I), including the substituents and preferences.

[0088] A further preferred aspect of the present application relates to compounds of general formula (I) and salts and solvates thereof, wherein R 1 is selected from the group consisting of residues comprised in the general definition of R 1 comprising four or more, preferably six or more, even more preferably seven or more carbon atoms,

[0089] and wherein R 1 comprises one or more, preferably 1 to 2, heteroatoms independently selected from O, S and N, substituting carbon atoms comprised in R 1 ,

[0090] and wherein R 1 is even more preferably selected from the group consisting of cyclic, bicyclic and tricyclic structures, or wherein R 1 is selected from the group consisting of residues comprising cyclic, bicyclic and tricyclic structures,

[0091] and wherein R 1 is even more preferably selected from the group consisting of tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azadamantyl and -O(adamantyl),

[0092] and wherein R 1 is most preferably tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicyclooctyl, azadamantyl and -O(adamantyl),

[0093] and R 2 -R 17 , X 1 -X 4 , Z 1 and Z 2as defined in general formula (I), including the substituents and preferred definitions.

[0094] In certain embodiments, the present application relates to compounds of general formula (I) and salts and solvates thereof, wherein R 1 is adamantyl,

[0095] and wherein Z 1 and Z 2 as defined in general formula (I) (including general formula (la), general formula (lb) and general formula (lc)), including the substituents and preferred definitions,

[0096] and wherein R 15 as defined in general formula (la), including the substituents and preferred definitions, and wherein R 16 and R 17 as defined in general formula (lb), including the substituents and preferred definitions,

[0097] and wherein R 2 -R 8 , R 11 -R 14 and X 1 -X 4 as defined in general formula (I), including the substituents and preferred definitions,

[0098] and wherein the compounds share the following structure (I-1):

[0099]

[0100] and wherein the compounds of structure (I-1) are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system (such as leukemias and lymphomas), skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0101] Examples are compounds XPF-0014, XPF-0042, XPF-0070, XPF-0182, XPF-0210, XPF-0266, XPF-0434, XPF-0476, XPF-0504, XPF-0518, XPF-0630, XPF-1162, XPF-1190, XPF-1330, XPF-1554, XPF-1596, XPF-1624, XPF-2242, XPF-2244, XPF-2245, XPF-2247, XPF-2251, XPF-2252, XPF-2253, and XPF-2254.

[0102] In yet another particular embodiment, the present application relates to compounds of general formula (I) and salts and solvates thereof, wherein R 1 as defined in general formula (I), including the substituents and preferred definitions, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N, as defined in general formula (I),

[0103] wherein R 6 as defined in general formula (I), including the substituents and preferred definitions, wherein R 6 is different from -H, with the optional proviso that R 6 is different from -CH3,

[0104] and wherein Z 1 and Z 2 as defined in general formula (I), including general formula (la), general formula (lb) and general formula (lc), including the substituents and preferred definitions,

[0105] and wherein R 15 as defined in general formula (la), including the substituents and preferred definitions, and wherein R 16 and R 17 as defined in general formula (lb), including the substituents and preferred definitions,

[0106] and wherein R 2 -R 5 , R 7 -R 14 and X 1 -X 4 as defined in general formula (I), including the substituents and preferred definitions,

[0107] and wherein the compounds share the following structure (I-2):

[0108]

[0109] and wherein the compounds of structure (I-2) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0110] Examples are the compounds XPF-0042, XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0426, XPF-0429, XPF-0434, XPF-0454, XPF-0469, XPF-0476, XPF-0496, XPF-0504, XPF-0518, XPF-0630, XPF-1162, XPF-1182, XPF-1185, XPF-1190, XPF-1196, XPF-1322, XPF-1325, XPF-1330, XPF-1546, XPF-1549, XPF-1554, XPF-1588, XPF-1596, XPF-1602, XPF-1616, XPF-1624, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2245, XPF-2246, XPF-2247, XPF-2248, XPF-2249, XPF-2250, XPF-2251, XPF-2252, XPF-2253 and XPF-2254.

[0111] In another particular embodiment, the present application relates to compounds of general formula (I) and salts and solvates thereof, and wherein R 1 as defined in general formula (I), including the substituents and preferred definitions, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally independently substituted with heteroatoms selected from O, S and N as defined in general formula (I),

[0112] as defined in general formula (I), including the substituents and preferred definitions, wherein R 8 as defined in general formula (I), including the substituents and preferred definitions, wherein R 8 is different from -H, optionally with the additional condition that R 8different from -CH3,

[0113] and wherein Z 1 and Z 2 as defined in general formula (I) (including general formula (la), general formula (lb) and general formula (lc)), including the substituents and preferred definitions,

[0114] and wherein R 15 as defined in general formula (la), including the substituents and preferred definitions, and wherein R 16 and R 17 as defined in general formula (lb), including the substituents and preferred definitions,

[0115] and wherein R 2 -R 7 , R 9 -R 14 and X 1 -X 4 as defined in general formula (I), including the substituents and preferred definitions,

[0116] and wherein the compounds share the following structure (I-3):

[0117]

[0118] and wherein the compounds of structure (I-3) - especially in the absence of additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system (such as leukemias and lymphomas), skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0119] Examples are compounds XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0426, XPF-0429, XPF-0434, XPF-0454, XPF-0469, XPF-0476, XPF-0496, XPF-0504, XPF-0518, XPF-0630, XPF-1182, XPF-1185, XPF-1190, XPF-1196, XPF-1322, XPF-1325, XPF-1330, XPF-1546, XPF-1549, XPF-1554, XPF-1588, XPF-1596, XPF-1602, XPF-1616, XPF-1624, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2245, XPF-2246, XPF-2247, XPF-2248, XPF-2249, XPF-2250, XPF-2251, XPF-2252, XPF-2253, and XPF-2254.

[0120] In another particular embodiment, the present application relates to compounds of general formula (I) and salts and solvates thereof, wherein R 6 , R 7 and R 8 are each -H, and wherein X 1 is CR 11 , X 2 is CR 12 , X 3 is CR 13 and X 4 is CR 14 ,

[0121] and wherein R 1 is as defined in general formula (I), including the substituents and preferred definitions, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 comprises six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), provided that R 1 comprising any substituents does not comprise a heteroatom selected from O, S, N, or comprises one such heteroatom,

[0122] and wherein Z 1 and Z 2 are as defined in general formula (I) (including general formula (la), general formula (lb) and general formula (lc)), including the substituents and preferred definitions,

[0123] and wherein R 15 as defined in general formula (Ia), including the substituents and preferred definitions, and wherein R 16 and R 17 as defined in general formula (Ib), including the substituents and preferred definitions,

[0124] and wherein R 2 -R 5 and R 9 -R 14 as defined in general formula (I), including the substituents and preferred definitions,

[0125] and wherein the compounds share the following structure (I-4):

[0126]

[0127] and wherein the compounds of structure (I-4) are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, oral mucosa cancer, tongue cancer, lung cancer, stomach cancer, breast cancer and cancer of the neuroendocrine system.

[0128] Examples are the compounds XPF-0006, XPF-0014, XPF-0174 and XPF-0182, XPF-0258, XPF-0266.

[0129] In another particular embodiment, the present application relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z 2 is -OR 15 and R 15 is -H, and wherein R 6 , R 7 and R 8 are each -F,

[0130] and wherein Z 1 as defined in general formula (Ia), including the substituents and preferred definitions, optionally with the additional proviso that Z 1 is different from -CF3,

[0131] and wherein R 1 -R 5 , R 9 -R 14 and X 1 -X 4as defined in general formula (I), including the definitions of substitution and preferences, optionally with the additional proviso that R

[0132] and wherein the compounds share the following structure (Ia-1):

[0133]

[0134] and wherein the compounds of structure (Ia-1) - especially without additional proviso - are preferred for use in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0135] Examples are the compounds XPF-0057, XPF-0058, XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0169, XPF-0170, XPF-0174, XPF-0182, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0630, XPF-1178, XPF-1182, XPF-1185, XPF-1190, XPF-1322, XPF-1325, XPF-1330, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2248, XPF-2251 and XPF-2252.

[0136] In yet another particular embodiment, the present application relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z 1 is cyclopropyl,

[0137] and wherein R 1 as defined in general formula (I), including the definitions of substitution and preferences, optionally with the additional proviso that R 1 different from -CF3and -CHF2,

[0138] and wherein Z 2 and R 15 as defined in general formula (Ia), including the definitions of substitution and preferences,

[0139] and wherein R 2 -R 14 and X 1 -X 4as defined in general formula (I), including the substituents and preferred definitions,

[0140] and wherein the compounds share the following structure (la-2):

[0141]

[0142] and wherein the compounds of structure (la-2) - especially without additional conditions - are preferred for use in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, ovarian cancer and cancer of the neuroendocrine system.

[0143] Examples are the compounds XPF-0202, XPF-0205, XPF-0210, XPF-1322, XPF-1325 and XPF-1330.

[0144] In a further particular embodiment, the present application relates to compounds of general formula (la) and salts and solvates thereof, wherein R 6 and R 7 together form a cyclic residue comprising the carbon atom to which they are bound, and wherein the cyclic residue is a C3cycloalkyl, i.e. cyclopropyl,

[0145] and wherein Z 1 , Z 2 and R 15 are as defined in general formula (la), including the substituents and preferred definitions,

[0146] and wherein R 1 -R 5 , R 8 -R 14 and X 1 -X 4 are as defined in general formula (la), including the substituents and preferred definitions,

[0147] and wherein the compounds share the following structure (la-3):

[0148]

[0149] and wherein the compounds of structure (la-3) are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, gastric cancer, breast cancer, ovarian cancer and cancer of the neuroendocrine system.

[0150] Examples are the compounds XPF-0042, XPF-0202, XPF-0205, XPF-0210, XPF-1162, XPF-1322, XPF-1325 and XPF-1330.

[0151] In another particular embodiment, the present application relates to compounds of general formula (la) and salts and solvates thereof, wherein R 6 , R 7 and R 8 are each -F,

[0152] and wherein Z 1 is as defined in general formula (la), including the definitions of substitution and preferences, 1 different from -CF3,

[0153] and wherein Z 2 and R 15 are as defined in general formula (la), including the definitions of substitution and preferences,

[0154] and wherein R 1 is -R 5 , R 9 is -R 14 and X 1 is -X 4 is as defined in general formula (I), including the definitions of substitution and preferences,

[0155] and wherein the compounds share the following structure (la-4):

[0156]

[0157] and wherein the compounds of structure (la-4) - especially in the absence of additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0158] Examples are the compounds XPF-0057, XPF-0058, XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0169, XPF-0170, XPF-0174, XPF-0182, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0630, XPF-1178, XPF-1182, XPF-1185, XPF-1190, XPF-1196, XPF-1322, XPF-1325, XPF-1330, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2248, XPF-2251 and XPF-2252.

[0159] In yet another particular embodiment, the present application relates to compounds of general formula (lb) and salts and solvates thereof, wherein Z 1 and Z 2 together are =NR 16 and wherein R 6 , R 7 and R 8 are each -F,

[0160] and wherein R 1 are as defined in general formula (I), including the definitions of substitution and preferences, optionally with the additional proviso that R 1 is different from -CF3,

[0161] and wherein R 16 are as defined in general formula (lb), including the definitions of substitution and preferences,

[0162] and wherein R 2 is -R 5 , R 9 is -R 14 and X 1 is -X 4 are as defined in general formula (I), including the definitions of substitution and preferences,

[0163] and wherein the compounds share the following structure (lb-1):

[0164]

[0165] and wherein the compounds of structure (lb-1) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present application, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined in the present application, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0166] Examples are the compounds XPF-0454, XPF-0469, XPF-0476, XPF-1588, XPF-1596, XPF-1602 and XPF-2249.

[0167] In yet another particular embodiment, the present application relates to compounds of general formula (lb) and salts and solvates thereof, wherein Z 1 and Z 2 together are a zwitterion =N [+] R 17 O [-] ,

[0168] and wherein R 17 are as defined in general formula (lb), including the substituents and preferred definitions,

[0169] and wherein R 1 -R 14 and X 1 -X 4 are as defined in general formula (I), including the substituents and preferred definitions,

[0170] and wherein the compounds share the following structure (lb-2):

[0171]

[0172] and wherein the compounds of structure (lb-2) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present application, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined in the present application, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer and cancer of the neuroendocrine system.

[0173] Examples are compounds XPF-0496, XPF-0504, XPF-1616 and XPF-1624.

