Aromatic molecules for treatment of pathological conditions

Abstract

The invention comprises novel aromatic molecules which can be used in human and veterinary medicine for 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. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese application with the invention name “Aromatic molecules for treating pathological conditions”, application number 201980069476.1 and application date August 23, 2019.

[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 treating pathological conditions including cancer, skin disorders, muscle disorders, lung disorders, hematopoietic disorders, including blood system and immune system related disorders. Summary of the invention

[0003] The present invention encompasses novel molecules that show significant biological activity to cells of human and animal origin. It has been found that the corresponding compounds affect the growth and survival of cancer cells and primary non-cancerous cells. In particular, molecules that can completely or partially inhibit cell growth or cause cell death have been identified. In addition, it has been found that some compounds affect cell signaling pathways, particularly the Notch signaling pathway. It has been found that the corresponding molecules enhance the Notch signaling pathway.

[0004] Thus, the present invention relates to compounds having antiproliferative activity as defined herein, which are useful for treating benign and malignant hyperproliferative disorders in human and veterinary medicine. In particular, the present invention relates to compounds as defined herein for use in treating the following disorders in human and veterinary medicine: disorders of the hematopoietic system (including hematopoietic and immune system related disorders), malignancies involving the myeloid and lymphoid lineages, malignant and non-malignant diseases of the skin and mucous membranes (e.g. keratosis), malignant and non-malignant diseases of muscle (including muscle hyperproliferative diseases such as myofasciitis and hypertrophy), disorders of the neuroendocrine system, hyperproliferative disorders of the skin and mucous membranes, cancers and precancerous lesions 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 hematopoietic system) (such as leukemias and lymphomas), hyperproliferative disorders and cancers of the lung, breast, stomach, urogenital tract, for example cervical cancer, including ovarian cancer.

[0005] The biological activity of the claimed compounds, such as antiproliferative activity, can be attributed to, but is not limited to, Notch signaling enhancing activity. Therefore, the present invention also relates to compounds characterized by Notch enhancing activity as defined herein, which can be used to treat pathological conditions responsive to Notch modulation in human and veterinary medicine, such as cancer, skin diseases, muscle disorders, hematopoietic disorders, including blood system and immune system related disorders.

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

[0007] The first aspect of the present invention relates to compounds of 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-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, 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-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 Bicycloalkyl, -OC7-C 12 Bicycloalkenyl, -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-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C14 Tricycloalkyl, -NHR 7 or -NR 7 R 8 , where R 7 and R 8 Independently selected from: 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-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl, or wherein R 7 Can be used with R 8 Together forming a ring structure, wherein the ring structure containing the N atom is selected from a 3- to 8-membered ring structure or a 5- to 12-membered bicyclic structure, and wherein all of the ring structures may additionally contain one or more heteroatoms independently selected from O, S and N to replace the carbon atoms contained in the ring structure, in particular wherein such replacement results in a residue containing at least twice the number of C atoms independently selected from O, S and N;

[0010] Included in R 1 , R 7 and R 8 All alkyl, alkenyl and alkynyl residues in the definition are straight-chain or branched and are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Substituted with tricycloalkyl, linear or branched -OC1-C5 alkyl such as -OCH3, -OC3-C5 cycloalkyl such as -O(cyclopropyl), linear or branched -NH(C1-C5 alkyl), linear or branched -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl) such as -NH(cyclopropyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl);

[0011] When included in R 1 , R 7 and R 8When the alkyl, alkenyl and alkynyl residues in the definition are substituted by one or more substituents being =O, such substitution with =O cannot result in one of the groups selected from C=O, S=O and N=O being directly bonded to the aromatic ring;

[0012] Included in R 1 , R 7 and R 8 All cyclic structures, bicyclic structures and tricyclic structures in the definition of include cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -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);

[0013] Included in R 1 , R 7 and R 8 All alkyl, alkenyl and alkynyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms, and wherein such substitution results in the residue containing at least twice the number of C atoms as 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=O, S=O and N=O being directly bonded to the aromatic ring;

[0014] Included in R 1 , R 7 and R 8 All cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms, and wherein such replacement results in the residue containing at least the same number of C atoms as the number of heteroatoms independently selected from O, S and N;

[0015] Included in R 1 , R 7 and R 8 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated;

[0016] Among them, bicyclic and tricyclic residues include fused, bridged, and spirocyclic systems;

[0017] And where R 1is selected from the group consisting of 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-amino 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, 1-Hydroxy, pyrrolidyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thiiranyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethylpiperazinyl, dithianly, morpholinyl, N-methylmorpholinyl, thiomorpholinyl, N-methylthiomorpholinyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, Thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methylazaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecanyl, N-methyloxa-azaspirodecanyl, azaspirodecanyl, N-methylazaspirononyl, oxa-azaspirodecanyl, N-methyloxa-azaspirodecanyl, azaspirodecanyl, N-methylazaspirononyl, dihydro-oxazinyl, N-methyldihydro-oxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxolanyl, imidazolidinyl, N-methylimidazolidinyl, N,N-dimethylimidazolidinyl, azepanyl, N-methylazepanyl, azaspirohexyl, N-methylazaspirohexyl, oxa-azadispirodecanyl, N-methyloxa-azadispirodecanyl, azadispirodecanyl, N-methylazadispirodecanyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N-methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N-methylazabicyclononyl, azaadamantane yl, -O(adamantyl), oxa-azabicyclononyl, N-methyloxa-azabicyclononyl, oxaazabicycloheptyl, N-methyldiazabicycloheptyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, N,N-dimethyldiazabicyclooctyl, diazabicycloheptyl, N-methyldiazabicycloheptyl, N,N-dimethyldiazabicycloheptyl; 4-oxocyclohexyl, 3-oxocyclopentyl; 2-oxocyclobutyl, 4-oxobicyclo[4.1.0]hept-1-yl;

[0018] And where R 1 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, include:

[0019]

[0020] R 2 -R 5 Independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C2-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] Included in R 2 -R 5 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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;

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

[0023] Where R 2 -R 3 Each is preferably -H, R 4 Preferably -H or -F, R 5 Preferred are -H, -F, -Cl, -Br, -CH3, -CF3, -CH=CH2, -C≡CH, -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;

[0024] Wherein the substituent R as defined in the general formula (I) 1 To R 5 The six-membered aromatic ring to be bonded is preferably selected from:

[0025]

[0026] X 1 -X 4 are independently selected from N, CR 9 , CR 11 , CR 12 ;

[0027] R 9 -R 12 Independently selected from -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);

[0028] Included in R 9 -R 12All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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] Included in R 9 -R 12 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N in substitution of a carbon atom, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring;

[0030] Where R 9 -R 12 Preferably selected from -H, -F, -Cl, -Br, -CH3, -CF3, -OH, -OCH3, -OCF3, cyclopropyl, oxirane, -C(CH3)3, -N(CH3)2, -NH2, -CN, -CH2OCH3, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2OH, -NO2, -CH2-N-morpholinyl;

[0031] And wherein the X-containing 1 -X 4 The six-membered aromatic ring is preferably selected from:

[0032]

[0033] R 6 =-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 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl groups and aromatic and heteroaromatic residues, preferably 6-membered aromatic rings and 5- to 6-membered heteroaromatic rings;

[0034] and wherein bicyclic and tricyclic residues include fused, bridged, and spiro ring systems;

[0035] Included in R 6 The cycloalkyl, cycloalkenylbicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definition of are optionally linked to R via a C1 alkylene or C2 alkylene or C3 alkylene linker. 6 The combined N;

[0036] Included in R 6All aromatic and heteroaromatic residues in the definition of are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, straight or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), straight or branched -NH(C1-C3 alkyl), straight or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight or branched -N(C1-C3 alkyl)(cyclopropyl);

[0037] Included in R 6 all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues and alkylene linkers in the definition of are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, =O, 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] Included in R 6 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaryl residues and alkylene linkers in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0039] Where R 6 Preferred are -H, -CH3, -CH2CH3, n-propyl, isopropyl, cyclopropyl, -CF3 and -CF2CF3, benzyl, tert-butyl, phenyl, cyclohexyl, 1-phenylethyl, 2,2-dimethyl-1-phenylpropyl, (1-naphthyl)-methyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, tetrahydropyranyl;

[0040] Included in R 2 -R 6 and R 9 -R 12 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definition of may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated;

[0041] Y=-H, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, -OH, linear or branched-OC1-C6 alkyl, linear or branched-OC2-C6 alkenyl, linear or branched-OC2-C6 alkynyl, -OC3-C6 cycloalkyl, -OC5-C6 cycloalkenyl, -CN, aromatic and heteroaromatic residues, preferably six-membered aromatic rings and five- to six-membered heteroaromatic rings, -S(O)R 13 and -S(O)2R 13 , where R 13 Selected from linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, -CF3 and -C6H4CH3;

[0042] wherein all cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues included in the definition of Y may be optionally linked to the N to which Y is bound via a C1 alkylene, or C2 alkylene, or C3 alkylene, or -O-, or -O-CH2-, or -O-CH2-CH2-linker;

[0043] wherein all aromatic and heteroaromatic residues contained in the definition of Y are unsubstituted or substituted with substituents selected from -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);

[0044] wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues and alkylene linkers contained in the definition of Y are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, =O, 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);

[0045] wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and heteroaryl residues and alkylene linkers included in the definition of Y may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0046] wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues and alkylene linkers comprised in the definition of Y may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated;

[0047] Wherein Y is preferably -H, -CH3, -CH2CH3, n-propyl, isopropyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, -CF3, -CF2CF3, -OH, -OCH3, -OCH2CH3, -OCH2(cyclopropyl), -CN, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, -S(O)2C6H4CH3, -OCH2C6H5 and -OC6H5; and for R 6 =-H or -CH3 or benzyl, then Y is preferably -OH, -OCH3, -OCH2CH3, -OCH2(cyclopropyl);

[0048] Where Y can be 6 Together, they form a ring structure, wherein the ring structure containing the N atom of Formula I is selected from a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 5- to 12-membered bicyclic residue, an 8- to 14-membered tricyclic residue, and a heteroaromatic residue, wherein all of the rings, bicyclics, tricyclics, and heteroaromatic residues may additionally contain one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in the ring structure, and wherein all of the rings, bicyclics, tricyclics, and heteroaromatic residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3, -CF3, morpholinyl;

[0049] and wherein bicyclic and tricyclic residues include fused, bridged, and spiro ring systems;

[0050] Wherein the Y and R containing N atom of formula I 6The ring structures taken together are preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, difluoropiperidinyl, morpholinyl, morpholinylazetidinyl, hydroxyazetidinyl, azetidinonyl, azetidinyl, difluoroazetidinyl, azaspirohexyl, azaspiroheptyl, difluoroazaspiroheptyl, hydroxyazaspiroheptyl, methylhydroxyazaspiroheptyl, trifluoromethylhydroxyazaspiroheptyl, azaspirooctyl, azaspirononyl, oxa-azaspiroheptyl, oxa-azaspirooctyl, oxa-azaspirononyl, thia-azaspiroheptyl, oxazolidinyl, tetrahydro-oxazinyl, isoxazolidinyl, oxazinane, isoxazolidine, piperazine;

[0051] and wherein Y and R of Formula I containing N atoms 6 The ring structures taken together are even more preferably selected from:

[0052]

[0053] Z 1 and Z 2 Selected from the following groups:

[0054]

[0055] Where Z 1 is selected from linear or branched C1-C3 alkyl, preferably -CH3, cyclopropyl, oxiranyl, N-methyl-aziridine, thiirane, -CN, -N3, -CF3, -CF2CF3, and wherein Z 2 Independently selected from -H and straight or branched C1-C3 alkyl, preferably -CH3, -CF3, -CF2CF3 (Formula Ia);

[0056] Where Z 1 Preferably -CH3, -CF3, -CN, cyclopropyl; and / or wherein Z 2 Preferred are -H, -CH3 and -CF3; for example:

[0057]

[0058] or where Z 1 and Z 2 Together = O, = S, = NR 14 (Formula Ib); wherein R 14 Selected from -H, -OH, -OCH3, -CN, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, linear or branched C1-C3 alkyl, preferably -CH3, cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5, -CH2C6H5;

[0059] Where Z1 and Z 2 Preferably, =O, =NR 14 ; where R 14 Preferably it is selected from -H, -CH3, cyclopropyl, -OH, -OCH3, -CN:

[0060]

[0061] or where Z 1 and Z 2 Together they form a cyclic residue comprising the carbon atom to which they are attached (Formula Ic); wherein the cyclic residue is selected from a three-membered ring, a four-membered ring, a five-membered ring and a six-membered ring, wherein all rings optionally may contain one or more heteroatoms independently selected from O, S and N to replace the carbon atoms contained in the ring structure; wherein all rings are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3;

[0062] Where Z 1 and Z 2 Together, preferably form a 3- or 4-membered cyclic residue comprising the carbon atom to which they are attached; wherein the cyclic residue is preferably selected from cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl and thietanyl; and wherein the cyclic residue is optionally preferably substituted by -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3;

[0063] and wherein the cyclic residue is even more preferably selected from:

[0064]

[0065] This is included in Z 1 and Z 2 All alkyl and cyclic residues in the definition of may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated.

[0066] R 1 -R 14 , X 1 -X 4 , Z 1 , Z 2The following preferred definitions of Y 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 subgenera defined in the present invention:

[0067] 1) R 1 preferably contains four or more, preferably six or more, even more preferably seven or more carbon atoms;

[0068] 2) R 1 Preferably selected from branched alkyl, alkenyl and alkynyl residues;

[0069] 3) R 1 Preferably selected from cyclic, bicyclic and tricyclic structures, wherein bicyclic and tricyclic residues include fused, bridged and spiro ring systems;

[0070] 4) R 1 Preferably, it contains no heteroatoms;

[0071] 5) R 1 Preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl, most preferably adamantyl, such as 1-adamantyl and 2-adamantyl;

[0072] 6) R 1 Preferably, one or more heteroatoms, preferably one, two or three heteroatoms independently selected from O, S and N, are included to replace R 1 The carbon atoms contained in

[0073] 7) R 1 Preferably selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azaadamantyl and -O(adamantyl);

[0074] 8) preferably two, or more preferably three independently selected from R 2 -R 5 The substituent is -H, preferably two, more preferably one independently selected from R 2 -R 5 The substituent is different from -H;

[0075] 9) at two independently selected 2 -R 5 In the case where the substituents are different from -H and are in the ortho position relative to the ether bond, the two substituents are preferably different from -F, -C1, -Br, -I and -NO2, and more preferably different from each other;

[0076] 10) By X 1 -X 4 The composition of the defined ring atoms is preferably selected from the following: all X 1 -X 4 Independently selected from CR 9 , CR 10 , CR 11 , CR 12 , or X 1 -X 4 One of them is N, and the other three are independently selected from CR 9 , CR 10 , CR 11 , CR 12 , or X 1 -X 4 Two of them are N, and the other two are independently selected from CR 9 , CR 10 , CR 11 , CR 12 ; That is, the aromatic ring or heterocyclic ring is selected from benzene, pyridine, pyrimidine, pyridazine and pyrazine;

[0077] 11) preferably two, or more preferably three independently selected from R 9 -R 12 The substituent is -H, preferably two, more preferably one independently selected from R 9 -R 12 The substituent is different from -H;

[0078] 12) Choose R in two independent 9 -R 12 In the case where the substituents are different from -H and are in the ortho position relative to the ether bond, the two substituents are preferably different from -F, -C1, -Br, -I and -NO2, and more preferably different from each other;

[0079] 13) Y is preferably selected from the residues included in the general definition of Y which, together with the oxygen atom, are bound to the N to which Y is bound;

[0080] A preferred aspect of the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 =0, and R 6 and Y are different from H,

[0081] And R 1 -R 5 , R 7 -R 13 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions.

[0082] Another preferred aspect of the present invention relates to compounds of the general formula (I) and their salts and solvates, wherein Y is selected from the residues included in the general definition of Y which, together with the oxygen atom, are bound to the N to which Y is bound,

[0083] and wherein Y is even more preferably -OH, -OCH3, -OCH2CH3, -OCH2(cyclopropyl), -OC6H5 and -OCH2C6H5,

[0084] And R 1 -R 12 , R 14 , X 1 -X 4 , Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions.

[0085] Another preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R 1 Selected from the 1 The residue in the general definition of contains 4 or more, preferably 6 or more, even more preferably 7 or more carbon atoms,

[0086] And where R 1 Contains no heteroatoms,

[0087] And where R 1 More preferably, it is selected from cyclic, bicyclic and tricyclic structures,

[0088] And where R 1 Even more preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and adamantyl,

[0089] And where R 1 Most preferably, it is adamantyl group,

[0090] And R 2 -R 6 , R 9 -R 14 , X 1 -X 4 , Z 1 , Z 2 and Y are as defined in formula (I), including substitutions and preferred definitions.

[0091] Another preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R 1 Selected from R 1The residues included in the general definition of contain 4 or more, preferably 6 or more, even more preferably 7 or more carbon atoms,

[0092] And where R 1 Contains one or more (preferably 1 to 2) heteroatoms independently selected from O, S and N to replace R 1 The carbon atoms contained in

[0093] And where R 1 Even more preferably, it is selected from cyclic, bicyclic and tricyclic structures, or wherein R 1 is selected from residues comprising cyclic, bicyclic and tricyclic structures,

[0094] And where R 1 Even more preferred are tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azaadamantyl and -O(adamantyl),

[0095] And where R 1 Most preferred are tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, azaadamantyl and -O(adamantyl),

[0096] And R 2 -R 14 , X 1 -X 4 , Z 1 , Z 2 and Y are as defined in formula (I), including substitutions and preferred definitions.

[0097] A further preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, which fall within the subgenera defined herein:

[0098] S.1 If Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions thereof, provided that Z 1 and Z 2 Different from being =O or =S together,

[0099] Then R 1 -R 13 , X 1 -X 4 and Y are as defined in formula (I), including substitutions and preferred definitions thereof.

[0100] S.2 If R6 As defined in formula (I), including substitutions and preferred definitions thereof, provided that R 6 Different from -H, or linear unsubstituted or branched unsubstituted -C1-C6 alkyl,

[0101] Then R 1 -R 5 , R 7 -R 14 , X 1 -X 4 , Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions thereof. S.3 If Y is as defined in formula (I), including substitutions and preferred definitions thereof, provided that Y is different from -H, a linear unsubstituted

[0102] or a branched unsubstituted C1-C6 alkyl group or -OH,

[0103] Then R 1 -R 14 , X 1 -X 4 , Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions.

[0104] S.3 If Y is as defined in formula (I), including substitutions and preferred definitions, provided that Y is different from -H, linear unsubstituted or branched unsubstituted C1-C6 alkyl or -OH,

[0105] Then R 1 -R 14 , X 1 -X 4 , Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions.

[0106] S.4 If Z 1 and Z 2 together are =O or =S, and Y is -OH,

[0107] Then R 6 As defined in formula (I), including substitution and preferred definitions, provided that R 6 Different from -H,

[0108] And then R 1 -R 5 , R 7 -R 12 and X 1 -X 4As defined in formula (I), including substitutions and preferred definitions.

[0109] S.5 If Z 1 and Z 2 =O or =S together, and R 6 is -H, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group or -OH,

[0110] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0111] Then R 1 =C1-C 12 Alkyl, preferably C1-C6 alkyl, C2-C 12 Alkenyl, preferably C2-C6 alkenyl, C2-C 12 Alkynyl, preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-

[0112] C 14 Tricycloalkyl-OC1-C 12 Alkyl, preferably -OC1-C6 alkyl, -OC2-C 12 Alkenyl, preferably -OC2-C6 alkenyl, -OC2-

[0113] C 12 Alkynyl, preferably -OC2-C6 alkynyl, -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 Bicycloalkyl, -OC7-C 12 Bicycloalkenyl, -OC8-C 14 Tricycloalkyl-SC1-C 12 Alkyl, preferably -SC1-C6 alkyl, -SC2-C 12 Alkenyl, preferably -SC2-C6 alkenyl, -SC2-C 12 Alkynyl, preferably -SC2-C6 alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 Tricycloalkyl, -NHR 7 or -NR 7 R 8 , where R 7and R 8 Independently selected from: C1-C 12 Alkyl, preferably C1-C6 alkyl, C2-C 12 Alkenyl, preferably C2-C6 alkenyl, C2-C 12 Alkynyl, preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl, or wherein R 7 Can be used with R 8 The ring structures are formed together, wherein the ring structures containing N atoms are selected from 3 to 8-membered ring structures or 5 to 12-membered bicyclic structures, and wherein all of the ring structures may further contain one or more heteroatoms independently selected from O, S and N to replace the carbon atoms contained in the ring structures, wherein all C1-C 12 The alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, norbornyl and adamantyl residues are straight or branched and are substituted with one or more substituents (referred to herein as pendant substituents) independently selected from: -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C8 12 Bicycloalkyl (including norbornyl), C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl (including adamantyl), 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)(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); and wherein all of the C1-C 12 The alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, adamantyl or norbornyl residue may optionally further comprise one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS;

[0114] And all C9-C 12 Alkenyl, C9-C 12 Alkynyl, -OC1-C 12 Alkyl, -OC2-C 12 Alkenyl, -OC2-C 12 Alkynyl, -SC1-C 12Alkyl, -SC2-C 12 Alkenyl, -SC2-C 12 Alkynyl and those contained in R 7 and R 8 All alkyl, alkenyl and alkynyl residues in the definition of are linear or branched and are unsubstituted or substituted by one or more substituents (referred to herein as pendant substituents) independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricyclic alkyl, linear or branched -OC1-C5 alkyl such as -OCH3, -OC3-C 5环 Alkyl such as -O(cyclopropyl), 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 -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl residues, and those contained in R 7 and R 8 All cycloalkyl and cycloalkenyl residues included in the definition of and in the selection referred to as side substituents, as well as those included in R 1 , R 7 and R 8 all bicyclic and tricyclic structures (including bicycloalkyl, bicycloalkenyl and tricycloalkyl residues) in the definition of (provided that they are different from adamantyl and norbornyl) are unsubstituted or substituted with one or more substituents independently selected from -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);

[0115] Included in R 7 and R 8All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylbicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms; and the residues contained in R 1 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylbicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N in place of a carbon atom, optionally with the proviso that if not explicitly included in R 1 In the definition of , the combination of the heteroatoms in the terminal position is different from the residues -CN, -NCO, -NCS and -N3;

[0116] Included in R 1 , R 7 and R 8 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylbicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated;

[0117] Among them, bicyclic and tricyclic residues include fused, bridged, and spirocyclic systems;

[0118] And R 2 -R 5 , R 9 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0119] S.6 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group or -OH,

[0120] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0121] Then R 2Selected from -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-

[0122] C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight chain or branched -N(C1-C3 alkyl)(cyclopropyl);

[0123] wherein all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C4 cycloalkyl residues are substituted by one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0124] wherein the C5-C6 cycloalkyl residue is unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CH3,

[0125] Substitution with -CF3, -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2 substituents;

[0126] Included in R 2 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms;

[0127] And R 3 -R 5 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,

[0128] -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);

[0129] Included in R 3 -R 5All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are unsubstituted or replaced by one or more independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3,

[0130] -N(CH3)2 substitution;

[0131] Included in R 3 -R 5 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0132] And R 1 ,R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0133] S.7 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group or -OH,

[0134] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0135] Then X 1 CR 9 ,

[0136] And R 9 Selected from -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-

[0137] C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight chain or branched -N(C1-C3 alkyl)(cyclopropyl);

[0138] wherein all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C4 cycloalkyl residues are substantially substituted with one or more substitutions independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0139] The C5-C6 cycloalkyl residue is unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CH3, -CF3,

[0140] Substitution with -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0141] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0142] And then R 1 -R 5 , R 7 , R 8 , R 10 -R 12 and X 2 -X 4 As defined in formula (I), including substitution and preferred definitions. S.8 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, linear unsubstituted or branched unsubstituted C1-C6 alkyl or -OH,

[0143] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0144] Then X 2 CR 9

[0145] And R 9 Selected from -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-

[0146] C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight chain or branched -N(C1-C3 alkyl)(cyclopropyl);

[0147] wherein all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C4 cycloalkyl residues are substituted by one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0148] The C5-C6 cycloalkyl residue is unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CH3, -CF3,

[0149] Substitution with -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0150] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0151] And then R 1 -R 7 , R 7 , R 8 , R 10 -R 12 , X 1 , X 3 and X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0152] S.9 If Z 1 and Z 2 =O or =S, and R 6 is -H, Y is -H, a straight chain unsubstituted or branched chain unsubstituted C1-

[0153] C6 alkyl or -OH,

[0154] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0155] Then X 3 CR 9

[0156] And R 9Selected from -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-

[0157] C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight chain or branched -N(C1-C3 alkyl)(cyclopropyl);

[0158] wherein all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C4 cycloalkyl residues are substituted by one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0159] The C5-C6 cycloalkyl residue is unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CH3, -CF3,

[0160] Substitution with -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0161] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0162] And R 1 -R 5 , R 7 , R 10 -R 12 , X 1 , X 2 and X 4 As defined in formula (I), including substitutions and preferred definitions thereof. S.10 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, linear unsubstituted or branched unsubstituted

[0163] C1-C6 alkyl or -OH,

[0164] Or if Z 1 and Z 2 =O or =S, and R 6is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0165] Then X 4 CR 9

[0166] And R 9 Selected from -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-

[0167] C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight chain or branched -N(C1-C3 alkyl)(cyclopropyl);

[0168] wherein all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and C3-C4 cycloalkyl residues are substituted by one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0169] The C5-C6 cycloalkyl residue is unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CH3, -CF3,

[0170] Substitution with -OH, -OCH3, -OCF3, -NH2, -NHCH3 and -N(CH3)2;

[0171] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0172] And R 1 -R 5 , R 7 , R 8 , R 10 -R 12 and X 1 -X 3 As defined in formula (I), including substitutions and preferred definitions thereof. S.11 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, linear unsubstituted or branched unsubstituted

[0173] C1-C6 alkyl or -OH,

[0174] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0175] Then X 1 , X 2 and X 3 Each is N

[0176] And then R 1 -R 5 , R 7 -R 12 and X 4 As defined in formula (I), including substitutions and preferred definitions.

[0177] S.12 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group or -OH,

[0178] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0179] Then X 1 , X 2 and X 4 Each is N

[0180] And then R 1 -R 5 , R 7 -R 12 and X 3 As defined in formula (I), including substitutions and preferred definitions.

[0181] S.13 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group or -OH,

[0182] Or if Z 1 and Z2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0183] Then X 1 , X 3 and X 4 Each is N

[0184] And then R 1 -R 5 , R 7 -R 12 and X 2 As defined in formula (I), including substitutions and preferred definitions.

[0185] S.14 If Z 1 and Z 2 =O or =S, and R 6 is -H, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group or -OH,

[0186] Or if Z 1 and Z 2 =O or =S, and R 6 is -H or a linear unsubstituted or branched unsubstituted C1-C6 alkyl group, and Y is -H, a linear unsubstituted or branched unsubstituted C1-C6 alkyl group,

[0187] Then X 2 , X 3 and X 4 Each is N

[0188] And then R 1 -R 5 , R 7 -R 12 and X 1 As defined in formula (I), including substitutions and preferred definitions thereof S.15 If R 1 As defined in formula (I), including substitution and preferred definitions, provided that R 1 Contains one or more independent

[0189] heteroatoms selected from O, S and N, provided that the combination of said heteroatoms in the terminal position is different from the residues -CN, -NCO,

[0190] -NCS,

[0191] Then R 2 -R 14 , X 1 -X4 , Y, Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions thereof.

[0192] S.16 If Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions thereof, provided that Z 1 and Z 2 Not together

[0193] =O,

[0194] Then R 1 -R 14 , X 1 -X 4 and Y are as defined in formula (I), including substitutions and preferred definitions thereof.

[0195] S.17 If R 6 As defined in formula (I), including substitution and preferred definitions, provided that R 6 Different from -H, or -OC1-C6 alkyl, or -C3-C6 cycloalkyl,

[0196] wherein all of the -C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0197] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0198] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0199] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0200] Then R 1 -R 5 , R 7 -R 14 , X 1 -X 4 , Y, Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions. S.18 If Y is as defined in formula (I), including substitutions and preferred definitions, provided that Y is different from -H, or C1-C6 alkane

[0201] alkyl, or C3-C6 cycloalkyl, or -OH, or -OC1-C6 alkyl,

[0202] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0203] and wherein all of the -C3-C6 cycloalkyl residues are unsubstituted or are substituted by one or more independently selected from -F, -Cl, -Br,

[0204] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0205] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0206] Then R 1 -R 14 , X 1 -X 4 , Z 1 and Z 2 As defined in formula (I), including substitutions and preferred definitions thereof.