[0174] In a further particular embodiment, the present application relates to compounds of the general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 together are a zwitterion =N [+] R 17 O [-] ,

[0175] wherein R 6 , R 7 and R 8 each is -F,

[0176] and wherein R 17 are as defined in general formula (Ib), including the substituents and preferred definitions,

[0177] and wherein R 1 -R 5 , R 9 -R 14 and X 1 -X 4 are as defined in general formula (I), including the substituents and preferred definitions,

[0178] and wherein the compounds share the following structure (Ib-3):

[0179]

[0180] and wherein the compounds of structure (Ib-3) are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, gastric cancer, breast cancer and cancer of the neuroendocrine system.

[0181] Examples are compounds XPF-0496, XPF-0504, XPF-1616 and XPF-1624.

[0182] In a further particular embodiment, the present application relates to compounds of the general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 together are =O, and wherein R 6 , R 7 and R 8 each is -F,

[0183] and wherein R 1 as defined in general formula (I), including the substituents and preferred definitions, optionally with the additional proviso that R 1 different from -CH3and -OCH3,

[0184] and wherein R 2 -R 5 , R 9 -R 14 and X 1 -X 4 as defined in general formula (I), including the substituents and preferred definitions,

[0185] and wherein the compounds share the following structure (lb-4):

[0186]

[0187] and wherein the compounds of structure (lb-4) - especially in the absence of additional provisos - are preferred for use in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer and cancer of the neuroendocrine system.

[0188] Examples are the compounds XPF-0421, XPF-0422, XPF-0426, XPF-0429, XPF-0434, XPF-1541, XPF-1542, XPF-1546, XPF-1549, XPF-1554, XPF-2245, XPF-2246, XPF-2247, XPF-2250, XPF-2253 and XPF-2254.

[0189] In yet another particular embodiment, the present application relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z 1 and Z 2 together form a cyclic residue comprising the carbon atoms to which they are bound, and wherein Z 1 and Z 2 as defined in general formula (Ic), including the substituents and preferred definitions,

[0190] and wherein R 6 , R 7 and R 8 are each -F,

[0191] and wherein R 1-R 5 , R 9 -R 14 and X 1 -X 4 as defined in general formula (I), including the substituents and preferred definitions,

[0192] and wherein the compounds share the following structure (Ic-1):

[0193]

[0194] and wherein the compounds of structure (Ic-1) are preferably used in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0195] One example is the compound XPF-0518.

[0196] In yet another particular embodiment, the present application relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z 1 and Z 2 together form a cyclic residue comprising the carbon atoms to which they are bound, and wherein Z 1 and Z 2 are as defined in general formula (Ic), including the substituents and preferred definitions, and wherein the cyclic residue is selected from the group consisting of a three-membered ring and a four-membered ring,

[0197] and wherein R 8 is as defined in general formula (I), including the substituents and preferred definitions, with the optional proviso that R 8 is different from -H,

[0198] and wherein R 1 -R 7 , R 9 -R 14 and X 1 -X 4 as defined in general formula (I), including the substituents and preferred definitions,

[0199] and wherein the compounds share the following structure (Ic-2):

[0200]

[0201] and wherein the compounds of structure (Ic-2) - especially without additional conditions - are preferred for use in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0202] One example is the compound XPF-0518.

[0203] In another particular embodiment, the present application relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z 1 and Z 2 together form a cyclic residue comprising the carbon atom to which they are bound, and wherein Z 1 and Z 2 are as defined in general formula (Ic), including the substituents and preferred definitions, and wherein the cyclic residue is selected from a three-membered ring and a four-membered ring, optionally with the proviso that the cyclic residue is different from an oxiranyl group,

[0204] and wherein R 1 -R 14 and X 1 -X 4 are as defined in general formula (I), including the substituents and preferred definitions,

[0205] and wherein the compounds share the following structure (Ic-3):

[0206]

[0207] and wherein the compounds of structure (Ic-3) - especially without additional conditions - are preferred for use in human and veterinary medicine, in particular for the medical uses described herein, preferably for immune system related applications including immunotherapy and other immunotherapy methods as defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood system such as leukemias and lymphomas, skin cancer, cancer of the oral mucosa, cancer of the tongue, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and cancer of the neuroendocrine system.

[0208] One example is the compound XPF-0518.

[0209] In some embodiments, the following compounds shown in Tables 1 to 3 are explicitly excluded from the scope of the present application:

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238] Other definitions:

[0239] The term "C1-C" 12 "Alkyl" includes all isomers of the corresponding saturated aliphatic hydrocarbon group containing 1 to 12 carbon atoms; this includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, isopentyl, 2-methylbut-2-yl, 3-methylbut-2-yl, all hexyl isomers, all heptyl isomers, all octyl isomers, all nonyl isomers, all decyl isomers, all undecyl isomers, and all dodecyl isomers.

[0240] The term "C2-C" 12 "Alkenyl" includes all isomers of the corresponding unsaturated alkene group, which comprises 2 to 12 carbon atoms connected by (i.e., including) one or more double bonds; this includes vinyl, all propenyl isomers, all butenyl isomers, all pentenyl isomers, all hexenyl isomers, all heptenyl isomers, all octenyl isomers, all nonenyl isomers, all decenyl isomers, all undecenyl isomers, and all dodecenyl isomers.

[0241] The term "C2-C" 12 The term "alkynyl" includes all isomers of the corresponding unsaturated alkynyl group, which comprises 2 to 12 carbon atoms linked by (i.e., including) one or more triple bonds; this includes ethynyl, all propynyl isomers, all butynyl isomers, all pentyynyl isomers, all hexynyl isomers, all heptyynyl isomers, all octyynyl isomers, all nonynyl isomers, all decanynyl isomers, all undecynyl isomers, and all dodecaynyl isomers. The term "alkynyl" also includes compounds having one or more triple bonds and one or more double bonds.

[0242] The term "C3-C8 cycloalkyl" includes corresponding saturated hydrocarbon groups containing 3-8 carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0243] The term "C5-C8 cycloalkenyl" includes corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing 5-8 carbon atoms, at least one of which is sp. 3Hybridized, and they are arranged in a monocyclic structure and connected by (i.e., containing) one or more double bonds; this includes all cyclopentenyl isomers, all cyclohexenyl isomers, all cycloheptenyl isomers, and all cyclooctenyl isomers.

[0244] The term "C5-C" 12 "Bicycloalkyl" includes corresponding saturated hydrocarbon groups containing 5 to 12 carbon atoms arranged in a bicyclic structure; wherein these bicyclic structures include fused, bridged, and spirocyclic systems;

[0245] The term "C7-C" 12 "Bicyclic alkenyl" includes the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon group, which contains 7 to 12 carbon atoms arranged in a bicyclic structure and connected by (i.e., including) one or more double bonds; wherein these bicyclic structures include fused, bridged and spirocyclic systems;

[0246] The term "C8-C" 14 "Tricyclic alkyl" includes corresponding saturated hydrocarbon groups containing 8 to 14 carbon atoms arranged in a tricyclic structure; wherein these tricyclic structures include fused, bridged, and spirocyclic systems;

[0247] For R 1 In general, the terms "cyclic," "bicyclic," "tricyclic," "cycloalkyl," "cycloalkenyl," "bicycloalkyl," "bicycloalkenyl," and "tricycloalkyl" refer to cyclic, bicyclic, or tricyclic residues that are directly linked to R by chemical bonds. 1 On the bound aromatic ring; and where R 1 The terms “cyclic,” “bicyclic,” “tricyclic,” “cycloalkyl,” “cycloalkenyl,” “bicycloalkyl,” “bicycloalkenyl,” and “tricycloalkyl” for substituents refer to cyclic, bicyclic, or tricyclic residues that are directly attached to R by a chemical bond. 1 It contains one of the following: C, N, O, or S atoms; for example, "R 1 "It is cyclohexyl" means that the cyclohexyl residue is related to R. 1 The bonded aromatic rings are connected; "R 1 It is methyl, and R 1 "Replaced by cyclohexyl" means that the resulting -CH2 (cyclohexyl) residue is related to R. 1 The connected aromatic rings are linked together.

[0248] If a carbon atom is replaced by a heteroatom selected from O, N, or S, the number of substituents on the corresponding heteroatom is adjusted according to its valence. For example, the -CR2- group can be replaced by -NR- or -NR2-. + -, -O- or -S- groups can be substituted.

[0249] The term "perhalogenated" relates to the complete halogenation of the carbon scaffold; the corresponding residues include the corresponding perfluorinated, perchlorinated, perbrominated and perchlorinated groups. Preferably, the term "perhalogenated" relates to perfluorinated or perchlorinated groups, more preferably perfluorinated groups.

[0250] The following contains definitions of terms used in the present specification. Unless otherwise indicated, the initial definition provided herein for a group or term applies throughout the specification for that group or term, either alone or as part of another group.

[0251] The compounds of the present application can form salts, which are also within the scope of this application. Unless otherwise specified, reference herein to a compound of the present application shall be understood to include reference to a salt thereof. As used herein, the term "one or more salts" means acidic and / or basic salts formed from inorganic and / or organic acids and bases. Zwitterions (internal salts or inner salts) are included in the term "one or more salts" as used herein (and can form, for example, where a substituent includes an acid moiety (such as a carboxyl group) and an amino group). Also included herein are quaternary ammonium salts, such as alkylammonium salts. Salts of compounds can be formed, for example, by reacting a compound with an amount of an acid or a base, such as an equivalent amount of an acid or a base, in a medium such as one in which the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0252] Exemplary salts resulting from addition of an acid include acetates (such as those formed from acetic acid or a trihaloacetic acid, for example trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hypochlorites, hypobromites, hypoiodites, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed from sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0253] Exemplary salts produced by addition of bases include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, di-cyclohexylamines, hydrabamines, N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (for example, decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (for example, benzyl and phenethyl bromides), and others.

[0254] The present application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salt" refers to a derivative of the disclosed compounds wherein the parent compound is modified by converting at least one of its existing acid or base moieties into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present application include the conventional non-toxic salts of the parent compound, for example, salts of inorganic acids or organic acids formed by the reaction of the parent compound with inorganic or organic acids. The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both; usually, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science 1977, 66(2), each of which is incorporated herein by reference in its entirety.

[0255] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0256] Further, in cases where the compounds of the present application contain asymmetric carbon atoms or atropoisomeric bonds, the present application is directed to the D-form, the L-form, as well as D, L mixtures, and, when there is more than one asymmetric carbon atom or atropoisomeric bond, to the diastereomeric forms. Those compounds of the present application which contain asymmetric carbon atoms or atropoisomeric bonds and which are normally obtained in racemic form, can be separated into the optically active isomers in known manner, for example using optically active acids. It is also possible, however, to use optically active starting materials from the outset and then to obtain the corresponding optically active or diastereomeric compounds as end products.

[0257] The compounds of the present application also include tautomeric forms. Tautomeric forms arise from the exchange of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropictautomers, which are isomeric protonation states having the same empirical formula and overall charge. Examples of prototropictautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and rings, in which a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium, or can be spatially locked into one form by appropriate substitution.

[0258] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are intended to be included. Compounds of the present application containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present application. Cis and trans geometric isomers of the compounds of the present application are described and can be isolated as a mixture of isomers or as isolated isomeric forms.

[0259] The compounds of the present application can also include all isotopes of atoms occurring in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0260] Solvates and hydrates of the compounds of the present application, and solvates and hydrates of the pharmaceutically acceptable salts thereof, are also included.

[0261] The term "compound" as used herein, unless otherwise indicated, is intended to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the recited structure.

[0262] In some embodiments, the compounds can be provided as prodrugs. As used herein, the term "prodrug" refers to a compound which, upon administration to a subject, is chemically transformed by metabolic or chemical processes into a compound of the present application or a salt and / or solvate thereof.

[0263] In some embodiments, the compounds of the present application and salts thereof are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in a compound of the present application. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound of the present application or a salt thereof.

[0264] Pharmaceutical methods

[0265] It has been found that the compounds according to the present application have pharmacologically important properties and are useful in therapy. The compounds of the present application can be used alone, in combination with each other or in combination with other active compounds.

[0266] In certain embodiments, the compounds of the present application can exhibit growth inhibitory properties in hyperproliferative processes.