[0207] S.19 If Z 1 and Z 2 =O, and R 6 is -H, or -C1-C6 alkyl or -C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl or C3-C6 cycloalkyl, or -OH, or -OC1-C6 alkyl,

[0208] wherein all of the -C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -C1-C3 alkyl and -OC1-C3 alkyl,

[0209] and wherein all of the -C3-C6 cycloalkyl residues are unsubstituted or are substituted by one or more independently selected from -F, -Cl, -Br,

[0210] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0211] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0212] Then R 1 =C1-C 12 Alkyl, preferably C1-C6 alkyl, C2-C 12 Alkenyl, preferably C2-C6 alkenyl, C2-C 12Alkynyl, preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-

[0213] C 14 Tricycloalkyl, -OC1-C 12 Alkyl, preferably -OC1-C6 alkyl, -OC2-C 12 Alkenyl, preferably -OC2-C6 alkenyl, -OC2-C 12 Alkynyl, preferably -OC2-C6 alkynyl, -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 Bicycloalkyl, -OC7-C 12 Bicycloalkenyl, -OC8-C 14 Tricycloalkyl, -SC1-C 12 Alkyl, preferably -SC1-C6 alkyl, -SC2-

[0214] C 12 Alkenyl, preferably -SC2-C6 alkenyl, -SC2-C 12 Alkynyl, preferably -SC2-C6 alkynyl, -SC3-C8 cycloalkyl, -SC5-

[0215] C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 Tricycloalkyl, -NHR 7 or -NR 7 R 8 , where R 7 and R 8 Independently selected from: C1-C 12 , preferably C1-C6 alkyl, C2-C 12 Alkenyl, preferably C2-C6 alkenyl, C2-C 12 Alkynyl, preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl, or wherein R 7 Can be used with R 8 together forming a ring structure, wherein said ring structure comprising a N atom is selected from a 3- to 8-membered cyclic structure or a 5- to 12-membered bicyclic structure, and wherein all said ring structures may additionally comprise one or more heteroatoms independently selected from O, S and N replacing the carbon atoms comprised in the ring structure;

[0216] All C1-C 12Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl and C8-C 14 The tricycloalkyl residue is linear or branched and is substituted by one or more substituents (referred to herein as pendant substituents) independently selected from: -OH, -NH2, -NO2, =O, C3-

[0217] C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl linear or branched -OC4-C5 alkyl, -OC3-C5 cycloalkyl such as -O(cyclopropyl), linear or branched -NH(C1-C5), linear or branched -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl) such as -NH(cyclopropyl), -N(C3-C5 cycloalkyl)(C3-C 5环 alkyl), straight or branched-N(C1-C5 alkyl)(C3-C5 cycloalkyl); and wherein all of the C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl and C8-C 14 The tricycloalkyl residue may optionally further comprise one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS;

[0218] And all-OC1-C 12 Alkyl, -OC2-C 12 Alkenyl, -OC2-C 12 Alkynyl, -SC1-C 12 Alkyl, -SC2-C 12 Alkenyl, -SC2-C 12 Alkynyl and those contained in R 6 and R 7 All alkyl, alkenyl and alkynyl residues in the definition of are straight-chain or branched and are unsubstituted or substituted by one or more substituents (referred to herein as pendant substituents) independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl straight or branched -OC1-C5 alkyl such as -OCH3, -OC3-C 5环 Alkyl such as -O (cyclopropyl), straight chain or branched -NH (C1-C5 alkyl), straight chain or branched -N (C1-C5 alkyl) (C1-C5 alkyl), -NH (C3-C5 cycloalkyl) such as -NH (cyclopropyl), -N (C3-C 5环 -N(C1-C5 alkyl)(C3-C5 cycloalkyl), linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl);

[0219] Among them, all -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 Bicycloalkyl, -OC7-C 12 Bicycloalkenyl, -OC8-C 14 tricycloalkyl-SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 tricycloalkyl residues, and those contained in R 7 and R 8 All cycloalkyl, cycloalkenylbicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition and included in the selection referred to as pendant substituents are unsubstituted or substituted with one or more substituents independently selected from: -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);

[0220] Included in R 7 and R 8 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylbicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms; and the residues contained in R 1 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenylbicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N in place of a carbon atom, provided that if not explicitly included in R 1In the definition of , the combination of the heteroatoms in the terminal position is different from the residues -CN, -NCO, -NCS and -OC1-C3alkyl;

[0221] Among them, bicyclic or tricyclic residues include fused, bridged and spiro ring systems;

[0222] And R 2 -R 5 , R 9 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0223] S.20 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0224] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0225] and wherein all of the -C3-C6 cycloalkyl residues are unsubstituted or are substituted by one or more independently selected from -F, -Cl, -Br,

[0226] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0227] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0228] Then R 2 Selected from -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);

[0229] Included in R 2All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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;

[0230] Included in R 2 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms;

[0231] And then R 1 , R 3 -R 5 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions thereof. S.21 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0232] wherein all of the -OC1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -C1-C3 alkyl and -OC1-C3 alkyl,

[0233] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0234] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0235] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0236] Then X 1 CR 9

[0237] And R 9Selected from -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);

[0238] Wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues are included in the definition of R 9 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;

[0239] Wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues are included in the definition of R 9 may contain one or more heteroatoms independently selected from O, S and N to replace the carbon atoms;

[0240] And then R 1 -R 5 , R 7 , R 8 , R 10 -R 12 and X 2 -X 4 As defined in formula (I), including substitution and preferred definitions. S.22 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH, or -OC1-C6 alkyl,

[0241] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0242] and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0243] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0244] Then X 2 CR 9

[0245] And R 9 Selected from -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);

[0246] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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;

[0247] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0248] And then R 1 -R 5 , R 7 , R 8 , R 10 -R 12 , X 1 , X 3 and X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0249] S.23 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0250] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0251] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0252] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0253] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0254] Then X 3 CR 9

[0255] And R 9 Selected from -F, -Cl, -Br, -I, CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-

[0256] 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);

[0257] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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;

[0258] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0259] And R 1 -R 5 , R 7 , R 8 , R 10 -R 12 , X 1 , X 2 and X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0260] S.24 If Z 1 and Z 2 =O, and R6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0261] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0262] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0263] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0264] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0265] Then X 4 CR 9

[0266] And R 9 Selected from -F, -Cl, -Br, -I, CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-

[0267] 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);

[0268] Included in R 8 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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;

[0269] Included in R 9 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms;

[0270] And then R 1 -R 5 , R7 , R 8 , R 10 -R 12 and X 1 -X 3 As defined in formula (I), including substitutions and preferred definitions thereof. S.25 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0271] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0272] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0273] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0274] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0275] Then X 3 N

[0276] And then R 1 -R 5 , R 7 -R 12 , X 1 , X 2 and X 4 As defined in formula (I), including substitutions and preferred definitions thereof. S.26 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0277] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0278] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0279] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0280] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0281] Then X 4 N

[0282] And then R 1 -R 5 , R 7 -R 12 , X 1 To X 3 As defined in formula (I), including substitutions and preferred definitions thereof.

[0283] S.27 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0284] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0285] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0286] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0287] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0288] Then X 1 and X 4 Each is N

[0289] And then R 1 -R 5 , R 7 -R 12 , X 3 and X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0290] S.28 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0291] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0292] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0293] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0294] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0295] Then X 1 and X 3 Each is N

[0296] And R 1 -R 5 , R 7 -R 12 , X 2 and X 4 As defined in formula (I), including substitutions and preferred definitions thereof.

[0297] S.29 If Z 1 and Z 2 =O, and R 6 is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH or -OC1-C6 alkyl,

[0298] wherein all of the C1-C6 alkyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl,

[0299] and wherein all of the C3-C6 cycloalkyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br,

[0300] -I, C1-C3 alkyl and -OC1-C3 alkyl are substituted,

[0301] and wherein all said alkyl and cycloalkyl residues may optionally be halogenated or perhalogenated,

[0302] Then X 1 and X 4 Each is N

[0303] And R 1 -R 5 , R 7 -R 12 , X 2 and X 3 As defined in general formula (I), including substitutions and preferred definitions thereof.

[0304] S.30 If R 1 As defined in formula (I), including substitution and preferred definitions, provided that R 1 Different from C3-C8 cycloalkyl, wherein the C3-C8 cycloalkyl residue is unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CN,

[0305] -NCO, -NCS, C1-C3 alkyl and -OC1-C3 alkyl substituents,

[0306] wherein the C3-C8 cycloalkyl residue may be optionally perhalogenated

[0307] and wherein the C3-C8 cycloalkyl residues are selected from C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C8 cycloalkyl or C5-C8 cycloalkenyl substituents,

[0308] wherein all of the alkyl, alkenyl and alkynyl residues are linear or branched and are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS and -OC1-C3 alkyl,

[0309] Wherein all the cycloalkyl and cycloalkenyl residues are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I,

[0310] -CN, -NCO, -NCS, C1-C3 alkyl and -OC1-C3 alkyl substituents,

[0311] and wherein all of the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues are optionally perhalogenated,

[0312] Then R 2-R 14 , X 1 -X 4 , Y, Z 1 and Z 2 As defined in general formula (I), including substitutions and preferred definitions thereof.

[0313] In one embodiment, the present invention relates to compounds of formula (I) and salts and solvates thereof, wherein R 1 is adamantyl,

[0314] And where Z 1 and Z 2 As defined in Formula (I) (including Formula (Ia), Formula (Ib) and Formula (Ic)), including substitution and preferred definitions, optionally with the proviso that in the case of Formula (Ib), Z 1 and Z 2 Together is different from =O,

[0315] And where R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0316] And among them, Y, R 2 -R 6 , R 9 -R 13 , X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0317] And wherein the compounds share the following structure (I-1):

[0318]

[0319] And the compounds of structure (I-1) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0320] Examples are compounds XPW-0014, XPW-0028, XPW-0042, XPW-0182, XPW-0924, XPW-3038, XPW-3052, XPW-4633, XPW-4642 and XPW-4643.

[0321] In another specific embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y and R 6 As defined in formula (I), including substitution and preferred definitions, wherein Y and R 6 together to form a ring structure, and wherein the ring structure contains an O atom to replace the direct contact with Y and R 6 One of the ring C atoms to which the bound N atom is attached,

[0322] And where Z 1 and Z 2 As defined in Formula (I) (including Formula (Ia), Formula (Ib) and Formula (Ic)), including substitutions and preferred definitions,

[0323] And where R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0324] And where R 1 -R 5 , R 7 -R 12 , X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0325] And wherein the compounds share the following structure (I-2):

[0326]

[0327] And the compounds of structure (I-2) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, gastric cancer, breast cancer and neuroendocrine system cancer.

[0328] Examples are compounds XPW-4637 and XPW-4638.

[0329] In another specific embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y is selected from -S(O)R 13 and -S(O)2R 13 ,

[0330] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1comprising 4 or more, preferably 6 or more carbon atoms which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I),

[0331] And where Z 1 and Z 2 As defined in Formula (I) (including Formula (Ia), Formula (Ib) and Formula (Ic)), including substitutions and preferred definitions,

[0332] And where R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0333] And where R 2 -R 13 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0334] And wherein the compounds share the following structure (I-3):

[0335]

[0336] And the compounds of structure (I-3) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0337] Examples are compounds XPW-0547, XPW-0548, XPW-0552, XPW-0560, XPW-0566, XPW-0574, PW-0608, XPW-0616, XPW-2675, XPW-2676, XPW-2688, XPW-2703, XPW-2704,

[0338] In another specific embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, wherein Y is -OH,

[0339] And where R 6As defined in formula (I), including substitution and preferred definitions, provided that R 6 Different from -H,

[0340] And where Z 1 and Z 2 As in Formula (I) (including Formula (Ia), Formula (Ib) and Formula (Ic)), including substitutions and preferred definitions,

[0341] And where R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0342] And where R 1 -R 5 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0343] And the compounds described therein have the following structure (I-4):

[0344]

[0345] And the compounds of structure (I-4) are preferably used in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0346] Examples are compounds XPW-0182, XPW-0674, XPW-0675, XPW-0678, XPW-0679, XPW-0686, XPW- 0700, XPW-0734, XPW-0742, XPW-1750, XPW-2805, XPW-2806, 14. XPW-4616, XPW-4617, XPW-4618, XPW-4619, XPW-4620, XPW-4621, 2. XPW-4626, XPW-4631, XPW-4632, XPW-4640, XPW-4644, XPW-4646 and XPW-4647.

[0347] In another specific embodiment, the present invention relates to compounds of formula (I) and their salts and solvates, wherein Y is -OCH3,

[0348] And where R 1 As defined in formula (I), including substitution and preferred definitions, including any substituent R 1 does not contain heteroatoms selected from O, S, N, optionally with the proviso that R 1 Containing 2 or more carbon atoms,

[0349] And where Z 1 and Z 2 As defined in Formula (I) (including Formula (Ia), Formula (Ib) and Formula (Ic)), including substitutions and preferred definitions,

[0350] And where R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0351] And where R 2 -R 6 , R 9 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0352] And wherein the compounds share the following structure (I-5):

[0353]

[0354] And the compounds of structure (I-5) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer.

[0355] Examples are compounds XPW-0702, XPW-0706, XPW-0714, XPW-0716, XPW-0720, XPW-0728, XPW-2833, XPW-2834, XPW-2847, XPW-2848 and XPW-4605.

[0356] In another specific embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, wherein R 6 is -H and Y is -OCH3,

[0357] And where R 1As defined in formula (I), including substitution and preferred definitions, provided that R 1 is selected from a cyclic structure, a bicyclic structure and a tricyclic structure,

[0358] And where Z 1 and Z 2 As defined in Formula (I) (including Formula (Ia), Formula (Ib) and Formula (Ic)), including substitutions and preferred definitions,

[0359] And where R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0360] And where R 2 -R 5 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0361] And wherein the compounds share the following structure (I-6):

[0362]

[0363] And the compounds of structure (I-6) are preferably used in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer.

[0364] Examples are compounds XPW-0706, XPW-0714, XPW-2833 and XPW-2834.

[0365] In another specific embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y and R 6 As defined in formula (I), including substitution and preferred definitions, wherein Y and R 6 Together they form a ring structure,

[0366] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 is selected from a cyclic structure, a bicyclic structure and a tricyclic structure, optionally with the proviso that R including any substituent 1 does not contain a heteroatom selected from O, S, N or contains a heteroatom selected from O, S, N,

[0367] And where Z 1 , Z 2 and R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0368] And where R 2 -R 5 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0369] And wherein the compounds share the following structure (I-7):

[0370]

[0371] And the compounds of structure (I-7) - especially in the absence of additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, ovarian cancer and neuroendocrine system cancer.

[0372] Examples are compounds XPW-0762, XPW-0770, XPW-0776, XPW-0784, XPW-0790, XPW-0798, 18. XPW-2926, XPW-4576, XPW-4577, XPW-4578, XPW-4579, XPW-4580,

[0373] In another specific embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z 1 For -CF3,

[0374] and wherein Y is as defined in formula (I), including substitutions and preferred definitions, optionally with the proviso that Y is different from -H,

[0375] And where Z 2 As defined in formula (Ia), including substitution and preferred definitions,

[0376] And where R 1 -R 13 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0377] And wherein the compounds share the following structure (Ia-1):

[0378]

[0379] And wherein the compounds of structure (Ia-1) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0380] Examples are compounds XPW-0014, XPW-0020, XPW-0028, XPW-0042, XPW-0182, XPW-4633, XPW-4642 and XPW-4643.

[0381] In another specific embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z 1 For CF3,

[0382] And where R 6 As defined in formula (I), including substitution and preferred definitions, optionally with the proviso that R 6 Different from -H,

[0383] And where Z 2 As defined in formula (Ia), including substitution and preferred definitions,

[0384] And where R 1 -R 5 , R 7 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0385] And wherein the compounds share the following structure (Ia-2):

[0386]

[0387] And wherein the compounds of structure (Ia-2) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0388] Examples are compounds XPW-0014, XPW-0020, XPW-0028, XPW-0042, XPW-0182, XPW-4633, XPW-4642 and XPW-4643.

[0389] In another specific embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z 1 is -CF3, and where Y and R 6 Each is -H,

[0390] And where R 1 As defined in formula (I), including substitution and preferred definitions, optionally with the proviso that R 1 comprising 5 or more, preferably 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I),

[0391] And where Z 2 As defined in formula (I), including substitution and preferred definitions,

[0392] And where R 2 -R 5 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0393] And wherein the compounds share the following structure (Ia-3):

[0394]

[0395] And the compounds of structure (Ia-3) are preferably used in human and veterinary medicine, especially in the absence of additional conditions, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, ovarian cancer and neuroendocrine system cancer.

[0396] An example is compound XPW-0014.

[0397] In another specific embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Z 1 For -CN,

[0398] And where R 1 As defined in formula (I), including substitution and preferred definitions, and wherein R 1 comprising 3 or more, preferably 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I) optionally with the proviso that R including any substituent 1 does not contain heteroatoms selected from O, S, N,

[0399] And where Z 2 As defined in formula (Ia), including substitution and preferred definitions,

[0400] And where R 2 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0401] And wherein the compounds share the following structure (Ia-4):

[0402]

[0403] And wherein the compounds of structure (Ia-4) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia) and skin cancer.

[0404] An example is compound XPW-0314.

[0405] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 contains 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I), and wherein R 1 is selected from cyclic, bicyclic and tricyclic structures,

[0406] And where R 5 As defined in formula (I), including substitution and preferred definitions, provided that R 5 Different from -H,

[0407] And where Z 1 , Z 2 and R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0408] And where R 2 -R 4 , R 6 -R 13 and X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0409] And wherein the compounds share the following structure (Ib-1):

[0410]

[0411] And the compounds of structure (Ib-1) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0412] Examples are compounds XPW-4575, XPW-4577, XPW-4578, XPW-4579, XPW-4580, PW-4586, XPW-4587, XPW-4588, XPW-4589, XPW-4590, XPW-4591,XPW-4592, XPW-4593,

[0413] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein X 4 For N,

[0414] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 contains six or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I), and wherein R 1 is selected from cyclic, bicyclic and tricyclic structures,

[0415] And where Z 1 , Z 2 and R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0416] And where R 2 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0417] And wherein the compounds share the following structure (Ib-2):

[0418]

[0419] And the compounds of structure (Ib-2) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0420] Examples are compounds XPW-4623, XPW-4624, XPW-4628, XPW-4629, XPW-4630, XPW-4631, XPW-4632, XPW-4634, XPW-4635, XPW-4636 and XPW-4644.

[0421] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 Together they are =O, and wherein Y is -OCH3,

[0422] And where R 1 As defined in formula (I), including substitution and preferred definitions, including any substituent R 1 does not contain heteroatoms selected from O, S, N, optionally with the proviso that R 1 Contains two or more carbon atoms

[0423] And where R 2 -R 6 , R 9 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0424] And wherein the compounds share the following structure (Ib-3):

[0425]

[0426] And the compounds of structure (Ib-3) are preferably used in human and veterinary medicine, especially in the absence of additional conditions, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer.

[0427] Examples are compounds XPW-0702, XPW-0706, XPW-0714, XPW-0716, XPW-0720, XPW-0728, XPW-2833, XPW-2834, XPW-2847, XPW-2848 and XPW-4605.

[0428] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Y and R 6 As defined in formula (I), including substitution and preferred definitions, wherein Y and R 6 Together they form a ring structure,

[0429] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 is selected from a cyclic structure, a bicyclic structure and a tricyclic structure, optionally with the proviso that R including any substituent 1 does not contain a heteroatom selected from O, S, N or contains a heteroatom selected from O, S, N,

[0430] And where Z1 , Z 2 and R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0431] And where R 2 -R 5 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0432] And wherein the compounds share the following structure (Ib-4):

[0433]

[0434] And the compounds of structure (Ib-4) are preferably used in human and veterinary medicine, especially in the absence of additional conditions, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, ovarian cancer and neuroendocrine system cancer.

[0435] Examples are compounds XPW-0762, XPW-0770, XPW-0776, XPW-0784, XPW-0790, XPW-0798, 18. XPW-2926, XPW-4576, XPW-4577, XPW-4578, XPW-4579, XPW-4580,

[0436] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 =0, and R 1 is adamantyl,

[0437] And where R 5 As defined in formula (I), including substitution and preferred definitions, provided that R 5 Different from -H,

[0438] And among them, Y, R2 -R 4 , R 6 , R 9 -R 13 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0439] And wherein the compounds share the following structure (Ib-5):

[0440]

[0441] And the compounds of structure (Ib-5) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0442] Examples are compounds XPW-4585, XPW-4586, XPW-4587, XPW-4591, XPW-4592 and XPW-4593.

[0443] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 =0, and R 1 is adamantyl, and wherein X 4 For N,

[0444] And where R 2 -R 6 , R 9 -R 13 , X 1 -X 3 and Y is as defined in (I), including substitution and preferred definitions,

[0445] And wherein the compounds share the following structure (Ib-6):

[0446]

[0447] And the compounds of structure (Ib-6) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0448] Examples are compounds XPW-4623, XPW-4624, XPW-4628, XPW-4629, XPW-4630, XPW-4631, XPW-4632, XPW-4634, XPW-4635, XPW-4636 and XPW-4644.

[0449] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 together are =O, and wherein Y is -OH, and wherein R 6 For -H,

[0450] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 comprising 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I),

[0451] And where R 5 As defined in formula (I), including substitution and preferred definitions, provided that R 5 Different from -H,

[0452] And in R 2 -R 4 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0453] And wherein the compounds share the following structure (Ib-7):

[0454]

[0455] And the compounds of structure (Ib-7) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0456] Examples are compounds XPW-4584, XPW-4587, XPW-4590 and XPW-4593.

[0457] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 together are =O, and wherein Y is -OH, and wherein R 6 is -H, and where X 4 For N,

[0458] And where R 1 -R 5 , R 7 -R 12 and X 1 -X 3 As defined in formula (I), including substitutions and preferred definitions,

[0459] And wherein the compounds share the following structure (Ib-8):

[0460]

[0461] And the compounds of structure (Ib-8) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0462] Examples are compounds XPW-4623, XPW-4628, XPW-4630 and XPW-4636.

[0463] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2together are =O, and wherein Y is -OH, and wherein R 6 is -H, and where X 1 and X 2 Each is N,

[0464] And where R 1 -R 5 , R 7 -R 12 , X 3 and X 4 As defined in formula (I), including substitutions and preferred definitions,

[0465] And wherein the compounds share the following structure (Ib-9):

[0466]

[0467] And the compounds of structure (Ib-9) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0468] An example is the compound XPW-4625.

[0469] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 together are =O, and wherein Y is -OH, and wherein R 6 is -H, and where X 1 is N, and where X 4 CR 10 , and where R 10 As defined in formula (I), including substitution and preferred definitions, provided that R 10 Different from -H,

[0470] And where R 1 -R 5 , R 7 -R 9 , R 11 , R 12 , X 2 and X 3 As defined in formula (I), including substitutions and preferred definitions,

[0471] And wherein the compounds share the following structure (Ib-10):

[0472]

[0473] And the compounds of structure (Ib-10) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0474] An example is compound XPW-4639.

[0475] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 together are =O, and wherein Y is -CH3, and wherein R 6 For -CH3,

[0476] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 comprising 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I),

[0477] And where R 5 As defined in formula (I), including substitution and preferred definitions, wherein R 5 Different from -H, optionally with the additional condition R 5 Different from -OCH3,

[0478] And where R 2 -R 4 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions,

[0479] And wherein the compounds share the following structure (Ib-11):

[0480]

[0481] And the compounds of structure (Ib-11) are preferably used in human and veterinary medicine, especially in the absence of additional conditions, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer and neuroendocrine system cancer.

[0482] Examples are compounds XPW-4575, XPW-4585, XPW-4588, XPW-4591 and XPW-4595.

[0483] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 is selected from unsubstituted and substituted cycloalkyl and cycloalkenyl, wherein such ring contains 4 or more, preferably 6 or more, carbon atoms which cannot be replaced by heteroatoms selected from O, S and N,

[0484] And where R 5 As defined in formula (I), including substitution and preferred definitions, provided that R 5 Different from -H,

[0485] And where Z 1 , Z 2 and R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0486] And where R 2 -R 4 , R 6 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0487] And wherein the compounds share the following structure (Ib-12):

[0488]

[0489] And the compounds of structure (Ib-12) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0490] Examples are compounds XPW-4575, XPW-4585, XPW-4578, XPW-4579, XPW-4580, XPW-4581, XPW-4583, XPW-4584, XPW-4588, XPW-4589, XPW-4590, XPW-4594 and XPW-4595.

[0491] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 Together = NR 14 ,

[0492] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that any substituent R 1 does not contain a heteroatom selected from O, S, and N, or contains a heteroatom selected from O, S, and N,

[0493] And where R 14 As defined in formula (Ib), including substitution and preferred definitions,

[0494] And where R 2 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0495] And wherein the compounds share the following structure (Ib-13):

[0496]

[0497] and wherein the compounds of structure (Ib-13) are - especially without additional conditions - preferably 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 defined herein, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and hematological cancers (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer and breast cancer,

[0498] Examples are compounds XPW-0832 and XPW-4574.

[0499] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 together are =O, and wherein Y is -OH, and wherein R 6 is -H, and where X 1 CR 11 , X 2 CR 8 , X 3 CR 9 And X 4 CR 10 ,

[0500] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 contains 4 or more, preferably 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I), provided that R including any substituents 1 Contains 1 or 2 heteroatoms selected from O, S, N,

[0501] And where R 2 -R 5 and R 7 -R 12 As defined in formula (I), including substitutions and preferred definitions,

[0502] And wherein the compounds share the following structure (Ib-14):

[0503]

[0504] And the compounds of structure (Ib-14) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0505] Examples are compounds XPW-0661, XPW-0665, XPW-0667 and XPW-4613.

[0506] In another specific embodiment, the present invention relates to compounds of general formula (Ib) and salts and solvates thereof, wherein Z 1 and Z 2 =0, and R 6 is -CH3, and wherein X 1 CR 11 , X 2 CR 8 , X 3 CR 9 and X 4 CR 10 ,

[0507] And where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 is selected from a cyclic structure, a bicyclic structure and a tricyclic structure, provided that R including any substituent 1 Contains 1 or 2 heteroatoms selected from O, S, N,

[0508] And where R 2 -R 5 , R 7 -R 13 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0509] And wherein the compounds share the following structure (Ib-15):

[0510]

[0511] And the compounds of structure (Ib-15) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, breast cancer, ovarian cancer and neuroendocrine system cancer.

[0512] Examples are compounds XPW-0539, XPW-0541 and XPW-0679.

[0513] In another specific embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z 1 and Z 2 together to form a ring structure containing the carbon atoms to which they are attached, and wherein Z 1 and Z 2 As defined in formula (Ic), including substitution and preferred definitions,

[0514] And where R 6 As defined in formula (I), including substitution and preferred definitions, optionally with the proviso that R 6 Different from H,

[0515] And R 1 -R 5 , R 7 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0516] And wherein the compounds share the following structure (Ic-1):

[0517]

[0518] And wherein the compounds of structure (Ic-1) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0519] Examples are compounds XPW-0902, XPW-0916, XPW-0924, XPW-0930, XPW-3038 and XPW-3052.

[0520] In another specific embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z 1 and Z 2 together to form a ring structure containing the carbon atoms to which they are attached, and wherein Z 1 and Z 2 As defined in formula (Ic), including substitutions and preferred definitions, optionally with the proviso that the cyclic residue contains one or more heteroatoms independently selected from O, S and N to replace the carbon atoms contained in the ring structure, and / or the cyclic residue is substituted with one or more substituents as defined in formula (Ic),

[0521] And R 1 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0522] And wherein the compounds share the following structure (Ic-2):

[0523]

[0524] And the compounds of structure (Ic-2) are preferably used in human and veterinary medicine, especially in the absence of additional conditions, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0525] Examples are compounds XPW-0902, XPW-0916, XPW-0924, XPW-0930, XPW-3038 and XPW-3052.

[0526] In another specific embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z 1 and Z 2 together form a cyclic residue containing the carbon atom to which they are attached, and wherein Z 1 and Z 2 As defined in formula (Ic), including substitutions and preferred definitions, optionally with the proviso that the cyclic residue is a 4-membered ring,

[0527] And where R 2 -R 13 , X 1 -X 4 and Y is as defined in formula (I), including substitutions and preferred definitions,

[0528] And wherein the compounds share the following structure (Ic-3):

[0529]

[0530] And the compounds of structure (Ic-3) are preferably used in human and veterinary medicine, especially in the absence of additional conditions, in particular for the medical uses described in the present invention, preferably for immune system related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer.

[0531] Examples are compounds XPW-0902, XPW-0916, XPW-0924, XPW-0930, XPW-3038 and XPW-3052.

[0532] In another specific embodiment, the present invention relates to compounds of the general formula (Ic) and salts and solvates thereof, wherein Z 1 and Z 2 together form a cyclic residue containing the carbon atom to which they are attached, and wherein Z 1 and Z 2 As defined in formula (Ic), including substitutions and preferred definitions,

[0533] And where Y and R 6 Each is -H,

[0534] And where R 1 As defined in formula (I), including substitution and preferred definitions, optionally with the proviso that R 1 comprising 5 or more, preferably 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I),

[0535] And where R 2 -R 5 , R 7 -R 12 and X 1 -X 4As defined in formula (I), including substitutions and preferred definitions,

[0536] And wherein the compounds share the following structure (Ic-4):

[0537]

[0538] and wherein the compounds of structure (Ic-4) are - especially without additional conditions - preferably 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 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 hematological system (such as leukemias and lymphomas), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancer,

[0539] Examples are compounds XPW-0916, XPW-0924 and XPW-3052.

[0540] In some embodiments, the following compounds shown in Tables 1 to 3 are specifically excluded from the scope of the present invention:

[0541] The compounds of Table 1, specifically indicated by CAS registration numbers, have been identified by the inventors as being in the state of the art. In embodiments where these compounds are covered by the general formula (I) or any sub-generically defined herein, they are expressly excluded from the scope of the present invention with respect to compound protection. To the best of the inventors' knowledge, any medical use of these compounds is unknown. Therefore, the present invention covers any medical use of the compounds of Table 1.

[0542]

[0543]

[0544] The compounds of Table 2 specifically indicated by CAS registration numbers have been identified by the inventors as being state of the art. In embodiments, when these compounds are covered by the general formula (I) or any sub-genus defined herein, they are explicitly excluded from the scope of the present invention regarding compound protection. To the best of the inventors' knowledge, these compounds have not been recognized for any medical use defined herein. Therefore, with respect to the medical uses defined herein, particularly in the treatment of non-malignant or malignant hyperproliferative diseases, the compounds of Table 2 are explicitly included within the scope of the present invention.

[0545]

[0546]

[0547] The compounds of Table 3, specifically indicated by CAS registration numbers, have been identified by the inventors as being state of the art. In embodiments, when these compounds are covered by the general formula (I) or any sub-genus defined herein, they are explicitly excluded from the scope of the present invention regarding compound protection. In addition, to the inventors' knowledge, these compounds are known for medical use, and in some embodiments, they may be covered by the medical use defined herein. Therefore, in some embodiments defined herein, the compounds of Table 3 may be explicitly excluded from the scope of the present invention with respect to compound protection and certain medical uses.

[0548]

[0549]

[0550]

[0551]

[0552] In the present application specific examples of compounds falling within the scope of compounds contained in the pending application PCT / EP2018 / 054686 have been identified which have new medical uses, in particular muscle cells, keratinocytes and cells and malignant cells selected from cervical cancer, cutaneous T-cell lymphoma, acute promyelocytic leukemia, leukemia, acute myeloid leukemia, oral and tongue squamous cell carcinoma, epidermoid squamous cell carcinoma and lung squamous cell carcinoma cells have growth inhibitory properties.

[0553] Therefore, these compounds and their salts and solvates are particularly suitable for the treatment of hyperproliferative muscle diseases as defined herein, hyperproliferative skin diseases, and for the treatment of cervical cancer, cutaneous T-cell lymphoma, acute promyelocytic leukemia, leukemia, acute myeloid leukemia, epidermoid skin cancers such as non-melanoma skin cancer, oral cancer, tongue cancer and lung cancer as defined herein.

[0554] In the present application, specific examples of compounds falling within the scope of compounds contained in the pending application PCT / EP2018 / 054686 have been identified, having further novel medical uses, in particular growth inhibitory properties against a tumor selected from T-cell leukemia, B-cell leukemia, gastric cancer, breast cancer and medullary thyroid cancer.

[0555] Therefore, these compounds and their salts and solvates are particularly suitable for treating hematopoietic diseases, including hematopoietic diseases such as T-cell leukemia, B-cell leukemia, and gastric cancer, breast cancer, ovarian cancer and neuroendocrine system cancer as defined herein.