[0267] The antiproliferative activity of the compounds belonging to formulae (la), (lb) and (lc) was investigated on cell lines derived from the hematopoietic system (including myeloid and lymphoid cell compartments (T cells and B cells)), neuroendocrine system, cervix, breast, ovary, lung, gastrointestinal tract and mucosal epithelia, as well as from skin epithelium and from muscle. To this end, HL-60 cells, NB-4 cells, HH cells, RPMI-8402 cells, TANOUE cells, TT cells, HeLa cells, MDA-MB-231 cells, FU-OV-1 cells, LOU-NH91 cells, 23132 / 87 cells, CAL-27 cells, BHY cells, SCC-25 cells, A-431 cells, human primary epidermal keratinocytes (HPEK) and C2C12 cells were seeded in 96-well plates (CORNING #3598) at the following initial cell numbers: HL-60 1000 cells per well; NB-4 1000 cells per well; HH 5000 cells per well; RPMI-8402 5000 cells per well; TANOUE 1500 cells per well; TT 9000 cells per well; HeLa 2000 cells per well; MDA-MB-231 3000 cells per well; FU-OV-1 3000 cells per well; LOU-NH91 4000 cells per well; 23132 / 87 2000 cells per well; CAL-27 2000 cells per well; BHY 1500 cells per well; SCC-25 1500 cells per well; A-431 700 cells per well; HPEK 1000 cells per well; C2C12 500 cells per well. Cells were treated with the compounds at the indicated final concentrations (dilution from 1000-fold stock solutions in DMSO to a final DMSO concentration of 0.1% v / v in H2O (water for injection, WFI, Fisherscientific #10378939)) for 5 days, or with 0.1% v / v empty vehicle DMSO as control for 5 days. On day 5 after start of treatment, cells were subjected to a CellTiter 96® AQueous One Solution Cell Proliferation Assay (Promega, G5420) according to the manufacturer's protocol. Readout was performed in fluorescence mode using a multiwell plate reader. On each plate controls were included that were treated with commercial compounds such as methotrexate (MTR EX) and resveratrol (RES) to inhibit growth. Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B). Readout was performed in fluorescence mode using a multiwell plate reader using a filter (excitation at 560 nm (bandwidth 10 nm), emission at 590 nm (bandwidth 10 nm)). On each plate controls were included that were treated with commercial compounds such as methotrexate (MTR EX) and resveratrol (RES) to inhibit growth.

[0268] The assay was performed in independent single experiments in duplicate or more replicates, each experiment repeated 6 times for each condition. For each individual plate, the measured fluorescence intensity values under the conditions with compound treatment were normalized to the respective equally weighted arithmetic mean of the fluorescence intensity values of the six DMSO treated control wells to obtain relative values for a baseline level of 1.0.

[0269] Two independent outlier analyses according to the method of Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12) were performed. Outliers identified by at least one method were excluded from the calculation, but in individual experiments no more than one value out of the six values for each compound. From all normalized values of the individual experiments repeated six times, the weighted arithmetic mean (abbreviated here AVE w ) for each compound was calculated. The respective standard deviation of the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and combined with the Gaussian error propagation associated with the performed normalization calculation. The resulting standard deviation is referred to herein as the "combined standard deviation".

[0270] In case of considerable variation of the normalized equally weighted arithmetic mean derived from two independent replicates, the number of independent replicates was increased to three or more. In case of four or more independent replicates, a two-line outlier analysis according to the above described method of Peirce and Chauvenet was performed on all normalized equally weighted arithmetic means.

[0271] In certain embodiments, the compounds of the application can be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes.

[0272] In one embodiment, several compounds of the present application were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 3. HL-60 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37°C and 5% CO2.

[0273] A compound is considered to be a growth inhibitor of HL-60 cells if the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to the overall base level of 1.0, after addition of the respective combined standard deviation, at a reference concentration of 20 μΜ. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0274] According to the above method, several molecules falling within the scope of the compounds defined in formulae (la), (lb) and (Ic) herein, respectively, have been identified as growth inhibitors of HL-60 cells. The HL-60 growth inhibitors identified so far relate to the compounds listed in Table 29. The entries of Table 29 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0275] Table 29: Proliferation assay with HL-60 cells at 20 μM

[0276]

[0277]

[0278]

[0279] In one embodiment, several compounds of the present application were found to inhibit the growth of NB-4 cells (human acute promyelocytic leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 207. The NB-4 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal calf serum (Fisher scientific, #15517589) at 37°C and 5% C02.

[0280] If the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or below 0.9, in particular equal to or below 0.8, equal to or below 0.7, equal to or below 0.6, equal to or below 0.4, equal to or below 0.2, if the respective combined standard deviation is added at a reference concentration of 20 pm, the compound is considered to be a growth inhibitor of NB-4 cells. Similar to the calculation for the test compounds, the overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0281] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of NB-4 cells. The NB-4 growth inhibitors identified so far relate to the compounds listed in Table 30. The entries of Table 30 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0282] Table 30: Proliferation assay with NB-4 cells at 20 μM

[0283]

[0284]

[0285] In one embodiment, several compounds of the present application were found to inhibit the growth of HH cells (human cutaneous T-cell lymphoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 707. HH cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% C02.

[0286] A compound is considered to be a growth inhibitor of HH cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0287] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of HH cells. The HH growth inhibitors identified so far relate to the compounds listed in Table 31. The entries of Table 31 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0288] Table 31: Proliferation assay with HH cells at 20 μM

[0289]

[0290]

[0291] In one embodiment, several compounds of the present application were found to inhibit the growth of RPMI-8402 cells (human T-cell acute lymphoblastic leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 290. RPMI-8402 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal calf serum (Fisher scientific, #15517589) at 37°C and 5% C02.

[0292] A compound is considered to be a growth inhibitor of RPMI-8402 cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0293] According to the above method, several molecules falling within the scope of the compounds defined in formulae (la), (lb) and (lc) herein, respectively, have been identified as growth inhibitors of RPMI-8402 cells. The RPMI-8402 growth inhibitors identified so far relate to the compounds listed in Table 32. The entries of Table 32 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0294] Table 32: Proliferation assay with RPMI-8402 cells at 20 μM

[0295]

[0296]

[0297]

[0298] In one embodiment, several compounds of the present application were found to inhibit the growth of TANOUE cells (human B-cell leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 399. TANOUE cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal calf serum (Fisherscientific, #15517589) at 37°C and 5% C02.

[0299] A compound is considered to be a growth inhibitor of TANOUE cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0300] According to the above method, several molecules falling within the scope of the compounds defined in formulae (la), (lb) and (Ic) herein, respectively, have been identified as growth inhibitors of TANOUE cells. The TANOUE growth inhibitors identified so far relate to the compounds listed in Table 33. The entries of Table 33 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0301] Table 33: Proliferation assay with TANOUE cells at 20 μM

[0302]

[0303]

[0304]

[0305] In one embodiment, several compounds of the present application were found to inhibit the growth of TT cells (human medullary thyroid carcinoma cells), which are available from the American Type Culture Collection (ATCC) under the accession number ATCC-CRL-1803. TT cells were cultured in F-12 K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% C02.

[0306] A compound is considered to be a growth inhibitor of TT cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similarly as for the calculation of the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0307] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of TT cells. The TT growth inhibitors identified so far relate to the compounds listed in Table 34. The entries of Table 34 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0308] Table 34: Proliferation assay with TT cells at 20 μM

[0309]

[0310]

[0311]

[0312] In one embodiment, several compounds of the present application were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells), which are available from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2. HeLa cells were cultured in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% C02.

[0313] If the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, equals or is lower than 0.9, in particular equals or is lower than 0.8, equals or is lower than 0.7, equals or is lower than 0.6, equals or is lower than 0.4, equals or is lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 μΜ, the compound is regarded as a growth inhibitor of HeLa cells. Similar to the calculation for the test compounds, the overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0314] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of HeLa cells. The HeLa growth inhibitors identified so far relate to the compounds listed in Table 35. The entries of Table 35 are sorted according to the respective weighted arithmetic mean of the compounds without considering the respective standard deviations, thus falling within the indicated range of activity.

[0315] Table 35: Proliferation assay with HeLa cells at 20 μM

[0316]

[0317]

[0318] In one embodiment, several compounds of the present application were found to inhibit the growth of MDA-MB-231 cells (human breast cancer cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 732. MDA-MB-231 cells were cultured in Leibovitz’s L-15 (without phenol red) medium (Fisherscientific, # 11540556) containing 10% fetal calf serum (Fisherscientific, # 15517589) at 37°C and 0% C02.

[0319] If the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 μΜ, the compound is considered to be a growth inhibitor of MDA-MB-231 cells. Similar to the calculation for the test compounds, the overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0320] According to the above method, several molecules falling within the scope of the compounds defined in formula (la), (lb) and (Ic) herein, respectively, have been identified as growth inhibitors of MDA-MB-231 cells. The MDA-MB-231 growth inhibitors identified so far relate to the compounds listed in Table 36. The entries of Table 36 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0321] Table 36: Proliferation assay with MDA-MB-231 cells at 20 μM

[0322]

[0323]

[0324]

[0325] In one embodiment, several compounds of the present application were found to inhibit the growth of FU-OV-1 cells (human ovarian cancer cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 444. FU-OV-1 cells were cultured at 37°C and 5% C02 in Ham’s F-12 / DMEM (1 : 1) medium (Fisherscientific, #11514436) containing 10% fetal calf serum (Fisherscientific, #15517589) and 1 mM sodium pyruvate (Fisherscientific, #11501871).

[0326] If the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, upon addition of the respective combined standard deviation at a reference concentration of 20 μΜ, the compound is considered to be a growth inhibitor of FU-OV-1 cells. Similar to the calculation for the test compounds, the overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0327] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) herein have been identified as growth inhibitors of FU-OV-1 cells. The FU-OV-1 growth inhibitors identified so far relate to the compounds listed in Table 37. The entries of Table 37 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0328] Table 37: Proliferation assay with FU-OV-1 cells at 20 μM

[0329]

[0330] In one embodiment, several compounds of the present application were found to inhibit the growth of LOU-NH91 cells (human lung squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 393. LOU-NH91 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal calf serum (Fisher scientific, #15517589) at 37°C and 5% C02.

[0331] If the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, upon addition of the respective combined standard deviation at a reference concentration of 20 μΜ, the compound is considered to be a growth inhibitor of LOU-NH91 cells. Similar to the calculation for the test compounds, the overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0332] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of LOU-NH91 cells. The LOU-NH91 growth inhibitors identified so far relate to the compounds listed in Table 38. The entries of Table 38 are sorted according to the respective weighted arithmetic mean of the compounds without taking into account the respective standard deviation, thus falling within the indicated range of activity.

[0333] Table 38: Proliferation assay with LOU-NH91 cells at 20 μM

[0334]

[0335]

[0336] In one embodiment, several compounds of the present application were found to inhibit the growth of 23132 / 87 cells (human gastric adenocarcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 201. The 23132 / 87 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal calf serum (Fisherscientific, #15517589) at 37°C and 5% C02.

[0337] A compound is considered a growth inhibitor of 23132 / 87 cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or below 0.9, in particular equal to or below 0.8, equal to or below 0.7, equal to or below 0.6, equal to or below 0.4, equal to or below 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements, similarly as for the calculation of the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0338] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of 23132 / 87 cells. The 23132 / 87 growth inhibitors identified so far relate to the compounds listed in Table 39. The entries of Table 39 are sorted according to the respective weighted arithmetic mean of the compounds without taking into account the respective standard deviation, thus falling within the indicated range of activity.

[0339] Table 39: Proliferation assay with 23132 / 87 cells at 20 μM

[0340]

[0341]

[0342]

[0343] In one embodiment, several compounds of the present application were found to inhibit the growth of CAL-27 cells (human tongue squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 446. CAL-27 cells were cultured in DMEM medium (Fisherscientific, #11584456) containing 10% fetal calf serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0344] A compound is considered to be a growth inhibitor of CAL-27 cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0345] According to the above method, several molecules falling within the scope of the compounds defined in formulae (la), (lb) and (lc) herein, respectively, have been identified as growth inhibitors of CAL-27 cells. The CAL-27 growth inhibitors identified so far relate to the compounds listed in Table 40. The entries of Table 40 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0346] Table 40: Proliferation assay with CAL-27 cells at 20 μM

[0347]

[0348]

[0349]

[0350] In one embodiment, several compounds of the present application were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 404. BHY cells were cultured in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0351] A compound is considered to be a growth inhibitor of BHY cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0352] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of BHY cells. The BHY growth inhibitors identified so far relate to the compounds listed in Table 41. The entries of Table 41 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0353] Table 41: Proliferation assay with BHY cells at 20 μM

[0354]

[0355]

[0356] In one embodiment, several compounds of the present application were found to inhibit the growth of SCC-25 cells (human tongue squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 617. The SCC-25 cells were cultured in Ham’s F-12 / DMEM (1 :1) medium (Fisher scientific, #11514436) containing 10% fetal bovine serum (Fisher scientific, #15517589) and 1 mM sodium pyruvate (Fisher scientific, #11501871) at 37°C and 5% C02.