[0556] Tables 4 and 5 show the novel medical uses identified herein for specific compounds falling within the scope of compounds contained in pending application PCT / EP2018 / 054686, wherein the medical uses are selected from the treatment of hyperproliferative muscle diseases (A), hyperproliferative skin diseases (B), cervical cancer (C), cutaneous T-cell lymphoma (D), acute promyelocytic leukemia (E), acute myeloid leukemia (F), epidermoid skin cancer (G), oral cancer (H), tongue cancer (I), lung cancer (J), T-cell leukemia (K), B-cell leukemia (L), gastric cancer (M), breast cancer (N), ovarian cancer (O) and neuroendocrine system cancer (P) as defined herein.

[0557] The following compounds described in PCT / EP2018 / 054686 are specifically claimed for the indicated medical uses.

[0558] Table 4:

[0559]

[0560]

[0561] The following compounds described in PCT / EP2018 / 054686 are specifically claimed for the indicated medical uses.

[0562] Table 5:

[0563]

[0564]

[0565] Specific examples of compounds falling within the scope of formula (I) are shown in Tables 6 to 54. The intermediates are denoted "XPW-I".

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611] Other definitions:

[0612] The term "C1-C 12 "Alkyl" includes all isomers of the corresponding saturated aliphatic hydrocarbon radicals 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.

[0613] The term "C2-C 12 "Alkenyl" includes all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing from 2 to 12 carbon atoms connected by (i.e., comprising) 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.

[0614] The term "C2-C 12"Alkynyl" includes all isomers of the corresponding unsaturated acetylenic hydrocarbon radicals containing from 2 to 12 carbon atoms connected by (i.e., containing) one or more triple bonds; this includes ethynyl, all propynyl isomers, all butynyl isomers, all pentynyl isomers, all hexynyl isomers, all heptynyl isomers, all octynyl isomers, all phenylynyl isomers, all decynyl isomers, all undecynyl isomers and all dodecynyl isomers. The term "alkynyl" also includes compounds having one or more triple bonds and one or more double bonds.

[0615] The term "C3-C8 cycloalkyl" includes the corresponding saturated hydrocarbon groups containing 3-8 carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0616] The term "C5-C8 cycloalkenyl" includes corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing 5 to 8 carbon atoms, at least one of which is sp 3 hybrid, and they are arranged in a single ring structure and connected by (ie, contain) one or more double bonds; this includes all cyclopentenyl isomers, all cyclohexenyl isomers, all cycloheptenyl isomers, all cyclooctenyl isomers.

[0617] 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 spiro ring systems;

[0618] The term "C7-C 12 "Bicycloalkenyl" includes corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups comprising 7 to 12 carbon atoms arranged in a bicyclic ring structure and connected by (i.e., containing) one or more double bonds; wherein these bicyclic ring structures include fused, bridged and spiro ring systems;

[0619] The term "C8-C 14 "Tricycloalkyl" includes corresponding saturated hydrocarbon groups containing 8 to 14 carbon atoms arranged in a tricyclic ring structure; wherein these tricyclic ring structures include fused, bridged and spiro ring systems;

[0620] For R 1 For purposes of the present invention, the terms "cyclic", "bicyclic", "tricyclic", "cycloalkyl", "cycloalkenyl", "bicycloalkyl", "bicycloalkenyl" and "tricycloalkyl" mean that such cyclic, bicyclic or tricyclic residues are directly attached to R by a chemical bond. 1 The aromatic ring to which it is attached; and R 1The terms "cyclic", "bicyclic", "tricyclic", "cycloalkyl", "cycloalkenyl", "bicycloalkyl", "bicycloalkenyl" and "tricycloalkyl" as used herein refer to substituents of R, wherein the cyclic, bicyclic or tricyclic residue is directly attached to R by a chemical bond. 1 On one of the C atoms, N atoms, O atoms or S atoms contained therein; for example, "R 1 is cyclohexyl" means that the cyclohexyl residue and R 1 The aromatic rings are connected; "R 1 is a methyl group, and R 1 "substituted by cyclohexyl" means that the resulting -CH2(cyclohexyl) residue is 1 The connected aromatic rings are connected.

[0621] 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, a -CR2- group can be replaced by -NR-, -NR2 + -, -O- or -S- groups.

[0622] The term "perhalogenated" relates to the complete halogenation of the carbon scaffold; corresponding residues include corresponding perfluorinated, perchlorinated, perbrominated and perchlorinated groups. Preferably, the term "perhalogenated" relates to perfluorinated or perchlorinated groups, more preferably perfluorinated groups.

[0623] The following contains definitions of terms used in this specification. Unless otherwise stated, the initial definitions provided for a group or term herein apply to the group or term throughout the specification, either alone or as part of another group.

[0624] The compounds of the present invention can form salts, which are also within the scope of the present invention. Unless otherwise indicated, the reference to the compounds of the present invention herein should be understood to include reference to their salts. As used herein, the term "one or more salts" means acidic and / or basic salts formed by inorganic and / or organic acids and bases. Zwitterions (internal salts or inner salts) are included in the term "one or more salts" used herein (and can be formed when, for example, a substituent includes an acid moiety (such as a carboxyl group) and an amino group). Quaternary ammonium salts, such as alkyl ammonium salts, are also included herein. The salt of a compound can be, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount of acid or base, in a medium such as a medium in which a salt is precipitated or in an aqueous medium, and then lyophilized to form.

[0625] Exemplary salts resulting from the addition of an acid include acetates (such as those formed from acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionates, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate , caproates, hydrochlorides, hydrobromides, hydroiodides, chlorates, bromates, iodates, 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 with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as toluenesulfonates, undecanoates, and the like.

[0626] Exemplary salts resulting from the addition of a base (e.g., formed where the substituent includes an acidic moiety such as a carboxyl group) 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 (e.g., organic amines) such as benzathine penicillin, dicyclohexylamine, hydrabamine, N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl and octadecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0627] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, wherein the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound, such as salts formed by non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water or in an organic solvent or in a mixture of the two; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Lists of suitable salts may be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and in Journal of Pharmaceutical Science 1977, 66(2), each of which is incorporated herein by reference in its entirety.

[0628] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which 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.

[0629] In addition, in the case where the compounds of the invention contain asymmetric carbon atoms or atropoisomeric bonds, the invention relates to the D-form, the L-form and the D, L mixtures, and when there are more than one asymmetric carbon atom or atropoisomeric bond, it also relates to the diastereomeric forms. Those compounds of the invention that contain asymmetric carbon atoms or atropoisomeric bonds and are usually obtained in the form of racemates can be separated into optically active isomers in a known manner, for example using optically active acids. However, it is also possible to use optically active starting materials from the outset and then obtain the corresponding optically active or diastereomeric compounds as final products.

[0630] Compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include proton tautomers (prototropictautomers), which are isomeric protonation states with the same empirical formula (empirical formula) and total charge. Examples of proton tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs and rings, wherein protons can occupy two or more positions of heterocyclic systems, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles and 1H- and 2H-pyrazoles. Tautomeric forms can be in equilibrium, or can be spatially locked into a form by appropriate substitution.

[0631] The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are intended to be included. Compounds of the present invention containing atoms of asymmetrically substituted carbons can be separated in optically active or racemic forms. Methods for preparing 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 alkenes, C=N double bonds, etc. may also be present in the compounds described herein, and all such stable isomers are within the contemplation of the present invention. Cis and trans geometric isomers of the compounds of the present invention are described, and they can be separated into mixtures of isomers or separated isomeric forms.

[0632] The compounds of the present invention may also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0633] Also included are solvates and hydrates of the compounds of the present invention and solvates and hydrates of pharmaceutically acceptable salts thereof.

[0634] Unless otherwise indicated, the term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotational isomers, and isotopes of the depicted structure.

[0635] In some embodiments, the compound can be provided in the form of a prodrug. As used herein, the term "prodrug" refers to a compound that undergoes chemical conversion by metabolic or chemical processes after administration to a subject to produce a compound of the invention or a salt and / or solvate thereof.

[0636] In some embodiments, the compounds of the present invention and their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched in the compounds of the present invention. Substantially isolated can include a composition 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 the compounds of the present invention or their salts.

[0637] Pharmaceutical methods

[0638] It has been found that the compounds according to the invention have pharmacologically important properties and can be used in therapy.The compounds according to the invention can be used alone, in combination with one another or in combination with other active compounds.

[0639] In certain embodiments, compounds of the invention may exhibit growth inhibitory properties in hyperproliferative processes.

[0640] The antiproliferative activity of the compounds of formula (Ia), (Ib) and (Ic), respectively, was studied on cells or cell lines derived from the hematopoietic system (including the myeloid cell compartment and lymphoid cells (T cells and B cells)), the neuroendocrine system, the cervical, breast, ovarian, lung, gastrointestinal tract and mucosal epithelium, as well as from the skin epithelium and from the 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 into 96-well plates (CORNING #3598) suitable for fluorescence assays at the following initial cell numbers: 1000 cells per well for HL-60; 1000 cells per well for NB-4; and 1000 cells per well for HH. 5000 cells per well; 5000 cells per well of RPMI-8402; 1500 cells per well of TANOUE; 9000 cells per well of TT; 2000 cells per well of HeLa; 3000 cells per well of MDA-MB-231; 3000 cells per well of FU-OV-1; 4000 cells per well of LOU-NH91; 2000 cells per well of 23132 / 87; 2000 cells per well of CAL-27; 1500 cells per well of BHY; 1500 cells per well of SCC-25; 700 cells per well of A-431; 1000 cells per well of HPEK; 500 cells per well of C2C12. Cells were treated for 5 days with compounds at the indicated final concentrations (diluted 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)) or with 0.1% v / v of empty vehicle DMSO as a control. On day 5 after the start of treatment, cells were plated according to the manufacturer's protocol. Proliferation assay (Bio-Rad Serotec GmbH, BUF012B). Readout was performed using a multiwell plate reader in fluorescence mode using filters (excitation at 560 nm (bandwidth 10 nm) and excitation at 590 nm (bandwidth 10 nm). Control treatments for growth inhibition with commercial compounds such as methotrexate (MTREX) and resveratrol (RES) were included on each plate. Some test compounds of the present invention were obtained and used in the form of their salts. The "Specification" column in Tables 55 to 92 and their overall chemical formula in Table 93 show the corresponding situation.

[0641] The assay was performed in duplicate or more independent single experiments, each experiment was repeated 6 times for each condition. For each individual plate, the measured fluorescence intensity values ​​under compound-treated conditions were normalized to the corresponding equally weighted arithmetic mean of the fluorescence intensity values ​​of six DMSO-treated control wells to obtain relative values ​​against a baseline level of 1.0.

[0642] Two independent outlier analyses were performed according to the method of Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one method were excluded from the calculations, but no more than 1 value out of 6 values ​​for each compound in a single experiment. The weighted arithmetic mean (abbreviated here as AVE) was calculated for each compound from the normalized values ​​of all independent replicates of each single experiment repeated 6 times. w ). The corresponding standard deviation of the weighted arithmetic mean is calculated according to the method described by Bronstein et al. (Bronstein, Semindjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and combined with Gaussian error propagation (Gauβ'error propagation), which is associated with the normalization calculation performed. The resulting standard deviation is referred to herein as the "combined standard deviation".

[0643] In cases where the normalized equally weighted arithmetic means derived from two independent replicates varied considerably, the number of independent replicates was increased to three or more. In cases where four or more independent replicates were obtained, a second-line outlier analysis was performed on all normalized equally weighted arithmetic means according to the method of Peirce and Chauvenet described above.

[0644] In certain embodiments, the compounds of the invention may be growth inhibitors of hyperproliferative processes, including both malignant and non-malignant hyperproliferative processes.

[0645] In one embodiment, several compounds of the present invention 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 accession number ACC 3. HL-60 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0646] A compound is considered a growth inhibitor of HL-60 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, specifically adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. Analogously to the calculation performed for the test compound, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0647] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) 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 55 and Table 56. The entries in Table 55 and Table 56 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0648] Table 55: Proliferation assay using HL-60 cells at 20 μM

[0649]

[0650]

[0651]

[0652]

[0653]

[0654] Table 56: Proliferation assay using HL-60 cells at 20 μM

[0655]

[0656] The data in Table 55 relate to novel compounds, wherein the data in Table 56 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0657] In one embodiment, several compounds of the present invention 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. NB-4 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0658] Compounds are considered growth inhibitors of NB-4 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM sums up to 0.9 or less, specifically sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. The overall basal level is calculated similarly to the calculation performed for the test compounds as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0659] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of NB-4 cells. The NB-4 growth inhibitors identified to date relate to the compounds listed in Table 57 and Table 58. The entries in Table 57 and Table 58 are sorted according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0660] 表57 ： exist 20 μ M Next use NB-4 Cell proliferation assay

[0661]

[0662]

[0663]

[0664]

[0665] Table 58: Proliferation assay using NB-4 cells at 20 μM

[0666]

[0667]

[0668]

[0669] The data in Table 57 relate to novel compounds, wherein the data in Table 58 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0670] In one embodiment, several compounds of the present invention 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 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% CO2.

[0671] A compound is considered a growth inhibitor of HH cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 sums up to 0.9 or less, specifically sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. Analogously to the calculation performed for the test compound, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0672] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) 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 59 and Table 60. The entries in Table 59 and Table 60 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0673] Table 59: Proliferation assay using HH cells at 20 μM

[0674]

[0675]

[0676]

[0677]

[0678] Table 60: Proliferation assay using HH cells at 20 μM

[0679]

[0680]

[0681]

[0682] The data in Table 59 relate to novel compounds, wherein the data in Table 60 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0683] In one embodiment, several compounds of the present invention 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 accession number ACC 290. RPMI-8402 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0684] Compounds are considered growth inhibitors of RPMI-8402 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, specifically adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. The overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements similarly to the calculation performed for the test compounds. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0685] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) 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 61 and Table 62. The entries in Table 61 and Table 62 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0686] Table 61: Proliferation assay using RPMI-8402 cells at 20 μM

[0687]

[0688]

[0689]

[0690]

[0691]

[0692] Table 62: Proliferation assay using RPMI-8402 cells at 20 μM

[0693]

[0694]

[0695]

[0696]

[0697]

[0698] The data in Table 61 relate to novel compounds, wherein the data in Table 62 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0699] In one embodiment, several compounds of the present invention 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 accession number ACC 399. TANOUE cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0700] Compounds are considered growth inhibitors of TANOUE cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 sums up to 0.9 or less, specifically sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. The overall basal level is calculated similarly to the calculation performed for the test compounds as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 110 -2 .

[0701] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of TANOUE cells. The RPMI-8402 growth inhibitors identified so far relate to the compounds listed in Table 63 and Table 64. The entries in Table 63 and Table 64 are classified according to the corresponding weighted arithmetic means of the compounds without considering the respective standard deviations, and therefore fall within the indicated activity ranges.

[0702] Table 63: Proliferation assay using TANOUE cells at 20 μM

[0703]

[0704]

[0705]

[0706]

[0707]

[0708] Table 64: Proliferation assay using TANOUE cells at 20 μM

[0709]

[0710]

[0711]

[0712]

[0713]

[0714] The data in Table 63 relate to novel compounds, wherein the data in Table 64 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0715] In one embodiment, several compounds of the present invention 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-12K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0716] A compound is considered to be a growth inhibitor of TT cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 sums up to 0.9 or less, in particular sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. Analogously to the calculation performed for the test compound, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0717] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) 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 65 and Table 66. The entries in Table 65 and Table 66 are sorted according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0718] Table 65: Proliferation assay using TT cells at 20 μM

[0719]

[0720]

[0721]

[0722]

[0723] Table 66: Proliferation assay using TT cells at 20 μM

[0724]

[0725]

[0726] The data in Table 65 relate to novel compounds, wherein the data in Table 66 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0727] In one embodiment, several compounds of the present invention 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% CO2.

[0728] Compounds are considered growth inhibitors of HeLa cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 sums up to 0.9 or less, specifically sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. Analogously to the calculation performed for the test compounds, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0729] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) 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 67 and Table 68. The entries in Table 67 and Table 68 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0730] Table 67: Proliferation assay using HeLa cells at 20 μM

[0731]

[0732]

[0733] Table 68: Proliferation assay using HeLa cells at 20 μM

[0734]

[0735]

[0736] The data in Table 67 relate to novel compounds, wherein the data in Table 68 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0737] Growth of MDA-MB-231 cells (human breast cancer cells) obtained from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 732. MDA-MB-231 cells were cultured in Leibovitz's L-15 (phenol red free) medium (Fisherscientific, #11540556) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0738] A compound is considered a growth inhibitor of MDA-MB-231 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, specifically adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. The overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements similarly to the calculation performed for the test compound. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0739] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) 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 Tables 69 and 70. The entries of Tables 69 and 70 are classified according to the corresponding weighted arithmetic means of the compounds without considering the respective standard deviations, and therefore fall within the activity ranges shown.

[0740] Table 69: Proliferation assay using MDA-MB-231 cells at 20 μM

[0741]

[0742]

[0743]

[0744]

[0745]

[0746] Table 70: Proliferation assay using MDA-MB-231 cells at 20 μM

[0747]

[0748]

[0749]

[0750]

[0751]

[0752] The data in Table 69 relate to novel compounds, wherein the data in Table 70 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0753] In one embodiment, several compounds of the present invention 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 accession number ACC 444. FU-OV-1 cells were cultured at 37°C and 5% CO2 in Ham's F-12 / DMEM (1:1) medium (Fisherscientific, #11514436) containing 10% fetal bovine serum (Fisherscientific, #15517589) and 1 mM sodium pyruvate (Fisherscientific, #11501871).

[0754] A compound is considered to be a growth inhibitor of FU-OV-1 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, specifically adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. Analogously to the calculation performed for the test compound, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1·10 -2 .

[0755] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ib) and (Ic) herein, respectively, 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 71 and Table 72. The entries in Table 71 and Table 72 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations and therefore fall within the indicated activity ranges.

[0756] Table 71: Proliferation assay using FU-OV-1 cells at 20 μM

[0757]

[0758]

[0759]

[0760] Table 72: Proliferation assay using FU-OV-1 cells at 20 μM

[0761]

[0762]

[0763] The data in Table 71 relate to novel compounds, wherein the data in Table 72 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0764] In one embodiment, several compounds of the present invention 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 bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0765] A compound is considered a growth inhibitor of LOU-NH91 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, specifically adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. Analogously to the calculation performed for the test compounds, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0766] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) 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 73 and Table 74. The entries in Table 73 and Table 74 are classified according to the corresponding weighted arithmetic means of the compounds, without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0767] Table 731: Proliferation assay using LOU-NH91 cells at 20 μM

[0768]

[0769]

[0770]

[0771] Table 742: Proliferation assay using LOU-NH91 cells at 20 μM

[0772]

[0773]

[0774]

[0775] The data in Table 73 relate to novel compounds, wherein the data in Table 74 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0776] In one embodiment, several compounds of the present invention 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 accession number ACC 201. 23132 / 87 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0777] A compound is considered a growth inhibitor of 23132 / 87 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, specifically adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. The overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements similarly to the calculation performed for the test compound. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0778] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of 23132 / 87 cells. The 23132 / 87 growth inhibitors identified to date relate to the compounds listed in Table 75 and Table 76. The entries in Table 75 and Table 76 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations and therefore fall within the indicated activity ranges.

[0779] Table 75: Proliferation assay using 23132 / 87 cells at 20 μM

[0780]

[0781]

[0782]

[0783]

[0784] Table 76: Proliferation assay using 23132 / 87 cells at 20 μM

[0785]

[0786]

[0787] The data in Table 75 relate to novel compounds, wherein the data in Table 76 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0788] In one embodiment, several compounds of the present invention 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 accession number ACC 446. CAL-27 cells were cultured in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0789] Compounds are considered growth inhibitors of CAL-27 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 sums up to 0.9 or less, in particular sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. The overall basal level is calculated similarly to the calculation performed for the test compounds as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0790] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of CAL-27 cells. The CAL-27 growth inhibitors identified to date relate to the compounds listed in Table 77 and Table 78. The entries in Table 77 and Table 78 are sorted according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0791] Table 773: Proliferation assay using CAL-27 cells at 20 μM

[0792]

[0793]

[0794]

[0795]

[0796] Table 784: Proliferation assay using CAL-27 cells at 20 μM

[0797]

[0798]

[0799] The data in Table 77 relate to novel compounds, wherein the data in Table 78 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0800] In one embodiment, several compounds of the present invention 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 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.

[0801] Compounds are considered growth inhibitors of BHY cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 sums up to 0.9 or less, specifically sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. Similar to the calculation performed for the test compounds, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0802] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of BHY cells. The BHY growth inhibitors identified to date relate to the compounds listed in Table 79, Table 80 and Table 81. The entries in Table 79, Table 80 and Table 81 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0803] Table 795: Proliferation assay using BHY cells at 20 μM

[0804]

[0805]

[0806]

[0807]

[0808] Table 806: Proliferation assay using BHY cells at 20 μM

[0809]

[0810]

[0811]

[0812] Table 817: Proliferation assay using BHY cells at 20 μM

[0813]

[0814]

[0815] The data in Table 79 relate to novel compounds, wherein the data in Tables 80 and 81 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0816] In one embodiment, several compounds of the present invention 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. SCC-25 cells were cultured at 37° C. and 5% CO2 in Ham's F-12 / DMEM (1:1) medium (Fisherscientific, #11514436) containing 10% fetal bovine serum (Fisherscientific, #15517589) and 1 mM sodium pyruvate (Fisherscientific, #11501871).

[0817] A compound is considered a growth inhibitor of SCC-25 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, specifically adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. The overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements similarly to the calculation performed for the test compound. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10-2 .

[0818] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia) (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of SCC-25 cells. The SCC-25 growth inhibitors identified to date relate to the compounds listed in Table 82 and Table 83. The entries in Table 82 and Table 83 are sorted according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0819] Table 828: Proliferation assay using SCC-25 cells at 20 μM

[0820]

[0821]

[0822]

[0823] Table 839: Proliferation assay using SCC-25 cells at 20 μM

[0824]

[0825]

[0826]

[0827] The data in Table 82 relate to novel compounds, wherein the data in Table 83 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0828] In one embodiment, several compounds of the present invention were found to inhibit the growth of A-431 cells (human epidermoid squamous cell carcinoma cells), which are available from Cell Lines Service GmbH (CLS) under accession number 300112. A-431 cells were cultured in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

[0829] A compound is considered a growth inhibitor of A-431 cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 at a reference concentration of 20 μM adds up to 0.9 or less, in particular adds up to 0.8 or less, adds up to 0.7 or less, adds up to 0.6 or less, adds up to 0.4 or less, adds up to 0.2 or less. The overall basal level is calculated similarly to the calculation performed for the test compound as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0830] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of A-431 cells. The A-431 growth inhibitors identified to date relate to the compounds listed in Table 84 and Table 85. The entries in Table 84 and Table 85 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the indicated activity ranges.

[0831] Table 84: Proliferation assay using A-431 cells at 20 μM

[0832]

[0833]

[0834]

[0835]

[0836] Table 85: Proliferation assay using A-431 cells at 20 μM

[0837]

[0838]

[0839]

[0840] The data in Table 84 relate to novel compounds, wherein the data in Table 85 relate to novel medical uses of compounds disclosed in PCT / EP2018 / 054686.

[0841] In one embodiment, several compounds of the present invention were found to inhibit the growth of human epidermal keratinocyte progenitor cells (HPEKp, pooled), which can be obtained from CELLnTEC Advanced CellSystems AG under the accession number HPEKp. Human epithelial cells were cultured at 37°C and 5% CO2 in CnT-Prime epithelial medium (CELLnTEC, #CnT-PR, a completely defined low calcium formulation completely free of components of animal or human origin) without the addition of additional components.

[0842] A compound is considered a growth inhibitor of HPEKp cells if the weighted arithmetic mean of the normalized fluorescence intensity values ​​relative to an overall basal level of 1.0 after adding the corresponding combined standard deviations at a reference concentration of 10 μM 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. Analogously to the calculation performed for the test compounds, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0843] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein, respectively, have been identified as growth inhibitors of HPEKp cells. The HPEKp growth inhibitors identified to date relate to the compounds listed in Table 86, Table 87 and Table 88. The entries in Table 86, Table 87 and Table 88 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations and therefore fall within the indicated activity ranges.

[0844] Table 86: Proliferation assay using HPEKp cells at 10 μM

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851] Table 87: Proliferation assay using HPEKp cells at 10 μM

[0852]

[0853]

[0854]

[0855] Table 8810: Proliferation assay using HPEKp cells at 10 μM

[0856]

[0857]

[0858]

[0859] The data in Table 86 relate to novel compounds, wherein the data in Tables 87 and 88 relate to novel medical uses of the compounds disclosed in PCT / EP2018 / 054686.

[0860] In one embodiment, several compounds of the present invention were found to inhibit the growth of C2C12 cells (murine myoblasts), 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.

[0861] A compound is considered a growth inhibitor of C2C12 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding combined standard deviations relative to an overall basal level of 1.0 sums up to 0.9 or less, in particular sums up to 0.8 or less, sums up to 0.7 or less, sums up to 0.6 or less, sums up to 0.4 or less, sums up to 0.2 or less. Analogously to the calculation performed for the test compounds, the overall basal level is calculated as the weighted arithmetic mean of all normalized values ​​from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2 .

[0862] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) 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 89, Table 90 and Table 91. The entries of Table 89, Table 90 and Table 91 are classified according to the corresponding weighted arithmetic means of the compounds without considering the respective standard deviations, and therefore fall within the indicated activity ranges.

[0863] Table 89: Proliferation assay using C2C12 cells at 20 μM

[0864]

[0865]

[0866]

[0867] Table 90: Proliferation assay using C2C12 cells at 20 μM

[0868]

[0869]

[0870]

[0871] Table 9111: Proliferation assay using C2C12 cells at 20 μM

[0872]

[0873]

[0874] The data in Table 89 relate to novel compounds, wherein the data in Tables 90 and 91 relate to novel medical uses of the compounds disclosed in PCT / EP2018 / 054686.

[0875] In certain embodiments, the compounds of the invention may be modulators, particularly enhancers of Notch signaling.

[0876] Communication between cells through Notch signaling (reviewed in Kopan et al., Cell 2009, 137, 216-233; Bray, Nat. Rev. Mol. Cell Biol. 2016, 17, 722-735) is the first step mediated by two transmembrane proteins: Notch receptors distributed on the cell membrane of the signal receiving cell and Notch ligands covering the cell membrane of the signal sending cell. Mechanistically, Notch signaling is activated by receptor-ligand interaction, which leads to the proteolysis of the intracellular domain (NICD) of the membrane-bound Notch receptor and released into the interior of the signal receiving cell. NICD is then transferred to the nucleus, leading to the transcriptional activation of certain cell type-specific genes. Notch-mediated changes in the previous gene expression program of the cell are manifested as corresponding cellular changes, which represent the response of the cell to the Notch signal.

[0877] By measuring the expression level of Notch specific target genes, the activation level of Notch signaling can be reliably quantified in vitro. This can be achieved by quantitatively detecting the corresponding mRNA or protein of a specific Notch target gene. Alternatively, cells can be genetically modified to carry a luciferase gene as an artificial Notch target gene, the expression of which depends on Notch activity. In this case, the Notch signaling level can be quantified by measuring the bioluminescence value derived from luciferase.

[0878] Here, a corresponding Notch reporter assay, i.e. a luciferase-based luminescence readout, was used to quantitatively detect the ability of the claimed compounds to enhance Notch signaling in cell systems. For this purpose, the Notch reporter assay was used. HD (Promega, #E2311) as a transfection reagent, HeLa cells obtained from the American Type Culture Collection (ATCC) with accession number ATCC-CCL-2 were transiently transfected for 24 hours with a membrane-tethered form of the constitutively active intracellular domain of the human Notch1 receptor (hNotch1ΔE) that activates the Notch signaling cascade (BPS Bioscience, a custom human analog of component C of Notch Pathway Reporter Kit #60509), luciferase expressed under the control of a Notch-responsive promoter to monitor Notch signaling (BPS Bioscience, Notch Pathway Reporter Kit #60509, CSL luciferase reporter vector from component A not premixed with Renilla luciferase vector), and an expression vector for Renilla luciferase constitutively expressed in a manner independent of Notch signaling to include measurements of cell number per sample. HeLa cells were cultured in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). Transfection was performed in 100 mm-culture dishes (StarLab, #CC7682-3394), and the cells were properly attached to the plate at 80-90% cell confluence in a total volume of 7 mL of culture medium. For each culture dish to be transfected, 40 μL of hNotch1ΔE expression vector (100 ng / μL), 80 μL of CSL luciferase reporter vector (40 ng / μL), 4 μL of PRl-SV40-Sea Renilla luciferase vector (10 ng / μL) were added to 238 μL Opti-MEM (Fisherscientific, #10149832), and in the last step, 18.1 μL of HD to prepare the transfection mixture. After HD, the transfection mixture was allowed to stand at room temperature for 15 minutes and then evenly distributed into the culture dish. 24 hours after transfection, the transfected cells were carefully detached from the culture dish with 0.5mM EDTA in PBS and seeded into a 96-well plate suitable for luminescence reading (CORNING, #3610) at a density of 10,000 cells per well. The cells were then incubated for 20 hours with the test compound at a final concentration of 10μM (diluted from a 10mM stock solution in DMSO to a final DMSO concentration of 0.1% v / v in H2O (water for injection, WFI, Fisherscientific #10378939)) or with 0.1% v / v of empty vector DMSO as a control. Thereafter, the cells were washed once with PBS and then lysed with 30μL / well of passive lysis buffer (Promega, #E194A, Promega) by gently shaking the plate with an orbital plate shaker for 20 minutes at room temperature. After lysis, the firefly luciferase value and then the Renilla luciferase value were measured sequentially from the same well using a luminescence reader (Promega, Dual- Reporter Assay System, #E1910).

[0879] The suitability of the assay for monitoring Notch signaling was controlled by additionally including a generally accepted commercial Notch inhibitor (i.e., DAPT) as a negative control, and a reported Notch enhancer, resveratrol (RES), as a positive control (Pinchot et al., Cancer 2011, 117, 1386-1398; Truong et al., Ann. Surg. Oncol. 2011, 18, 1506-1511; Yu et al., Mol. Cancer Ther. 2013, 12, 1276-1287). Both control compounds were also tested at 10 μM.