[0357] A compound is considered to be a growth inhibitor of SCC-25 cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0358] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of SCC-25 cells. The SCC-25 growth inhibitors identified so far relate to the compounds listed in Table 42. The entries of Table 42 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0359] Table 42: Proliferation assay with SCC-25 cells at 20 μM

[0360]

[0361]

[0362] In one embodiment, several compounds of the present application were found to inhibit the growth of A-431 cells (human epidermoid squamous cell carcinoma cells), which are available from CellLines Service GmbH (CLS) under the accession number 300112. A-431 cells were cultured in DMEM medium (Fisher scientific, #11584456) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37°C and 5% CO2.

[0363] A compound is considered to be a growth inhibitor of A-431 cells if the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 mM. The overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurement, similar to the calculation for the test compounds. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0364] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of A-431 cells. The A-431 growth inhibitors identified so far relate to the compounds listed in Table 43. The entries of Table 43 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0365] Table 43: Proliferation assay with A-431 cells at 20 μM

[0366]

[0367]

[0368]

[0369] In one embodiment, several compounds of the present application were found to inhibit the growth of human epidermal keratinocyte progenitor cells (HPEKp, pooled), which are available from CELLnTEC Advanced CellSystems AG under the accession number HPEKp. HPEKp cells were cultured in CnT-Prime epithelial medium (CELLnTEC, #CnT-PR, fully defined low-calcium formulation completely free of animal- or human-derived components) without the addition of further components at 37°C and 5% CO2.

[0370] If the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 10 μΜ, the compound is considered a growth inhibitor of HPEKp cells. Similar to the calculation for the test compounds, the overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0371] According to the above method, several molecules falling within the scope of the compounds defined in formula (la), (lb) and (Ic) herein, respectively, have been identified as growth inhibitors of HPEKp cells. The HPEKp growth inhibitors identified so far relate to the compounds listed in Table 44. The entries of Table 44 are sorted according to the respective weighted arithmetic mean of the compounds, without taking into account the respective standard deviations, thus falling within the indicated range of activity.

[0372] Table 44: Proliferation assay with HPEKp cells at 10 μM

[0373]

[0374]

[0375]

[0376] In one embodiment, several compounds of the present application were found to inhibit the growth of C2C12 cells (murine myoblast cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 565. C2C12 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0377] If the weighted arithmetic mean of the normalized fluorescence intensity values, relative to the overall base level of 1.0, is equal to or lower than 0.9, in particular equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, if the respective combined standard deviation is added at a reference concentration of 20 μΜ, the compound is regarded as a growth inhibitor of C2C12 cells. Similar to the calculation for the test compounds, the overall base level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The respective combined standard deviation of the DMSO values is less than 1-10 -2 .

[0378] According to the above method, several molecules falling within the scope of the compounds defined in formula (la) and (lb) herein, respectively, have been identified as growth inhibitors of C2C12 cells. The C2C12 growth inhibitors identified so far relate to the compounds listed in Table 45. The entries of Table 45 are sorted according to the respective weighted arithmetic mean of the compounds without considering the respective standard deviations, thus falling within the indicated range of activity.

[0379] Table 45: Proliferation assay with C2C12 cells at 20 μM

[0380]

[0381]

[0382]

[0383] In one aspect, the present application relates to the treatment of skin, skin appendages, mucosa, mucosa appendages, cornea and all kinds of epithelial tissue. The term "skin" relates to the tissue comprising the epidermis and the dermis. The term "mucosa" relates to the mucosa and submucosa, including the oral mucosa, the nasal mucosa, the ocular mucosa, the ear mucosa, the respiratory mucosa, the genital mucosa, the uroepithelial mucosa, the anal mucosa and the rectal mucosa. The term "appendages" relates to the tissue comprising hair follicles, hair, finger nails, toe nails and glands, including sebaceous glands, sweat glands, e.g. apocrine or eccrine sweat glands, and mammary glands.

[0384] In one embodiment, the present application relates to the treatment of non-melanoma skin cancer and precancerous lesions, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), sebaceous carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, cutaneous fibrosarcoma, actinic keratosis (AK) or Bowen's disease (BD), as well as other squamous epithelium cancers and precancerous lesions, for example cutaneous SCC, lung SCC, head and neck SCC, oral cavity SCC, tongue SCC, esophageal SCC, cervical SCC, perioptic SCC, thyroid SCC, penile SCC, vaginal SCC, prostatic SCC and bladder SCC.

[0385] In yet another embodiment, the present application relates to the treatment of skin and mucosa disorders with a keratinization defect (keratosis) and / or abnormal keratinocyte proliferation, such as psoriasis, Darier's disease, lichen planus, lupus erythematosus, ichthyosis or verruca vulgaris (senile).

[0386] In another embodiment, the present application relates to the treatment of skin and mucosa diseases and skin and mucosa cancers each associated with and / or caused by viral infections, such as warts, and warts associated with HPV (human papillomavirus), papillomas, HPV-associated papillomas, papillomatosis and HPV-associated papillomatosis, for example warts (plantar warts), flat warts (flat wart / plane wart), filiform warts (filiform wart), mosaic warts, periungual warts, subungual warts, oral warts, genital warts, fibroepithelial papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovascular papilloma, florid papillomatosis, nasal papilloma, pharyngeal papilloma, papillomatosis cutis carcinoides, Papillomatosis cutis lymphostatica, Papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis), herpes-associated diseases, for example lip herpes, genital herpes, herpes zoster, corneal herpes or Kaposi's sarcoma and HPV-associated cancers of the cervix, vulva, penis, vagina, anus, oropharynx, tongue and oral cavity.

[0387] In yet another embodiment, the present application relates to the treatment of atopic dermatitis.

[0388] In yet another embodiment, the present application relates to the treatment of acne.

[0389] In yet another embodiment, the present application relates to the treatment of skin wounds, wherein the process of wound healing is accelerated.

[0390] In yet another embodiment, the present application relates to the treatment of cancers associated with and / or caused by viral infections, i.e. cancer virus infections, such as cancers associated with HBV- and HCV (hepatitis B and C virus), such as hepatocarcinomas, cancers associated with EBV (Epstein-Barr virus), such as Burkitt's lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma and gastric cancer, cancers associated with HPV (human papilloma virus), such as cervical cancer, cancers associated with HHV (human herpes virus), such as Kaposi's sarcoma, and cancers associated with HTLV (human T cell lymphotrophic virus), such as T cell leukemia and T cell lymphoma.

[0391] Yet another aspect of the present application relates to the treatment of immune system related disorders. As used herein, the term "immune system related disorder" applies to pathological conditions of the hematopoietic system including the blood system, in particular of immune cells belonging to the innate or adaptive immune system.

[0392] Examples are diseases of the hematopoietic system including the blood system, such as myeloid malignancies, including acute and chronic leukemias, e.g. chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL); or malignancies of the lymphoid lineage, including acute and chronic forms of leukemia and lymphoma, e.g. T-cell acute lymphoblastic leukemia (T-ALL), pre-T-cell acute lymphoblastic leukemia (pre-T-ALL), cutaneous T-cell lymphoma, chronic lymphocytic leukemia (CLL), including T-cell CLL (T-CLL) and B-cell CLL (B-CLL), prolymphocytic leukemia (PLL) including T-cell PLL (T-PLL) and B-cell PLL (B-PLL), B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), cutaneous B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, mantle cell lymphoma, myeloma or multiple myeloma; or acute lymphoblastic and acute myeloid mixed lineage leukemia with MLL gene translocation.

[0393] Another aspect of the invention relates to therapeutic uses in immune system-related applications. As used herein, the term "immune system-related application" applies to interventions affecting the proliferation, differentiation, and / or activation of cell lineages in the hematopoietic system, including the blood system, to modulate immune responses (immunomodulation). As used herein, the term "immune system-related application" also applies to interventions affecting the cellular and noncellular microenvironment at sites of action of immune cells to support and / or enable immune cells to perform their functions. In particular, interventions defined herein as "immune system-related applications" involve immune cells belonging to the innate or adaptive immune system.

[0394] Therefore, the compounds of the present invention can be used alone or in combination with other immunotherapeutic methods or compounds (as immune adjuvants, such as vaccine adjuvants, or as adjuvants for immunotherapy). As used herein, the term "immunotherapy" applies to activated immunotherapy in patients without immunodeficiency or with acquired or congenital immunodeficiency, as well as immune restoration to enhance the functionality of the immune system in its response to pathogens or pathologically transformed endogenous cells, such as cancer cells.

[0395] As used herein, the term "other immunotherapy methods" applies to the use of vaccines, antibody therapy, cytokine therapy, immune checkpoint inhibitors and immune response stimulating agents, as well as autologous transplantation of genetically modified or unmodified immune cells that can be stimulated by intercellular signals, signal transduction molecules, antigens or antibodies, i.e., adoptive immune cell transfer.

[0396] The present invention relates to methods of use in immune system-related applications and other immunotherapies, including in vivo, in vitro, and ex vivo applications.

[0397] Specific examples include the activation and / or enhancement of peripheral T lymphocytes (including T helper cells and cytotoxic T cells) to amplify the immune response, particularly by stimulating proliferation and / or the production and / or secretion of cytokines and / or cytotoxic agents during antigen recognition; and the activation and / or enhancement of B lymphocyte activation to amplify the immune response, particularly by stimulating proliferation and / or antibody production and / or secretion; and by increasing the number of specific immune cell subtypes, by regulating differentiation and / or cell fate determination during immune cell development (e.g., regulating, particularly increasing, the number of immune cells belonging to the T cell and B cell lineages, including marginal zone B cells, cytotoxic T cells, or T helper (Th) subsets (especially Th1, Th2, Th17) and regulatory T cells) to enhance the immune response; or by using them as immune adjuvants such as vaccine adjuvants.

[0398] Another aspect of the present invention relates to the treatment of muscle diseases (including diseases of skeletal muscle, cardiac muscle and smooth muscle).

[0399] In one embodiment, the present application relates to the treatment of muscular dystrophy (MD).

[0400] Specific examples are Duchenne MD, Becker MD, congenital MD, Limb-Girdle MD, facioscapulohumeral MD, Emery-Dreifuss MD, distal MD, myotonic MD or oculopharyngeal MD.

[0401] In another embodiment, the present application relates to the treatment of muscle hyperproliferative disorders, including myoblastoma, rhabdomyoma and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy.

[0402] In another embodiment, the compounds of the application can be used in muscle regeneration following pathological muscle degeneration or atrophy, for example caused by trauma, caused by muscle ischemia or caused by inflammation, in muscle atrophy associated with aging or in muscle atrophy associated with a disease, such as myositis and fibromyositis or poliomyelitis.

[0403] Another aspect relates to the treatment of a disorder of the neuroendocrine system, such as a cancer of the neuroendocrine system, including neuroendocrine small cell carcinoma, neuroendocrine large cell carcinoma and carcinoid tumors, for example tumors of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus and lung, such as neuroendocrine tumors of the pituitary gland, neuroendocrine tumors of the adrenal gland, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, clear cell oncocytic tumors, paraganglioma, pulmonary carcinoid, neuroblastoma, gastrointestinal carcinoid, Goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagonoma, somatostatinoma, VIPoma, insulinoma, non-functioning islet cell tumor, multiple endocrine neoplasm type 1 or pulmonary carcinoid.

[0404] Another aspect relates to the treatment of a pulmonary disorder such as lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), including lung squamous cell carcinoma, lung adenocarcinoma and lung large cell carcinoma.

[0405] Another aspect relates to the treatment of hyperproliferative diseases, cancers or precancerous lesions of the brain, pancreas, breast, ovary, liver, thyroid, urogenital tract, gastrointestinal tract, and endothelial tissues, including glioblastoma, mixed glioblastoma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, gliocytoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, visual pathway and hypothalamic glioma, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic pseudopapillary tumor, intraductal papillary-mucinous tumor of the pancreas, pancreatic mucinous cystadenocarcinoma, pancreatoblastoma, and pancreatic intraepithelial neoplasia, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, papillary thyroid carcinoma, and follicular thyroid carcinoma, cervical carcinoma, hormone receptor positive breast cancer, and hormone receptor negative breast cancer, ovarian cancer, gastric cancer, and angiosarcoma.

[0406] Methods of use of the present application relate to in vivo, in vitro, and ex vivo use, respectively.

[0407] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting the disease; e.g., arresting the development of a disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., halting further development of the pathology and / or symptomatology); and (2) ameliorating the disease; e.g., ameliorating the disease, condition, or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition, or disorder (i.e., reversing the pathology and / or symptomatology), such as lessening the severity of the disease; and (3) slowing the progression of the disease. The term "treating" also includes palliative treatment.

[0408] In some embodiments, administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, is effective to prevent a disease; e.g., to prevent a disease, condition, or disorder in an individual who can be predisposed to a disease, condition, or disorder but does not yet experience or display the pathology or symptomatology of the disease.