[0880] In each single experiment, each compound was measured six times in duplicate. For each compound, the experiment was repeated three or more times independently. The value of Notch reporter luciferase was normalized by dividing by the corresponding single Renilla value that is not dependent on Notch to eliminate the influence of absolute cell number changes between samples. For each individual plate, the equal weighted arithmetic mean (abbreviated as AVE here) of six related Renilla-normalized DMSO-control values ​​was standardized for the second time in a single experiment to obtain a relative value relative to a baseline level of 1.0. Statistical calculations were performed similarly to the above-mentioned proliferation assay. For this reason, two independent outlier analyses were performed according to the method of Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). The outliers confirmed by at least one method were excluded from the calculation, but in a single experiment, no more than one value in the 6 values ​​of each compound. The weighted arithmetic mean AVE of each compound w It is calculated based on the double normalized values ​​of all independent repeats of each single experiment including six repeats. The corresponding standard deviation of the weighted arithmetic mean is calculated according to the method described by Bronstein et al. (Bronstein, Semindjajew, Musiol, Mühlig, Taschenbuch der Mathematik, the 5th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun), and it is combined with the Gaussian error propagation associated with the execution normalization calculation. The standard deviation produced is referred to as "combined standard deviation" in this article.

[0881] If there was considerable variability in the doubly normalized equally weighted arithmetic means derived from three independent replicates, the number of independent replicates was increased to four or more. In the case of four or more independent replicates, all doubly normalized equally weighted arithmetic means were subjected to a second-line outlier analysis according to the method of Peirce and Chauvenet described above.

[0882] If the weighted arithmetic mean of the luminescence values ​​after subtracting the corresponding combined standard deviation relative to the overall basal level of 1.0 reaches 1.1 or more, in particular 1.2 or more, 1.3 or more, 1.4 or more, 1.5 or more, 1.7 or more and 2.0 or more, the compound is considered to be a Notch signaling enhancing molecule, i.e. an enhancer of Notch signaling. The overall basal level is calculated as the weighted arithmetic mean of all double normalized values ​​measured for the DMSO control, similarly to the calculation performed for the test compounds. The corresponding combined standard deviation of the DMSO values ​​is less than 1 10 -2.

[0883] According to the above method, several molecules falling within the range of compounds defined in formula (Ib) and (Ic) herein, respectively, have been identified as enhancers of Notch signaling. The enhancers of Notch signaling identified to date relate to the compounds listed in Table 92. The entries in Table 92 are classified according to the corresponding weighted arithmetic means of the compounds without taking into account the respective standard deviations, and therefore fall within the range of activity shown.

[0884] Table 92: Notch receptor assay

[0885]

[0886]

[0887]

[0888]

[0889] According to the above methods, several other molecules have not yet been identified as enhancers of Notch signaling.

[0890] In some cases, the growth inhibitory properties are associated with Notch enhancing properties, and in other cases, the growth inhibitory properties are not associated with Notch enhancing properties.

[0891] The biological activity of the claimed compounds can be attributed to, but not limited to, Notch signaling enhancing activity. The Notch modulating properties of the claimed compounds can be used in drug therapy, alternatively or in combination with mechanisms leading to antiproliferative effects, preferably for the treatment of hyperproliferative disorders including cancer and non-malignant hyperproliferative disorders.

[0892] In one aspect, the present invention relates to the treatment of skin, skin appendages, mucosa, mucosal appendages, cornea and all kinds of epithelial tissues. The term "skin" refers to tissues including the epidermis and dermis. The term "mucosa" refers to mucosal and submucosal tissues, including oral mucosa, nasal mucosa, ocular mucosa, ear mucosa, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa. The term "appendages" refers to tissues including hair follicles, hair, fingernails, toenails and glands, including sebaceous glands, sweat glands, such as apocrine sweat glands or eccrine sweat glands and mammary glands.

[0893] In one embodiment, the invention relates to the treatment of non-melanoma skin cancers and precancerous lesions, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, cutaneous fibrosarcoma, actinic keratosis (AK) or Bowen's disease (BD), and other squamous epithelial cancers and precancerous lesions, for example, cutaneous SCC, lung SCC, head and neck SCC, oral SCC, tongue SCC, esophageal SCC, cervical SCC, periocular SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate, and SCC of the bladder.

[0894] In another embodiment, the invention relates to the treatment of disorders of the skin and mucous membranes with keratinization defects (keratosis) and / or abnormal keratinocyte proliferation, such as psoriasis, Darier's disease, lichen planus, lupus erythematosus, ichthyosis or verruca vulgaris (senile).

[0895] In another embodiment, the present invention relates to the treatment of skin and mucosal diseases and skin and mucosal cancers each associated with and / or caused by a viral infection, such as warts, and HPV (human papillomavirus)-associated warts, papillomas, HPV-associated papillomas, papillomatosis and HPV-associated papillomatosis, for example warts (plantar warts), flat warts (flat warts / plane warts), filiform warts (filiform warts), mosaic warts, periungual warts, subungual warts, oral warts, genital warts, fibroepithelial papilloma, intraductal papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovascular papilloma, plexus papilloma, nasal papilloma, papillomatosis cutis carcinoid tumor (papillomatosis cutis carcinoides), lymphostatic cutaneous papillomatosis (Papillomatosis cutis lymphostatica), confluent reticular papillomatosis (Papillomatosis confluens et reticularis), or laryngeal papillomatosis (respiratory papillomatosis), herpes-related diseases such as herpes labialis, genital herpes, herpes zoster, corneal herpes, or Kaposi's sarcoma, and HPV-related cancers of the cervix, vulva, penis, vagina, anus, oropharynx, tongue, and oral cavity.

[0896] In another embodiment, the invention is directed to the treatment of atopic dermatitis.

[0897] In another embodiment, the present invention is directed to the treatment of acne.

[0898] In another embodiment, the present invention is directed to the treatment of skin wounds, wherein the process of wound healing is accelerated.

[0899] In another embodiment, the present invention relates to the treatment of cancers associated with and / or caused by viral infections, i.e., oncoviral infections, e.g., cancers associated with HBV and HCV (hepatitis B and C viruses), such as liver cancer, 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 papillomavirus), 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.

[0900] Another aspect of the present invention relates to the treatment of immune system related disorders. As used herein, the term "immune system related disorders" applies to pathological conditions of the hematopoietic system including the blood system, in particular pathological conditions of immune cells belonging to the innate or adaptive immune system.

[0902] Another aspect of the present invention relates to therapeutic uses in immune system related applications. As used herein, the term "immune system related applications" is applicable to the proliferation, differentiation and / or activation of the cell lineage of the hematopoietic system including the hematopoietic system to intervene to regulate immune response (immunomodulation). As used herein, the term "immune system related applications" is also applicable to the intervention of cells and non-cellular microenvironments at the site of immune cell action to support and / or enable immune cells to exert their performance. In particular, the intervention defined herein by the term "immune system related applications" relates to immune cells belonging to the innate or adaptive immune system.

[0903] Therefore, the compounds of the present invention can be used for immunotherapy alone or together with other immunotherapy methods or compounds (as immune adjuvants, for example as vaccine adjuvants, or as adjuvants for immunotherapy). As used herein, the term "immunotherapy" applies to activation immunotherapy for patients without immunodeficiency or with acquired or congenital immunodeficiency, as well as immune restoration to enhance the functionality of the immune system in the response to pathogens or pathologically transformed endogenous cells (such as cancer cells).

[0904] As used herein, the term "other immunotherapeutic approaches" applies to vaccination, antibody therapy, cytokine therapy, the use of immune checkpoint inhibitors and immune response stimulating drugs, as well as autologous transplantation of genetically modified or non-modified immune cells that can be stimulated with intercellular signals, signaling molecules, antigens or antibodies, i.e., adoptive immune cell transfer.

[0905] The methods of use of the present invention in immune system related applications and other immunotherapy methods involve in vivo, in vitro and ex vivo use, respectively.

[0906] Specific examples are activation and / or activation enhancement of peripheral T lymphocytes (including T helper cells and cytotoxic T cells) to enhance the immune response, in particular to stimulate proliferation and / or production and / or secretion of cytokines and / or cytotoxic agents upon antigen recognition to amplify the immune response, such as activating B lymphocytes and / or enhancing the activation of B lymphocytes to amplify the immune response, in particular to stimulate proliferation and / or antibody production and / or secretion, such as by increasing the number of specific immune cell subtypes, by regulating differentiation and / or cell fate determination during immune cell development (e.g., regulating, in particular 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 (in particular Th1, Th2, Th17) and regulatory T cells) to enhance the immune response; or use as an immune adjuvant such as a vaccine adjuvant.

[0907] Another aspect of the invention relates to the treatment of muscle diseases, including diseases of skeletal muscle, cardiac muscle and smooth muscle.

[0908] In one embodiment, the invention relates to the treatment of muscular dystrophy (MD).

[0909] Specific examples are Duchenne-type MD, Becker-type MD, congenital MD, Limb-Girdle-type MD, facioscapulohumeral MD, Emery-Dreifuss-type MD, distal MD, myotonic MD or oculopharyngeal MD.

[0910] In another embodiment, the invention relates to the treatment of muscle hyperproliferative disorders, including myoblastoma, rhabdomyoma, and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy.

[0911] In another embodiment, the compounds of the invention can be used in muscle regeneration after pathological muscle degeneration or atrophy, e.g. caused by trauma, caused by muscle ischemia or caused by inflammation, in muscle atrophy associated with aging or in muscle atrophy associated with diseases such as myositis and fibromyositis or poliomyelitis.

[0912] Another aspect relates to the treatment of disorders of the neuroendocrine system, such as cancers 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 carcinoma (ATC), parathyroid adenoma, intrathyroidal nodule, insular carcinoma, trabecular tumor, paraganglioma, pulmonary carcinoid tumor, neuroblastoma, gastrointestinal carcinoid, goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagonoma, somatostatinoma, VIPoma, insulinoma, non-functioning islet cell tumor, multiple endocrine neoplasia type 1, or pulmonary carcinoid.

[0913] Another aspect relates to the treatment of pulmonary disorders such as lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), including squamous cell carcinoma of the lung, adenocarcinoma of the lung, and large cell carcinoma of the lung.

[0914] Another aspect relates to the treatment of cancer or precancerous lesions of the brain, pancreas, breast, ovary, liver, thyroid, genitourinary tract, gastrointestinal tract, and endothelial tissue, including glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, ependymoblastoma, submenstrual tumors, brainstem gliomas, optic nerve gliomas and forebrain tumors, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic pseudopapillary tumors, pancreatic intraductal papillary-mucinous tumors, pancreatic mucinous cystadenocarcinomas, pancreatoblastomas and pancreatic intraepithelial neoplasms, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, papillary and follicular thyroid cancers, cervical cancer, hormone receptor-positive breast cancer and hormone receptor-negative breast cancer, ovarian cancer, gastric cancer and angiosarcoma.

[0915] As used herein, the terms "treating" or "treatment" refer to one or more of the following: (1) inhibiting a disease; e.g., inhibiting a disease, illness, or condition in an individual who is experiencing or showing signs or symptoms of the disease, disorder, or condition (i.e., preventing further development of the symptoms and / or symptoms); and (2) ameliorating a disease; e.g., ameliorating a disease, disorder, or condition in an individual who is experiencing or showing signs or symptoms of the disease, disorder, or condition (i.e., reversing the symptoms and / or symptoms), such as reducing the severity of the disease. The term "treatment" also encompasses post-treatment care.

[0916] In some embodiments, administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, is effective for preventing a disease; for example, preventing a disease, disorder, or condition in an individual who may be susceptible to the disease, disorder, or condition but who does not yet experience or display signs and / or symptoms of the disease.

[0917] The compounds of the invention 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 (e.g., cattle), poultry, pigs, sheep, goats, donkeys, yaks, and camels.

[0918] Pharmaceutical composition

[0919] The present invention also provides a pharmaceutical composition for use in medicine (eg, 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.

[0920] In addition to physiologically acceptable carriers, diluents and / or adjuvants, effective doses of compounds according to the present invention or their salts, solvates or prodrugs are also used to produce pharmaceutical compositions. The dosage of the active compound can vary according to the route of administration, the age and body 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 0.001-2000mg. Particularly preferably, a daily administration dose of 0.1-500mg (e.g., 0.1-100mg) is provided.

[0921] Suitable administration forms are topical or systemic, including enteral, oral, rectal and parenteral, such as infusion and injection, intravenous, intraarterial, intraperitoneal, intramuscular, intracardiac, epidural, intracerebral, intraventricular, intraosseous, intraarticular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalation, intranasal, oral, sublingual and intralesional preparations. Particular preference is given to using oral, parenteral (e.g. intravenous or intramuscular), intranasal preparations (e.g. dry powder or sublingual) of the compounds according to the invention. Conventional galenical forms may be used, such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, aqueous alcoholic solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lipsticks, mouthwashes, foams, pastes, tinctures, skin patches and tapes, occlusive forms or in combination with timed release drug delivery systems, with electrophoretic skin delivery systems including implants and devices, and with jet injectors, liposomes and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops.

[0922] Solid pharmaceutical forms may contain inert ingredients and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium stearate, aluminum stearate, methylcellulose, talc, highly dispersed silicic acid, silicone oil, high molecular weight fatty acids (such as stearic acid), gelatin, agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); if desired, preparations suitable for oral administration may contain additional flavoring and / or sweeteners.

[0923] Liquid drug form can be sterilized and / or comprise auxiliary material under suitable circumstances, such as preservative, stabilizer, wetting agent, penetrant, emulsifier, spreading agent, solubilizing agent, salt, sugar or sugar alcohol (for regulating osmotic pressure or for buffering), and / or viscosity modifier.The example of this type of additive is tartrate and citrate buffer, ethanol and chelating agent (such as ethylenediaminetetraacetic acid and non-toxic salt thereof).High molecular weight polymer, such as liquid polyethylene oxide, microcrystalline cellulose, carboxymethyl cellulose, polyvinyl pyrrolidone, dextran or gelatin, is suitable for regulating viscosity.The example of solid carrier material is starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, high molecular weight fatty acid (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fat and solid high molecular weight polymer, such as polyethylene glycol.

[0924] Oily suspensions for parenteral or topical application may be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case 8 to 22 carbon atoms in the fatty acid chain, for example palmitic acid, lauric acid, tridecanoic acid, heptadecanoic acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brassic acid, erucic acid or oleic acid, the fatty acids being esterified with mono- to trihydric alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, propanol, butanol, pentanol or isomers thereof, ethylene glycol or glycerol. The example of this type of fatty acid ester is, among others, commercialized miglitol, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, the caprylic acid / capric acid ester of saturated fatty alcohol, polyoxyethylene glyceryl trioleate, ethyl oleate, waxy fatty acid ester, such as artificial duck tail gland fat, isopropyl coconut fatty acid, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid ester. The silicone oil or fatty alcohol of different viscosities, such as isotridecanol, 2-octyldodecanol, cetearyl alcohol or oleyl alcohol, or fatty acid, such as oleic acid are also suitable. Vegetable oils can also be used, such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil.

[0925] Suitable solvents, gelling agents and solubilizing agents 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, methyl cellosolve, cellosolve, esters, morpholine, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

[0926] Cellulose ethers that are soluble or swellable in water or an organic solvent, such as hydroxypropylmethylcellulose, methylcellulose or ethylcellulose, or soluble starch can be used as film-forming agents.

[0927] Mixtures of gelling agents and film formers are also perfectly usable. In this case, ionic macromolecules are used in particular, such as sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and its salts, sodium pullulan hemiglycolate, 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 aids: glycerol, paraffin waxes of different viscosities, triethanolamine, collagen, allantoin and phenylbenzimidazole sulfonic acid (novantisolicacid). The formulation may also require the use of surfactants, emulsifiers or wetting agents, such as sodium lauryl sulfate, fatty alcohol ether sulfate, disodium N-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbate (e.g. Tween), cetyl alcohol, lecithin, glyceryl monostearate, polyoxyethylene stearate, alkylphenol polyethylene glycol ether, hexadecyl trimethyl ammonium chloride or mono / dialkyl polyethylene glycol ether orthophosphate monoethanolamine salt. Stabilizers such as montmorillonite or colloidal silicic acid, which are used to stabilize emulsions or prevent the decomposition of active substances such as antioxidants (e.g. tocopherol or butyl hydroxyanisole) or preservatives (such as parabens), can also be used to prepare the desired formulation.