[0409] The compounds of the present application can be used in human and veterinary medicine, including the treatment of companion animals, such as horses, dogs, cats, rabbits, guinea pigs, fish (e.g., koi), birds (e.g., falcons); and livestock, such as cattle, poultry, swine, sheep, goats, donkeys, yaks, and camels.

[0410] Pharmaceutical compositions

[0411] The present application also provides pharmaceutical compositions for use in medicine (e.g., human or veterinary medicine) comprising a compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0412] A pharmaceutical composition is produced using an effective dose of a compound according to the application or a salt, solvate or prodrug thereof, in addition to physiologically acceptable carriers, diluents and / or adjuvants. The dose of active compound can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated and similar factors. The daily dose can be administered in a single dose, which can be administered once, or can be subdivided into two or more daily doses, generally from 0.001 to 2000 mg. It is particularly preferred to provide a daily administration dose of 0.1 to 500 mg, for example 0.1 to 100 mg.

[0413] Suitable administration forms are topical or systemic, including enteral, oral, rectal and parenteral, such as infusion and injection, intravenously, intra-arterially, intraperitoneally, intramuscularly, intracardiacly, epidurally, intracerebrally, intracerebroventricularly, intraosseously, intraarticularly, intraocularly, intravitreally, intrathecally, intravaginally, intrasinusally, intravesically, subcutaneously, intradermally, transdermally, transmucosally, inhalationally, intranasally, buccal, sublingual and intralesional preparations. Oral, parenteral (e.g. intravenous or intramuscular), intranasal (e.g. dry powder or sublingual) preparations of the compounds according to the application are particularly preferred. Conventional galenic forms can be used, such as tablets, sugar-coated tablets, capsules, dispersible powders, granules, aqueous solutions, alcoholic aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lipsticks, mouthwashes, foams, pastes, tinctures, skin patches and adhesive tapes, occlusive forms or in combination with time-release drug delivery systems, electrophoretic dermal delivery systems including implants and devices, and in combination with jet injectors, liposomes and transfersome vesicles, vapours, sprays, syrups, fruit juices or drops and eye drops.

[0414] Solid pharmaceutical forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acid, silicone oil, high molecular weight fatty acids such as stearic acid, gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers such as polyethylene glycol; if desired, formulations suitable for oral administration can comprise additional flavourings and / or sweeteners.

[0415] Liquid pharmaceutical forms can be sterilized and / or, if appropriate, contain auxiliary substances such as preservatives, stabilizers, wetting agents, permeation agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols (for adjusting the osmotic pressure or for buffering), and / or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and chelating agents such as ethylenediaminetetraacetic acid and its nontoxic salts. High-molecular-weight polymers such as liquid polyethylene oxides, microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, dextran or gelatin are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high-molecular-weight fatty acids such as stearic acid, gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high-molecular-weight polymers such as polyethylene glycols.

[0416] Oily suspensions for parenteral or topical application can be vegetable oils, synthetic oils or semisynthetic oils, such as liquid fatty acid esters having 8 to 22 carbon atoms in the fatty acid chain, for example, palmitic acid, lauric acid, tridecylic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brassicic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, propanol, butanol, pentanol or its isomers, ethylene glycol or glycerol. Examples of such fatty acid esters are, inter alia, miglyol, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-decanoic acid, caprylic / capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleate, ethyl oleate, waxy fatty acid esters such as artificial uropygial fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters. Silicone oils or fatty alcohols of different viscosity, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. Vegetable oils, such as castor oil, apricot kernel oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil, can also be used.

[0417] Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropanol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, dipropylene glycol or tripropylene glycol, waxes, methylcellosolve, cellosolve, esters, morpholine, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone and the like.

[0418] Cellulose ethers, such as hydroxypropylmethylcellulose, methylcellulose or ethylcellulose, or soluble starch, which can be dissolved or swollen in water or in organic solvents, can be used as film formers.

[0419] Mixtures of gelling agents and film formers are also entirely possible. In this case, use is made in particular of ionic macromolecules such as sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium starch glycolate, alginic acid or propylene glycol alginate (as sodium salt), gum arabic, xanthan gum, guar gum or carrageenan. The following substances can be used as additional formulation adjuvants: glycerol, paraffin of different viscosities, triethanolamine, collagen, allantoin and phenylbenzimidazole sulfonic acid (novantisolic acid). The formulation also requires the use of surfactants, emulsifiers or wetting agents, for example sodium laurylsulfate, fatty alcohol ether sulfate, N-lauryl-beta-iminodipropionic acid disodium, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbate esters (for example Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride or mono / dialkyl polyglycol ether monoethanolamine phosphate. Stabilizers for stabilizing emulsions or preventing decomposition of active substances such as antioxidants (for example tocopherol or butylhydroxyanisole) or preservatives (such as p-hydroxybenzoic acid esters) such as montmorillonite or colloidal silicic acid can likewise be used for the production of the desired formulations.

[0420] Formulations for parenteral administration can be presented in unit dose form, such as ampoules or vials. It is preferred to use solutions of the active compounds, preferably aqueous solutions, especially isotonic solutions and also suspensions. These injection forms can be prepared by mixing the active compounds, for example lyophilizates, where appropriate with further solid carrier substances, with the required solvent or suspending agent, ready for use or only directly before use.

[0421] Intranasal formulations can be present in the form of aqueous or oily solutions or aqueous or oily suspensions. They can also be present in the form of lyophilizates, which are prepared using suitable solvents or suspending agents before use.

[0422] Inhalable formulations can be present in the form of powders, solutions or suspensions. Preferably, inhalable formulations are in the form of powders, for example mixtures of the active ingredient with suitable formulation adjuvants such as lactose.

[0423] The preparations are produced, aliquoted and sealed under conventional antibacterial and aseptic conditions.

[0424] As indicated above, the compounds of the present application can be administered with other active agents (e.g., therapeutically active compounds for treating the conditions described above) as combination therapy, sequential therapy, or concurrent combination therapy. These therapeutically active compounds can include, but are not limited to, chemotherapeutic agents such as nucleoside and nucleobase analogs, e.g., cytarabine, gemcitabine, azathioprine, mercaptopurine, fluorouracil, thioguanine, azacytosine, capecitabine, doxifuridine; such as platinum-based drugs, e.g., cisplatin, oxaliplatin, carboplatin, and nedaplatin; such as anthracyclines, e.g., doxorubicin, epirubicin, valrubicin, idarubicin, daunorubicin, zorubicin, pixantrone, and mitoxantrone; such as peptide antibiotics, e.g., actinomycin and bleomycin; such as alkylating agents, e.g., mechlorethamine, chlorambucil, melphalan, nitrosoureas, dacarbazine, temozolomide, and cyclophosphamide; such as anti-mitotic agents, including taxanes and vinca alkaloids, e.g., docetaxel, paclitaxel, Abraxane, cabazitaxel, vinblastine, vindesine, vinorelbine, and vincristine; such as topoisomerase inhibitors, e.g., irinotecan, topotecan, teniposide, and etoposide; such as other cell growth inhibitors, e.g., hydroxylurea and methotrexate; such as proteasome inhibitors, e.g., bortezomib, ixazomib; and other targeted therapeutics, such as kinase inhibitors, cell cycle inhibitors, modulators, i.e., inhibitors and activators of signaling pathways, including growth factor signaling, cytokine signaling, NF-κΒ signaling, AP1 signaling, JAK / STAT signaling, EGFR signaling, TGF-β signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g., erlotinib, lapatinib, dasatinib, imatinib, afatinib, vemurafenib, dabrafenib, nilotinib, cetuximab, trametinib, pembrolizumab, cobimetinib, capivasatin, pegaptanib, crizotinib, olaparib, panitumumab, cabozantinib, ponatinib, regorafenib, entrectinib, ranibizumab, ibrutinib, trastuzumab, rituximab, alemtuzumab, gefitinib, bevacizumab, lenvatinib, bosutinib, axitinib, pazopanib, everolimus, temsirolimus, ruxolitinib, tofacitinib, sorafenib, sunitinib, aflibercept, vandetanib, vismodegib, and sonidegib; retinoids, such as retinol, tretinoin, isotretinoin, alitretinoin, bexarotene, tazarotene, alitretinoin, adapalene, and tretinoin emollient;Hormone signaling modulators, including estrogen receptor modulators, androgen receptor modulators, and aromatase inhibitors, such as raloxifene, tamoxifen, fulvestrant, lasofoxifene, toremifene, bicalutamide, flutamide, anastrozole, letrozole, and exemestane; histone deacetylase inhibitors, such as vorinostat, romidepsin, panobinostat, belinostat, and chidamide; and ingenol mebutate; valproic acid, resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiotepa; N-methyl d-glucamine; and immune response modulators, including immune checkpoint inhibitors, such as imiquimod, ipilimumab, atezolizumab, ofatumumab, rituximab, nivolumab, and pembrolizumab; and anti-inflammatory drugs, including glucocorticoids and non-steroidal anti-inflammatory drugs, such as cortisone-based preparations, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolon-hexacetonid, mometason furoat, clobetasol propionat, acetylsalicylic acid, salicylic acid and other salicylates, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, loxoprofen, flurbiprofen, oxaprozin, indomethacin, ketorolac, tolmetin, diclofenac, etodolac, aceclofenac, nalfon, sulindac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, parecoxib, etoricoxib, and firocoxib; and ACE inhibitors; and beta-blockers; and myostatin inhibitors; and PDE-5 inhibitors; and antihistamines. For combination therapy, the active ingredients can be formulated as a composition comprising several active ingredients in a single dosage form and / or as a kit comprising separate active ingredients in separate dosage forms. The active ingredients used in combination therapy can be co-administered or administered separately.

[0425] The compounds of the present application can be administered in the form of antibody-drug conjugates.

[0426] The compounds of the present application can be administered in combination with surgery, cryotherapy, electrodesiccation, radiotherapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell-based transplant therapy, stem cell therapy, physical therapy, and occupational therapy.

[0427] Chemical synthesis

[0428] Abbreviations

[0429] Ac acetyl

[0430] aq aqueous

[0431] BRSM based on recycled material (yield)

[0432] Bu butyl

[0433] DCE 1,2-dichloroethane

[0434] DCM dichloromethane

[0435] DIBAL-H diisobutylaluminum hydride

[0436] DMF N,N-dimethylformamide

[0437] DMSO dimethyl sulfoxide

[0438] equiv equivalent

[0439] ESI electrospray ionization

[0440] Et ethyl

[0441] Me methyl

[0442] Ms methanesulfonyl

[0443] mol% mol percent

[0444] NMR nuclear magnetic resonance spectroscopy

[0445] PE petroleum ether

[0446] PTSA p-toluenesulfonic acid

[0447] sat saturated

[0448] TBAF tetrabutylammonium fluoride

[0449] THF tetrahydrofuran

[0450] TMS trimethylsilyl

[0451] UV ultraviolet light

[0452] General

[0453] The compounds listed in Tables 46 and 47 have been identified by TLC using pre-coated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, toluene, triethylamine or acetic acid (as eluent, preferably as binary or ternary solvent mixtures) as eluent. The compounds have been visualized using UV light at a wavelength of 254 nm or 366 nm and / or common staining solutions such as phosphomolybdic acid, potassium permanganate or ninhydrin. The completion of the reactions has also been monitored in this way. Unless otherwise stated, the reactions have been carried out under an inert atmosphere. Anhydrous solvents have been used wherever necessary. All reactions have been stirred using a stirrer plate and magnetic stirrer bar.

[0454] In addition, the compounds listed in Table 46 have also been identified by mass spectrometry (positive ions using formic acid in the mobile phase, and negative ions without the use of an additive). If the molecule is difficult to ionize in negative mode, ammonium carbonate is used. Representative compounds and those that show poor ionization in mass spectrometry have also been identified by nuclear magnetic resonance spectroscopy (Table 47). Chemical shifts (δ) are reported in parts per million (ppm) relative to the residual solvent peak, rounded to the nearest 0.01 ppm for protons and to the nearest 0.1 ppm for carbons (reference: CHCl3 1 H: 7.26 ppm, 13 C: 77.2 ppm], DMSO[ 1 H: 2.50 ppm, 13 C: 39.5 ppm). Coupling constants (J) are reported to the nearest 0.1 Hz in Hz. Peak multiplicities are represented as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (heptet), m (multiplet) and br (broad).

[0455] Synthesis of the compounds

[0456] The above compounds of the application falling within the scope of Formula I can be synthesized and purified by those skilled in the art, and preferably according to the general procedures (A to I) described herein, as illustrated in Scheme 1.

[0457]

[0458] Scheme 1: General synthesis scheme.

[0459] A) Under an argon atmosphere and stirring, K2CO3 (1.5 eq.) was added to the corresponding mono- or di-substituted phenol (1.0-1.5 eq.) and 4-alkyl ester halo(hetero)aryl (1 eq.) dissolved in DMSO (0.5 M) and the mixture was stirred at room temperature or heated between 40 and 160 °C until complete conversion. The mixture was brought back to room temperature and partitioned between an organic solvent (preferably petroleum ether and water). The aqueous layer was re-extracted twice and the combined organic phases were washed with NaOH (aqueous solution, 2 M), then with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt, DCM / MeOH or petroleum ether / AcOEt / NEt3) to give the desired bis(hetero)aryl ether ester.

[0460] B) Under an argon atmosphere and stirring, the corresponding bis(hetero)aryl ether alkyl ester (1 eq.) was dissolved in dry THF (0.2 M) and the resulting solution was cooled to 0 °C with an ice bath. DIBAL-H (2.5 eq., 1.2 M in toluene) was then added dropwise and the mixture was stirred at this temperature until complete conversion. The reaction was quenched by the Fieser method, filtered, concentrated in vacuo and the residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired alcohol.

[0461] C) Use either of these procedures depending on the scale and substrate.

[0462] Under vigorous stirring, MnO2 (2-4 eq.) was added to the corresponding alcohol (1 eq.) dissolved in DCM (0.2 M). The resulting suspension was stirred at room temperature or 40 °C until complete conversion. The reaction was then diluted with AcOEt, filtered over celite and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired aldehyde.

[0463] Under vigorous stirring, Des-Martin periodinane (1.2 eq.) was added to the corresponding alcohol (1 eq.) dissolved in DCM or DMSO (0.2 M). The resulting suspension was stirred at room temperature until complete conversion. The solution was diluted in AcOEt and quenched with saturated aqueous NaHCO3, then phase separation was performed. The aqueous layer was re-extracted twice and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired aldehyde.

[0464] To a solution of oxalyl chloride (2 eq.) in DCM (0.2 M) at -78°C, anhydrous DMSO (4 eq.) was added and the mixture was stirred for 30 min. Then a solution of the corresponding alcohol (1 eq.) in DCM (0.2 M) was added, followed by freshly distilled NEt3(8 eq.). The resulting solution was stirred for 1 h, then slowly brought to room temperature. The solution was diluted in AcOEt, quenched with HCI 1 M aqueous solution, phase separation was performed. The aqueous layer was reextracted twice and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give the desired aldehyde.

[0465] In some cases, the desired aldehyde proved to be unstable and was used directly in the subsequent step without characterization after a fast purification using the indicated method.

[0466] D) To the corresponding aldehyde (1 eq.) dissolved in anhydrous THF (0.2 M) at 0°C under argon atmosphere and stirring, TMSCF3(2 eq.) was added, followed by TBAF (1 mol%) to obtain the corresponding CF3-containing secondary alcohol, or Grignard reagent (2 eq.) to obtain the corresponding secondary alkyl alcohol. In both cases, the resulting solution was stirred at this temperature until complete conversion. Then HCI aqueous solution (2.5 M) was added and the reaction was stirred for another hour. Then the reaction was partitioned between AcOEt and water. The aqueous layer was reextracted twice and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give the desired secondary alcohol.

[0467] E) To a stirred solution of the corresponding secondary alcohol (1 eq.) in chloroform (0.2 M) at 0°C, Dess-Martin periodinane (1.5 eq.) was added. When the reaction was complete, it was partitioned between AcOEt and a saturated aqueous solution of NaHC03. The aqueous layer was reextracted twice and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give the desired ketone.

[0468] F) To a stirred solution of the corresponding ketone (1 equiv) in ethanol or methanol (0.2 M) was added the (hydroxy)amine (1.2-40 equiv) followed either by a catalytic amount of PTSA in the case of aliphatic amines or by a base (2.5-40 equiv) in the case of hydroxylamines. The reaction was then refluxed for 24-72 h. After this time, either celite was added and the volatiles evaporated under vacuum or the reaction was partitioned between AcOEt and an aqueous HCI solution (1 M), the aqueous layer was re-extracted twice and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated under vacuum. In both cases, the residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give the desired imine.

[0469] G) To a stirred solution of the corresponding alcohol (1 equiv) in DMF (0.2 M) was added trimethylamine (2 equiv) followed by methanesulfonyl chloride (1.2 equiv) under an argon atmosphere and stirring at 0 °C. The reaction was then stirred for 24 h before partitioning between AcOEt and H20. The aqueous layer was re-extracted twice and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give the desired mesylate.

[0470] H) To the corresponding ketone (1 equiv) dissolved in dry THF (0.2 M) was added TMSCF3 (1.3 equiv) followed by TBAF (1 mol%) to obtain the corresponding di-CF3alcohol or Grignard reagent (2 equiv) to obtain the corresponding tertiary alcohol under an argon atmosphere and stirring at 0 °C. In both cases, the resulting solution was stirred at this temperature until complete conversion. In the first case, upon completion, more TBAF (10 mol%) was added followed by water (5.6 equiv) and the reaction was stirred for another hour. In both cases, the reaction was then partitioned between AcOEt and an aqueous HCI solution (1 M). The aqueous layer was re-extracted twice and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give the desired tertiary alcohol.

[0471] I) To the corresponding 4-substituted phenol (1-2 equivalents) and 4-substituted bromoaryl (1-2.5 equivalents) dissolved in DMF (0.2 M) was added Cs2CO3(2 equivalents), Cul (10 mol%) and tBuXPhos (20 mol%). The mixture was degassed using the freeze-pump-thaw method, placed under argon, stirred vigorously and refluxed (165 °C) for 72 h. The mixture was allowed to come to room temperature and partitioned between petroleum ether and aqueous NaOH (2 M). The aqueous layer was re-extracted twice and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired diaryl ether.

[0472] Analytical data

[0473] The following compounds were synthesized according to the above scheme and characterized by mass spectrometry (Table 46) or NMR (Table 47).

[0474] Table 46:

[0475]

[0476]

[0477]

[0478] Table 47:

[0479]

[0480]

[0481]

[0482] For illustrative purposes, the synthesis and characterization of the following examples are described in detail.

[0483] XPF-0062: 1 -(4-(4-cyclohexylphenoxy)phenyl)-2,2,2-trifluoroethyl-1 -ol

[0484]

[0485] To 4-(4-cyclohexylphenoxy)benzaldehyde (1.84 g, 6.55 mmol, 1 equiv) dissolved in dry THF (26.2 mL, 0.2 M) was added TMSCF3(1.93 mL, 13.1 mmol, 2 equiv) followed by TBAF (65 μL, 66 μmol, 1 mol%) at 0°C under argon and stirring. The resulting solution was stirred at this temperature until complete conversion. Then, aqueous HC1 (2.5 M) was added and the reaction was stirred for an additional hour. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give 2.13 g of 1-(4-(4-cyclohexylphenoxy)phenyl)-2,2,2-trifluoroethyl-1-ol (93%).

[0486] MS: m / z [M-OH] + , [C 20 H 20 F3O] + Calculated = 333.14; found 333.19

[0487] 1 H-NMR (300 MHz, CDC13) δ 7.41 (dt, J = 9.0, 0.6 Hz, 2H), 7.23-7.16 (m, 2H), 7.04-6.91 (m, 4H), 5.00 (qd, J = 6.7, 4.4 Hz, 1H), 2.61-2.37 (m, 2H), 1.99-1.67 (m, 5H), 1.50-1.19 (m, 5H).

[0488] 13 C-NMR (75 MHz, CDC13) δ 159.1, 154.2, 143.9, 128.9, 128.1, 128.0, 124.3 (q, J = 282.0 Hz), 119.4, 118.1, 72.47 (q, J = 32.2 Hz), 43.9, 34.6, 26.9, 26.1.

[0489] XPF-0434: 1-(4-(4-(adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl-1-one

[0490]

[0491] To a stirred solution of 1-(4-(4-(adamantan-1-yl)phenoxy)phenyl)-2,2,2- trifluoroethan-1-ol (750 mg, 1.86 mmol, 1 equiv) in chloroform (9.3 mL, 0.2 M) at 0 °C was added Dess-Martin periodinane (1.03 g, 2.42 mmol, 1.5 equiv). Once the reaction was complete, it was partitioned between AcOEt and a saturated aqueous solution of NaHC03. The aqueous layer was extracted twice more and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give 647 mg of 1-(4-(4-(adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethan-1-one (87%).

[0492] MS: m / z [M+H] + ,[C 24 H 21 F3O2] + Calculated = 399.16; found 399.16

[0493] 1 H-NMR (300 MHz, CDC13) δ 8.10 - 7.89 (m, 2H), 7.44 - 7.25 (m, 2H), 7.02 - 6.86 (m, 4H), 2.05 (p, J = 3.1 Hz, 3H), 1.86 (d, J = 2.9 Hz, 6H), 1.80 - 1.60 (m, 6H).

[0494] 13 C-NMR (75 MHz, CDC13) δ 179.1 (q, J = 31 Hz), 164.6, 152.0, 148.7, 132.7 (q, J = 2.3 Hz), 126.7, 123.9 (q, J = 291 Hz), 120.2, 117.1, 43.3, 36.7, 36.1, 28.9.

[0495] XPF-1330: 1-(6-(4-(adamantan-1-yl)phenoxy)pyridin-3-yl)-1-cyclopropyl-2,2,2- trifluoroethan-1-ol

[0496]

[0497] To 1-(6-(4-(adamantan-1-yl)phenoxy)pyridin-3-yl)-2,2,2-trifluoroethan-1-one (52 mg, 0.13 mmol, 1 equiv) dissolved in dry THF (0.8 mL, 0.16 M) was added cyclopropylmagnesium bromide (0.6 mL, 0.26 mmol, 2 equiv, 0.4 M in THF) at 0 °C under argon and stirring. The resulting solution was stirred at this temperature until complete conversion. Upon completion, the reaction was partitioned between AcOEt and aqueous HC1 (1 M). The aqueous layer was extracted twice more and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give 43 mg of 1-(6-(4-(adamantan-1-yl)phenoxy)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethan-1-ol (75%).

[0498] MS: m / z [M+H] + ,[C 26 H 29 F3NO2] + Calculated = 444.21; found 444.30

[0499] 1 H-NMR (300 MHz, CDC13) δ 8.38 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.7, 2.6 Hz, 1H), 7.45-7.31 (m, 2H), 7.17-6.96 (m, 3H), 6.23 (s, 1H), 2.08 (q, J = 3.1 Hz, 3H), 1.89 (d, J = 3.0 Hz, 6H), 1.79-1.62 (m, 7H), 0.87-0.72 (m, 1H), 0.64-0.48 (m, 1H), 0.40 (tdd, J = 9.1, 5.9, 4.1 Hz, 1H), 0.27 (dtd, J = 9.5, 5.9, 4.2 Hz, 1H).

[0500] 13 C-NMR (300 MHz, CDC13) δ 163.6, 151.7, 147.7, 146.5, 139.3, 130.4, 126.3, 121.3, 110.7, 73.68 (d, J = 27.6 Hz), 43.1, 36.5, 35.9, 28.7, 14.8, 1.6. (one remaining CF3group not visible due to relaxation time)

[0501] XPF-2249: 1-(4-(4-cyclohexyl-2-methylphenoxy)phenyl)-2,2,2-trifluoroethan-1-one oxime

[0502]

[0503] To a stirred solution of l-(4-(4-cyclohexyl-2-methylphenoxy)phenyl)-2,2,2- trifluoroethan-l-one (50 mg, 0.14 mmol, 1 equiv) in methanol (0.7 mL, 0.2 M) was added hydroxylamine hydrochloride (11.5 mg, 0.17 mmol, 1.2 equiv) followed by sodium acetate (34 mg, 0.41 mmol, 3 equiv). The reaction was then refluxed for 24 h, then partitioned between AcOEt and aqueous HC1 (1 M). The aqueous layer was extracted twice more and the combined organic phases were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (Si02, gradient petroleum ether / AcOEt) to give 38 mg of l-(4-(4-cyclohexyl-2-methylphenoxy)phenyl)-2,2,2-trifluoroethan-l-one oxime (73%).

[0504] MS: m / z [M-H] - ,[C 21 H 21 F3NO2] - Calculated = 376.15; found 376.58

[0505] 1 H NMR (400 MHz, CDC13) δ 8.56 (br s, 0.3 H), 8.54 (s, 0.7 H), 7.56 - 7.47 (m, 1.5 H), 7.45 - 7.38 (m, 0.5 H), 7.15 - 7.06 (m, 1 H), 7.07 - 7.01 (m, 1 H), 6.98 - 6.85 (m, 3 H), 2.49 (tt, J = 11.5, 3.8 Hz, 1 H), 2.18 (s, 2 H), 2.17 (s, 1 H), 1.96 - 1.80 (m, 4 H), 1.80 - 1.72 (m, 1 H), 1.49 - 1.33 (m, 4 H), 1.33 - 1.19 (m, 1 H).

[0506] 13 C NMR (101 MHz, CDC13) δ 160.33, 160.22, 151.08, 150.93, 145.01, 144.93, 130.59, 130.07, 130.01, 125.62, 120.71, 120.58, 118.96, 116.36, 116.22, 44.02, 34.63, 26.92, 26.16, 16.22.

[0507] XPF-0518: 1 -(4-(4-(1 -(trifluoromethyl)cyclopropyl)-phenoxy)phenyl)adamantane

[0508]

[0509] To 4-(adamantan-1 -yl)phenol (137 mg, 0.6 mmol, 1.5 equiv) and 1 -bromo-4-(1 -(trifluoromethyl)cyclopropyl)benzene (106 mg, 0.4 mmol, 1 equiv) dissolved in DMF (1.6 mL, 0.2 M) was added Cs2CO3(260 mg, 0.8 mmol, 2 equiv), CuI (7.6 mg, 40 μηιοΐ, 10 mol%) and tBuXPhos (34 mg, 80 μηιοΐ, 20 mol%). The mixture was degassed using the freeze-pump-thaw method, placed under argon atmosphere, stirred vigorously and refluxed (165 °C) for 72 h. The mixture was brought back to room temperature and partitioned between petroleum ether and aqueous NaOH 2 M. The aqueous layer was extracted twice more and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give 120 mg of 1 -(4-(4-(1 -(trifluoromethyl)cyclopropyl)- phenoxy)phenyl)adamantane (72%).

[0510] MS: [C 26 H 26 F3O] + Calculated = 411.19; found 411.20

[0511] 1 H-NMR (300 MHz, CDCI3) δ 7.43-7.36 (m, 2H), 7.36-7.30 (m, 2H), 7.03-6.91 (m, 4H), 2.18-2.04 (m, 3H), 1.95-1.88 (m, 6H), 1.86-1.68 (m, 6H), 1.38-1.30 (m, 2H), 1.05-0.97 (m, 2H).

[0512] 13 C-NMR (300 MHz, CDCI3) δ 157.9, 154.2, 146.9, 132.6, 130.3, 126.2, 126.42 (q, J = 273.5 Hz) 1 18.9, 1 18.0, 43.3, 36.8, 35.9, 27.5 (q, J = 33.3 Hz), 9.81 (q, J = 2.3 Hz).

Claims

1. A compound according to formula (I) as defined herein or a salt or solvate thereof: R 1 = C1–C 12 alkyl, preferably C4–C 12 alkyl, C2–C 12 alkenyl, preferably C4–C 12 alkenyl, C2–C 12 alkynyl, preferably C4–C 12 alkynyl, C3–C8cycloalkyl, C5–C8cycloalkenyl, C5–C 12 dicycloalkyl, C7–C 12 dicycloalkenyl, C8–C 14 tricycloalkyl, -OC1–C 12 alkyl, preferably -OC3–C 12 alkyl, -OC2–C 12 alkenyl, preferably -OC3–C 12 alkenyl, -OC2–C 12 alkynyl, preferably -OC3–C 12 alkynyl, -OC3–C8cycloalkyl, -OC5–C8cycloalkenyl, -OC5–C 12 dicycloalkyl, -OC7–C 12 dicycloalkenyl, -OC8–C 14 tricycloalkyl, -SC1–C 12 alkyl, preferably -SC3–C 12 alkyl, -SC2–C 12 alkenyl, preferably -SC3–C 12 alkenyl, -SC2–C 12 alkynyl, preferably -SC3–C 12 alkynyl, -SC3–C8cycloalkyl, -SC5–C8cycloalkenyl, -SC5–C 12 dicycloalkyl, -SC7–C 12 dicycloalkenyl, -SC8–C 14 tricycloalkyl, -NHR 9 or -NR 9 R 10 wherein R 9 and R 10 are independently of each other selected from the group consisting of: C1–C 12 alkyl, preferably C3–C 12 alkyl, C2–C 12 alkenyl, preferably C3–C 12 alkenyl, C2–C 12 alkynyl, preferably C3–C 12 alkynyl, C3–C8cycloalkyl, C5–C8cycloalkenyl, C5–C 12 dicycloalkyl, C7–C 12 dicycloalkenyl, C8–C 14 tricycloalkyl, or wherein R 9 R1may form a ring structure together with R 10 wherein the ring structure comprising N atoms is selected from a 3- to 8-membered ring structure or a 5- to 12-membered bicyclic ring structure, and wherein all of the ring structures can additionally comprise one or more heteroatoms independently selected from O, S and N in place of carbon atoms contained in the ring structure, in particular wherein such replacement results in the residue containing at least twice as many C atoms as the number of heteroatoms independently selected from O, S and N; all alkyl, alkenyl and alkynyl residues contained in the definitions of R 1 , R 9 and R 10 are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =0, C3-C8cycloalkyl, C5-C8cycloalkenyl, C5-C 12 dicycloalkyl, C7-C 12 dicycloalkenyl, C8-C 14 tricycloalkyl, linear or branched -OC1-C5alkyl such as -OCH3, -OC3-C5cycloalkyl such as -O(cyclopropyl), linear or branched -NH(C1-C5alkyl), linear or branched -N(C1-C5alkyl)(C1-C5alkyl), -NH(C3-C5cycloalkyl) such as -NH(cyclopropyl), -N(C3-C5cycloalkyl)(C3-C5cycloalkyl), linear or branched -N(C1-C5alkyl)(C3-C5cycloalkyl); wherein when the alkyl, alkenyl and alkynyl residues in the definition of R 1 , R 9 and R 10 are substituted by one or more substituents which are =0, such substitution by =0 cannot lead to the direct attachment of one of the groups selected from the group consisting of C=0, S=0 and N=0 to the aromatic ring; wherein all cyclic, bicyclic, and tricyclic structures contained in the definitions of R 1 , R 9 , and R 10 include cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, straight or branched C1-C5 alkyl such as -CH3, straight or branched -OC1-C5 alkyl such as -OCH3, straight or branched -NH(C1-C5 alkyl), straight or branched -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl) such as -NH(cyclopropyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), straight or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms, and wherein such substitution results in the residue containing at least twice the number of C atoms than the number of heteroatoms independently selected from O, S and N, and wherein such substitution additionally cannot result in one of the groups selected from C=0, S=0 and N=0 being directly bound to the aromatic ring; wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R 1 , R 9 and R 10 may comprise one or more heteroatoms independently selected from O, S and N instead of C atoms, and wherein such replacement results in the residue comprising at least the same number of C atoms as heteroatoms independently selected from O, S and N; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R 1 , R 9 and R 10 may be partially or completely halogenated, in particular fluorinated, more particularly perfluorinated; wherein the bicyclic and tricyclic residues include fused, bridged and spiro systems; R 2 –R 5 independently of one another, are selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1–C4alkyl, linear or branched C2–C4alkenyl, linear or branched C2–C4alkynyl, C3–C6cycloalkyl, -CH2(C3–C6cycloalkyl), linear or branched -OC1–C3alkyl, -O(cyclopropyl), linear or branched -NH(C1–C3alkyl), linear or branched -N(C1–C3alkyl)(C1–C3alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1–C3alkyl)(cyclopropyl); wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R 2 - R 5 all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R 2 - R 5 all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R can contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms, and wherein such substitution cannot lead to one of the groups selected from C=0 and S=0 being directly bound to an aromatic ring; X 1 - X 4 are independently from each other selected from N, CR 11 , CR 12 , CR 13 , CR 14 ; R 11 –R 14 independently of each other selected from the group consisting of -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1–C4alkyl, linear or branched C2–C4alkenyl, linear or branched C2–C4alkynyl, C3–C6cycloalkyl, -CH2(C3–C6cycloalkyl), linear or branched -OC1–C3alkyl, -O(cyclopropyl), linear or branched -NH(C1–C3alkyl), linear or branched -N(C1–C3alkyl)(C1–C3alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1–C3alkyl)(cyclopropyl); wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R 11 - R 14 all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R 11 - R 14 all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R can contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms, and wherein such substitution cannot lead to one of the groups selected from C=0 and S=0 being directly bound to an aromatic ring; wherein R 11 - R 14 preferably selected from -H, -F, -CI, -Br, -CH3, -CF3, -OH, -OCH3, -OCF3, cyclopropyl, oxiranyl, -C(CH3)3, -N(CH3)2, -NH2, -CN, -CH2OCH3, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2OH, -NO2, -CH2-N-morpholinyl; R 6 and R 7 are independently selected from the group consisting of -H, -F, -CH3; or R 6 and R 7 together form a cyclic residue comprising the carbon atoms to which they are bound, and wherein said cyclic residue is a C3cycloalkyl; R 8 selected from the group consisting of -H, C1-C3 alkyl, preferably -CH3, C2-C3 alkenyl, C2-C3 alkynyl, -F, -CF3, and aromatic and heteroaromatic residues, preferably six-membered aromatic rings and five- to six-membered heteroaromatic rings; wherein the aromatic and heteroaromatic residues contained in the definition of R 8 may be optionally linked to the carbon atom to which R 8 is bound via a C1alkylene or C2alkylene linker; wherein all aromatic and heteroaromatic residues contained in the definition of R 8 are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl); wherein all heteroaromatic residues contained in the definition of R 8 All heteroaromatic residues contained in the definition of R are optionally substituted with one or more residues independently selected from the group consisting of halogen, CN, N02, oxo, thioxo, OR, SR, NR2, C(=0)R, C(=NR)R, C(=0)NR2, C(=NR)NR2 all alkyl, alkenyl, alkynyl residues contained in the definition of R 8 all alkyl, alkenyl, alkynyl residues contained in the definition of R wherein R 8 preferably -H, -F, -CH3, -CH2CH3-CF3, -C6H5; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, dicycloalkyl, dicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues contained in the definition of R 2 - R 8 and R 11 - R 14 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, dicycloalkyl, dicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definition of R Z 1 and Z 2 is selected from the group consisting of wherein Z 1 is selected from the group consisting of -H, linear or branched C1-C3 alkyl, preferably -CH3, cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -N3, -CF3, -CF2CF3, and wherein Z 2 is independently selected from the group consisting of linear or branched C1-C3 alkyl, preferably -CH3, -CF3, -CF2CF3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3, -CN and -OR 15 (Generic formula la), wherein R 15 is selected from the group consisting of -H, C1-C8, preferably C1-C4 alkyl, C2-C8, preferably C2-C4 alkenyl, C2-C8, preferably C2-C4 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, C5-C 12 dicycloalkyl, C7-C 12 dicycloalkenyl, C8-C 14 tricycloalkyl, and aromatic and heteroaromatic residues, preferably five- to six-membered aromatic and five- to six-membered heteroaromatic rings; and wherein the bicyclic and tricyclic residues include fused, bridged and spiro systems; wherein said cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues contained in the definition of R 15 may optionally be linked to R 15 through a C1alkylene or C2alkylene or C3alkylene linker; and wherein said C1alkylene, C2alkylene, C3alkylene, C4alkylene, C5alkylene, C6alkylene, C7alkylene, C8alkylene, C9alkylene, C10alkylene, C11alkylene, C12alkylene, C13alkylene, C14alkylene, C15alkylene, C16alkylene, C17alkylene, C18alkylene, C19alkylene, C20 wherein all aromatic and heteroaromatic residues contained in the definition of R 15 are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl); all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues and alkylene linkers contained in the definition of R 15 all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues and alkylene linkers contained in the definition of R are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, =0, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C1-C3 alkyl), linear or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, linear or branched -N(C1-C3 alkyl)(cyclopropyl); wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, and heteroaromatic residues and alkylene linkers contained in the definition of R 15 may contain one or more heteroatoms independently selected from O, S, and N in place of carbon atoms; wherein R 15 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaromatic residues and alkylene linkers in the definition can be partially or fully halogenated, in particular fluorinated, more particularly perfluorinated wherein R 15 preferably -H, -CH3, -CH2CH3, n-propyl, i-propyl, cyclopropyl, benzyl; or wherein Z 1 and Z 2 together are =0, =S, =NR 16 , or zwitterionic =N [+] R 17 O [–] (General Formula Ib); wherein R 16 is selected from the group consisting of -H, -OH, -OCH3, -CN, -S(O)CH3, -S(O)CF3, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, straight or branched C1-C3 alkyl, preferably -CH3, cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5, and -CH2C6H5; wherein R 17 is selected from the group consisting of straight or branched C1-C3 alkyl, preferably -CH3, cyclopropyl, -C6H5, and -CH2C6H5; or wherein Z 1 and Z 2 together form a cyclic residue comprising the carbon atoms to which they are bound (general formula Ic); wherein the cyclic residue is selected from the group consisting of a three-membered ring, a four-membered ring, a five-membered ring and a six-membered ring, wherein all rings optionally can comprise one or more heteroatoms independently selected from the group consisting of O, S and N instead of carbon atoms; wherein all rings are unsubstituted or substituted by one or more substituents independently selected from the group consisting of -F, -CI, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =0, -CH3and -CF3; wherein all alkyl and cyclic residues contained in the definition of Z 1 and Z 2 may be partially or completely halogenated, in particular fluorinated, more particularly perfluorinated.

2. A compound according to claim 1 of formula (la) or a salt or solvate thereof.

3. A compound according to claim 1 of formula (lb) or a salt or solvate thereof.

4. A compound according to claim 1 of formula (lc) or a salt or solvate thereof.

5. The compound of any one of claims 1 to 4, provided that (i) the compounds shown in Table 1 are excluded, (ii) the compounds shown in Table 2 are excluded, and / or (iii) the compounds shown in Table 3 are excluded.

6. The compound of any one of claims 1 to 5 and wherein R 1 selected from the group consisting of methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, i-propyl, sec-butyl, t-butyl, t-pentyl, t-octyl, 3-pentyl, -CF3, -CF2CF3, -(CF2)2CF3, -CH(CF3)2, -CH2SCH3, -CH2CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH2CH3, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, dimethyl-aminomethyl, dimethyl- aminoethyl, diethyl-aminomethyl, ethyl-methyl-aminomethyl, cyclopropyl, methyl-cyclopropyl, ethyl-cyclopropyl, trifluoromethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dicyclopentyl, dicyclohexyl, dicycloheptyl (preferably norbornyl), dicyclooctyl, dicyclooctenyl, dicyclononyl, methyl dicyclononyl, adamantyl, tricyclodecyl, oxiranyl, oxetanyl, tetrahydrofuranyl, methyl tetrahydrofuranyl, trimethyl tetrahydrofuranyl, tetrahydropyranyl, aziridinyl, N-methyl aziridinyl, azetidinyl, N-methyl azetidinyl, difluoro azetidinyl, pyrrolidinyl, N-methyl pyrrolidinyl, piperidinyl, N-methyl piperidinyl, difluoro piperidinyl, thiiridinyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethyl piperazinyl, dithianyl, morpholinyl, N-methyl morpholinyl, thiomorpholinyl, N-methyl thiomorpholinyl, oxa-aza spiroheptyl, N-methyloxa-aza spiroheptyl, aza spiroheptyl, N-methyl aza spiroheptyl, thia-aza spiroheptyl, N-methyl thia-aza spiroheptyl, difluoro thia-aza spiroheptyl, aza spirooctyl, N-methyl aza spirooctyl, oxa-aza spirooctyl, N-methyloxa-aza spirooctyl, oxa-aza spirononyl, N-methyloxa-aza spirononyl, aza spirononyl, N-methyl aza spirononyl, oxa-aza spirodecyl, N-methyloxa-aza spirodecyl, aza spirodecyl, N-methyl aza spirodecyl, dihydro-oxazinyl, N-methyl dihydro-oxazinyl, oxazolidinyl, N-methyl oxazolidinyl, dioxolanyl, imidazolidinyl, N-methyl imidazolidinyl, N,N-dimethyl imidazolidinyl, azepanyl, N-methyl azepanyl, azaspirohexyl, N-methyl azaspirohexyl, oxa-aza dispirodecyl, N-methyloxa-aza dispirodecyl, aza dispirodecyl, N-methyl aza dispirodecyl, oxa-aza dicyclooctyl, N-methyloxa-aza dicyclooctyl, aza dicyclooctyl, N-methyl aza dicyclooctyl, aza dicycloheptyl, N-methyl aza dicycloheptyl, aza dicyclononyl, N-methyl aza dicyclononyl, aza adamantyl, -O(adamantyl), oxa-aza dicyclononyl, N-methyloxa-aza dicyclononyl, oxa-aza dicycloheptyl, N-methyloxa-aza dicycloheptyl, diaza dicyclooctyl, N-methyldiaza dicyclooctyl, N,N-dimethyldiazabicyclooctyl, diazabicycloheptyl, N-methyldiazabicycloheptyl, N,N- dimethyldiazabicycloheptyl; 4-oxocyclohexyl, 3-oxocyclopentyl; 2-oxocyclobutyl, 4- oxobicyclo[4.1.0]hept-1-yl.

7. The compound of any one of claims 1 to 6, and wherein R 1 preferably selected from C4–C 12 alkyl, C4–C 12 alkenyl, C4–C 12 alkynyl, cyclic, bicyclic and tricyclic residues, wherein the alkyl, alkenyl and alkynyl residues are preferably branched, including:

8. The compound of any one of claims 1 to 7, wherein R 2 - R 3 each is -H, R 4 is preferably -H or -F, and / or R 5 -H, -F, -CI, -Br, -CH3, -CF3, -CH=CH2, -CºCH, -CH2OH, -CH2NHCH3, -OH, -OCH3, -OCF3, cyclopropyl, oxiranyl, -CH2-N-morpholinyl, -C(CH3)3, -CH2OCH3, -NO2, -CN, -NH2, -N(CH3)2, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2.

9. The compound of any one of claims 1 to 8, wherein the substituents R are as defined in general formula (I) 1 to R 5 the six-membered aromatic ring to which they are bound is selected from 10. The compound of any one of claims 1 to 9 wherein X is as defined in general formula (I) 1 X 4 the six-membered aromatic ring of said formula (I) is selected from:

11. The compound of any one of claims 1 to 10 Z 1 It is -H, -CH3, -CF3 or cyclopropyl; and / or Z is present in it. 2 For example: -OH, -OS(O)2CH3 and -CN; 12. The compound of any one of claims 1 to 10 wherein Z 1 and Z 2 together are =0, =NR 16 or zwitterionic =N [+] R 17 O [–] ; wherein R 16 is preferably selected from the group consisting of -H, -OH, -OCH3, -CH3, cyclopropyl and -CH2C6H5; wherein R 17 is preferably -CH3, -C(CH3)3 and -CH2C6H5:

13. The compound of any one of claims 1 to 10 wherein Z 1 and Z 2 together form a three-, four- or five-membered ring residue, including the carbon atom to which they are bound; wherein the cyclic residue is preferably selected from the group consisting of cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl, thienyl, thiazolyl, methylthiazolyl, thiazolidine-dionyl, methylthiazolidine-dionyl and oxazolidinyl, methyl-oxazolidinyl, oxazolidine-dionyl and methyl-oxazolidine-dionyl; and wherein the cyclic residue is optionally preferably substituted by -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =0, -CH3 and -CF3; and wherein the cyclic residue is even more preferably selected from:

14. The compound of any one of claims 1 to 13 wherein R 6 , R 7 and R 8 are each -F.

15. The compound of any one of claims 1 to 14 wherein R 6 and R 7 together form a cyclic residue comprising the carbon atoms to which they are bound, and wherein said cyclic residue is cyclopropyl.

16. The compound of any one of claims 1 to 15 wherein R 1 free of heteroatoms.

17. The compound of claim 16 wherein R 1 are selected from cyclic, bicyclic and tricyclic structures.

18. The compound of claim 16 or 17 wherein R 1 is selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecanyl, and adamantyl.

19. The compound of claim 18 wherein R 1 is adamantyl.

20. The compound of any one of claims 1 to 18 wherein R 1 are selected from residues containing four or more, preferably six or more, even more preferably seven or more carbon atoms.

21. The compound of any one of claims 1 to 15 or 20 wherein R 1 one or more, preferably 1-2, heteroatoms independently selected from O, S and N replace a carbon atom in R 1 one or more, preferably 1-2, heteroatoms independently selected from O, S and N replace a carbon atom in R 22. The compound of claim 21 wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, or wherein R 1 is selected from residues containing cyclic, bicyclic and tricyclic structures.

23. The compound of claim 21 or 22 wherein R 1 is selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxo-azabicycloheptyl, N- methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxo-azabicyclooctyl, azabicyclononyl, azadamantyl, and -O(adamantyl).

24. The compound of claim 23 wherein R 1 is azapinane and -O(adamantyl).

25. The compound of any one of claims 1 to 24 having the structure I-1: wherein Z 1 and Z 2 as defined in general formula (I), including general formula (la), general formula (lb) and general formula (lc), including the definitions of substitution and preferences, and wherein R 15 as defined in general formula (Ia), including the substituents and preferred definitions, and wherein R 16 and R 17 as defined in general formula (Ib), including the substituents and preferred definitions, and wherein R 2 - R 8 , R 11 - R 14 and X 1 - X 4 as defined in general formula (I), including the substituents and preferred definitions.

26. The compound of any one of claims 1 to 25 having the structure I-2: wherein R 1 As defined in general formula (I), including the substituents and preferred definitions, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally replaced independently by heteroatoms selected from O, S and N as defined in general formula (I), wherein R 6 As defined in general formula (I), including the substituents and preferred definitions, wherein R 6 other than -H, with the optional proviso that R 6 other than -CH3, and wherein Z 1 and Z 2 as defined in general formula (I), including general formula (la), general formula (lb) and general formula (lc), including the substituents and preferred definitions, and wherein R 15 as defined in general formula (Ia), including the substituents and preferred definitions, and wherein R 16 and R 17 as defined in general formula (Ib), including the substituents and preferred definitions, and wherein R 2 - R 5 , R 7 - R 14 and X 1 - X 4 as defined in general formula (I), including the substituents and preferred definitions.

27. The compound of any one of claims 1 to 26 having the structure I-3: wherein R 1 selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 comprise six or more carbon atoms, which are optionally independently substituted with heteroatoms selected from O, S and N as defined in general formula (I), wherein R 8 As defined in general formula (I), including the substituents and preferred definitions, wherein R 8 other than -H, with the optional proviso that R 8 other than -CH3, and wherein Z 1 and Z 2 as defined in general formula (I), including general formula (la), general formula (lb) and general formula (lc), including the substituents and preferred definitions, and wherein R 15 as defined in general formula (Ia), including the substituents and preferred definitions, and wherein R 16 and R 17 as defined in general formula (Ib), including the substituents and preferred definitions.

28. A compound as shown in any one of Tables 4 to 28 or a salt or solvate thereof.

29. A compound according to any one of claims 1 to 28 for use in medicine, for example in human medicine or veterinary medicine.

30. A compound according to any one of claims 1 to 28 for use in the treatment of hyperproliferative conditions, including malignant and non-malignant hyperproliferative disorders.

31. A compound according to any one of claims 1-28 for use in the treatment of diseases of the skin, mucosa, skin and mucosa appendages, cornea and epithelial tissue, and malignant, non-malignant and hyperproliferative disorders, including cancer such as non-melanoma skin cancer including squamous cell carcinoma and basal cell carcinoma and precancerous lesions including actinic keratosis, skin and / or mucosa disorders with a keratinization defect and / or abnormal keratinocyte proliferation, skin and / or mucosa diseases associated with viral infections, atopic dermatitis and acne, accompanying and / or caused by said diseases, and for promoting wound healing of the skin and mucosa.

32. A compound according to any one of claims 1-28 for use in the treatment of hyperproliferative disorders, cancer or precancerous lesions of the skin, oral mucosa, tongue, lung, stomach, breast, cancer of the neuroendocrine system such as medullary thyroid carcinoma, brain cancer, pancreatic cancer, liver cancer, thyroid cancer and cancer of the genitourinary tract including cervical cancer and ovarian cancer.

33. A compound according to any one of claims 1-28 for use in the treatment of malignant and non-malignant muscle diseases, including muscle dystrophies, or for muscle regeneration, or for hyperproliferative disorders of the muscle such as muscle hyperplasia and muscle hypertrophy.

34. A compound according to any one of claims 1-28 for use in the treatment of immune system related disorders, disorders of the hematopoietic system including the blood system, such as cancers of the hematopoietic and blood system such as leukemia and lymphoma, such as myeloid malignancies, for example acute and chronic myeloid leukemia and acute and chronic promyelocytic leukemia, and malignancies of the lymphoid lineage, for example acute and chronic T-cell leukemia and acute and chronic B-cell leukemia, and cutaneous T-cell lymphoma.

35. A compound according to any one of claims 1-28 for use in the treatment of sex immune system related applications, including immunotherapy and other immunotherapy methods, such as use as an immune or vaccine adjuvant.

36. A method of treating a hyperproliferative disorder, the method comprising administering to a subject, in particular a human subject, in need thereof a therapeutically effective amount of a compound according to any one of claims 1-28.

Images