[0928] Preparations for parenteral administration may be present in individual dosage unit forms such as ampoules or vials. Preference is given to using solutions of the active compound, preferably aqueous solutions, in particular isotonic solutions and also suspensions. These injection forms can be prepared as ready-to-use preparations or can be prepared directly just before use by mixing the active compound (e.g. lyophilisate, containing other solid carrier substances where appropriate) with the desired solvent or suspending agent.

[0929] Intranasal preparations can be in the form of aqueous or oily solutions or aqueous or oily suspensions. They can also be in the form of lyophilized preparations, which are prepared using a suitable solvent or suspending agent before use.

[0930] The inhalable formulation may be in the form of a powder, solution or suspension. Preferably, the inhalable formulation is in the form of a powder, for example a mixture of the active ingredient and a suitable formulation aid such as lactose.

[0931] Preparations were produced, aliquoted and sealed under routine antimicrobial and aseptic conditions.

[0932] As indicated above, the compounds of the invention may be administered as combination therapy, sequential therapy, or simultaneous combination therapy with other active agents (e.g., therapeutically active compounds for treating the above-mentioned conditions). These therapeutically active compounds may include, but are not limited to, chemotherapeutic agents such as nucleoside and nucleobase analogs, such as cytarabine, gemcitabine, azathioprine, mercaptopurine, fluorouracil, thioguanine, azacytidine, capecitabine, doxifluridine; such as platinum-based drugs, such as cisplatin, oxaliplatin, carboplatin, and nedaplatin; such as anthracyclines, such as doxorubicin, epirubicin, valrubicin, idarubicin, daunorubicin, sabrubicin, pixantrone, and mitoxantrone; such as peptide antibiotics, such as actinomycin and bleomycin; such as alkylating agents, such as mechlorethamine, chlorambucil, melphalan, nitrosoureas, dacarbazine, , temozolomide and cyclophosphamide; such as antimitotic agents, including taxanes and vinca alkaloids, such as docetaxel, paclitaxel, Abraxane, cabazitaxel, vinblastine, vindesine, vinorelbine and vincristine; such as topoisomerase inhibitors, such as irinotecan, topotecan, teniposide and etoposide; such as other cytostatic agents, such as hydroxyurea and methotrexate; such as proteasome inhibitors, such as bortezomib, ixazomib; and other targeted therapeutics, such as kinase inhibitors, cell cycle inhibitors, modulators, i.e., signaling pathways (including growth factor signaling, cytokine signaling, NF-κB signaling, AP1 signaling, Inhibitors and activators of JAK / STAT signaling, EGFR signaling, TGF-β signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling), such as erlotinib, lapatinib, dasatinib, imatinib, afatinib, vemurafenib, dabrafenib, nilotinib, cetuximab, trametinib, palbociclib, cobimetinib, cabozantinib, pegaptanib, crizotinib, olaparib, panitumumab, cabozantinib, povidone neratinib, 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, acitretin, adapalene, and etretinate;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, panostat, belinostat and cedabendine; and ingenol mebutate; and other Notch enhancers not covered by the compounds of the present invention, such as valproic acid, resveratrol, hesperidin, chrysin, phenethyl isothiocyanate, thiocarbamide; N-methylhydroxyethyl chloride and Notch signaling activating peptides or antibodies; and immune response modulators, including immune checkpoint inhibitors, such as imiquimod, ipilimumab, atezolizumab, ofatumumab, anti-inflammatory drugs, including glucocorticoids and nonsteroidal anti-inflammatory drugs, such as cortisol-based preparations, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone-hexacetonid, mometasone furoate, clobetasol propionate, acetylsalicylic acid, salicylic acid and other salicylates, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, loxoprofen, flurbiprofen, oxaprozin, indomethacin, ketorolac, tolmetin, diclofenac, etodolac, aceclofenac, nabumetone, sulindac, mefenamic acid, 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 containing several active ingredients in a single dosage form and / or a kit containing separate active ingredients in separate dosage forms. The active ingredients used in combination therapy can be administered together or separately. ;

[0933] The compounds of the invention may be administered in the form of antibody-drug conjugates.

[0934] The compounds of the invention may be administered in combination with surgery, cryotherapy, electrodessication, radiation therapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell-based transplantation therapy, stem cell therapy, physical therapy, and occupational therapy.

[0935] Chemical synthesis

[0936] abbreviation

[0937] Ac Acetyl

[0938] aq water Alk Alkyl

[0939] Bn Benzyl

[0940] BRSM based on recycled raw materials (yield)

[0941] Bu Butyl

[0942] mCPBA Chloroperbenzoic acid

[0943] NMR Nuclear Magnetic Resonance Spectroscopy

[0944] DCE 1,2-Dichloroethane

[0945] DCM Dichloromethane

[0946] DIBAL-H Diisobutylaluminum hydride

[0947] DMF N,N-Dimethylformamide

[0948] DMSO Dimethyl sulfoxide

[0949] DMAP dimethylaminopyridine

[0950] equiv equivalent

[0951] ESI Electrospray ionization

[0952] EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide HOBt 1-Hydroxybenzotriazole

[0953] HATU Hexafluorophosphate azabenzotriazole tetramethyl urea Et Ethyl

[0954] LiHMDS Lithium bis(trimethylsilyl)amide Me Methyl

[0955] Ms Methanesulfonyl

[0956] PE Petroleum Ether

[0957] PG Protecting Group

[0958] PTSA p-Toluenesulfonic acid

[0959] Sat. Saturated

[0960] TBAF Tetrabutylammonium fluoride

[0961] Tf trifluoromethanesulfonyl

[0962] THF Tetrahydrofuran

[0963] TMS Trimethylsilyl

[0964] Ts p-Toluenesulfonyl

[0965] UV ultraviolet light

[0966] General

[0967] The compounds listed in Table 93 and Table 94 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 eluents, preferably as binary or ternary solvent mixtures thereof. The compounds were 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. Completion of the reactions was also monitored in this manner. Unless otherwise stated, the reactions were carried out under an inert atmosphere. Anhydrous solvents were used wherever necessary. All reactions were stirred using a stirring plate and magnetic stirring bar.

[0968] In addition, the compounds listed in Table 93 were identified by mass spectrometry (using formic acid in the mobile phase to detect positive ions and no additives to detect negative ions). If the molecule was difficult to ionize in the negative mode, ammonium carbonate was used. Representative compounds and those compounds that showed poor ionization in the mass spectrum were also identified by nuclear magnetic resonance spectroscopy (Table 94). 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 carbon (reference: CHCl3[ 1 H:7.26ppm, 13 C:77.2ppm],DMSO[ 1 H:2.50ppm, 13 C: 39.5 ppm]). Coupling constants (J) are reported in Hz to the nearest 0.1 Hz. Peak multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (septet), m (multiplet), and br (broad peak).

[0969] Synthesis of the compounds

[0970] The above compounds of the present invention falling within the scope of Formula I can be synthesized and purified by one skilled in the art, and are preferably synthesized according to the general procedures (A to R) described herein, as shown in Scheme 1.

[0971]

[0972] Scheme 1: General synthetic scheme.

[0973] A) Under argon atmosphere and stirring, KCO (1.5 equivalents) was added to the corresponding mono- or di-substituted phenol (1.0-1.5 equivalents) and 4-alkyl ester halo (hetero) aryl (1 equivalent) dissolved in DMSO (0.5M), and the mixture was stirred at room temperature or heated between 40°C and 160°C until complete conversion. The mixture was returned to room temperature and distributed between an organic solvent (preferably petroleum ether and water). The aqueous layer was extracted twice more, and then the combined organic phases were washed with NaOH (aqueous solution, 2M), then with brine, dried over NaSO, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO, gradient petroleum ether / AcOEt, DCM / MeOH or petroleum ether / AcOEt / NEt3) to give the desired bis (hetero) aryl ether ethyl ester.

[0974] B) Under argon atmosphere and stirring, the corresponding bis(hetero)aryl ether alkyl ester (1 equivalent) was dissolved in anhydrous THF (0.2 M), and the resulting solution was cooled to 0° C. with an ice bath. DIBAL-H (2.5 equivalents, 1.2 M in toluene) was then added dropwise, and the mixture was stirred at this temperature until complete conversion. The reaction was terminated 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.

[0975] C) Depending on the scale and substrate, use any of these procedures.

[0976] Under vigorous stirring, MnO2 (2-4 equivalents) was added to the corresponding alcohol (1 equivalent) dissolved in DCM (0.2M). The resulting suspension was stirred at room temperature or 40°C until complete conversion. The reaction was then diluted with AcOEt, filtered on celite and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired aldehyde.

[0977] Under vigorous stirring, add Des-Martin periodinane (1.2 equivalents) in the corresponding alcohol (1 equivalent) dissolved in DCM or DMSO (0.2M). The gained suspension is stirred at room temperature until fully converted. The solution is diluted in AcOEt and quenched with saturated NaHCO The aqueous solution is then separated. The water layer is extracted twice again, and the organic phases merged are washed with salt water, through Na SO Drying, filtered and concentrated in vacuo. Then residue is passed through flash chromatography (SiO , gradient petroleum ether / AcOEt) purifying, and required aldehyde is obtained.

[0978] At -78 ° C, anhydrous DMSO (4 equivalents) was added to a solution of oxalyl chloride (2 equivalents) in DCM (0.2M), and the mixture was stirred for 30 minutes. Then a solution of the corresponding alcohol (1 equivalent) in DCM (0.2M) was added, followed by freshly distilled NEt (8 equivalents). The resulting solution was stirred for 1 hour and then slowly returned to room temperature. The solution was diluted in AcOEt, quenched with HCl 1M aqueous solution, and phase separated. The water layer was extracted twice more, and then the combined organic phases were washed with brine, dried over Na SO, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO, gradient petroleum ether / AcOEt) to obtain the desired aldehyde.

[0979] D). At 0°C in an argon atmosphere and under stirring, TMSCF3 (2 equivalents) was added to the corresponding aldehyde (1 equivalent) dissolved in anhydrous THF (0.2M), followed by TBAF (1 mol%) to obtain the corresponding CF3-containing secondary alcohol, or Grignard reagent (2 equivalents) was added to obtain the corresponding secondary alkyl alcohol. In both cases, the resulting solution was stirred at this temperature until complete conversion. Aqueous HCl solution (2.5M) was then added and the reaction was continued to stir for 1 hour. The reaction was then distributed between AcOEt and water. The aqueous layer was extracted twice more, and the combined organic phases were then 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 obtain the desired secondary alcohol.

[0980] E). To a stirred solution of the corresponding secondary alcohol (1 eq.) in chloroform (0.2 M) at 0°C was added Des-Martin periodinane (1.5 eq.). After the reaction was complete, it was partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted twice more, then 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 ketone.

[0981] F). To a stirred solution of the corresponding ketone (1 eq.) in ethanol (0.2 M) is added an amine (2.5-40 eq.), followed by a catalytic amount of PTSA in the case of aliphatic amines or a base (2.5-40 eq.) in the case of hydroxylamines. The reaction is then refluxed for 24-72 hours. Thereafter, celite is added and the volatiles are evaporated in vacuo. The residue is then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired imine.

[0982] G). Sodium borohydride (4 equivalents) was added to the corresponding aldehyde or crude imine solution in DCM (0.25 M) obtained before purification in procedure (F), and the solution was stirred for another 2 hours. The reactant was then distributed between AcOEt and saturated NaHCO3 water. The aqueous layer was extracted twice more, and the combined organic phases were then 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 product.

[0983] H). To a stirred solution of the corresponding aldehyde (1 eq.) in toluene (0.2 M) was added amine (2 eq.) and then TMSCN (2 eq.) under argon and the reaction was stirred for 16 hours. The reaction was then partitioned between AcOEt and saturated NaHCO3 aqueous solution. The aqueous layer was extracted twice more and the combined organic phases were then 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 cyanamide.

[0984] 1) add NaOH aqueous solution 2M (2 equivalents) to the corresponding bis (hetero) aryl ether alkyl ester (1 equivalent) dissolved in EtOH or THF (0.5M), and stir the reaction until completion.Then the reaction is distributed between AcOEt and HCl aqueous solution (1M).The water layer is extracted twice again, the organic phase merged is washed with salt water, through Na2SO4 drying, filtered and concentrated in vacuo.Then the residue is purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) or recrystallization (AcOEt) to obtain the required carboxylic acid.

[0985] J) Depending on the amine used, either of these procedures is employed.

[0986] Under argon, first SOCl2 (2.5 equivalents) was added to the corresponding bis(hetero)aryl ether carboxylic acid (1 equivalent) suspended in stirred toluene (0.2 M), then DMF (1 mol%) was added, and the mixture was heated to 80 ° C for 3 hours. The reaction mixture was then evaporated to dryness, the resulting residue was placed under an argon atmosphere again, and redissolved in THF (0.2 M). Trimethylamine (2.5 equivalents), DMAP (1 mol%) and the corresponding amine or amide (1.2-1.5 equivalents) were added to the solution in sequence, and the suspension was stirred for 16 hours. The reaction was then distributed between AcOEt and HCl aqueous solution (1 M). The water layer was extracted twice more, and the combined organic phases were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt or petroleum ether / AcOEt / AcOH or DCM / MeOH) to obtain the desired amide.

[0987] In the corresponding bis (hetero) aryl ether carboxylic acid (1 equivalent) in DCM (0.2M), NEt (3 equivalents) and HOBt / EDCI (1.5 equivalents / 1.5 equivalents) or HATU (1.5 equivalents) are added successively. Then the reaction mixture is stirred for 5-60 minutes, then the corresponding amine (1.25 equivalents) is added, and the mixture is stirred to complete. Then the reaction is distributed between AcOEt and the HCl aqueous solution (1M). The water layer is extracted twice again, then the organic phase washed with salt water, through Na SO Drying, filter and vacuum concentration. Then the residue is purified by flash chromatography (SiO , gradient petroleum ether / AcOEt or petroleum ether / AcOEt / AcOH or DCM / MeOH) to obtain required amides.

[0988] Under argon atmosphere, first add SOCl2 (2.5 equivalents) to the corresponding bis (hetero) aryl ether carboxylic acid (1 equivalent) suspended in stirred toluene (0.2M), then add DMF (1mol%), and heat the mixture to 80°C for 3 hours. Then the reaction mixture is evaporated to dryness, and the resulting residue is placed under argon atmosphere again and redissolved in toluene (0.2M). The solution is added to a saturated aqueous solution of the corresponding hydroxylamine. Stir NaHCO3 and the reaction mixture until completion. Then the reactant is distributed between AcOEt and 1M HCl aqueous solution or water. The water layer is extracted twice more, and then the combined organic phase is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt or petroleum ether / AcOEt / AcOH or DCM / MeOH) to obtain the desired amide.

[0989] K). To the corresponding 4-substituted phenol (1 eq.) and 1,4-dibromoaryl (2.5 eq.) dissolved in DMF (0.2 M) were added Cs2CO3 (2 eq.), CuI (10 mol%) and tBuXPos (20 mol%). The mixture was degassed using the freeze-pump-thaw method, placed under an argon atmosphere, stirred vigorously and refluxed (165°C) for 72 hours. The mixture was allowed to return to room temperature and partitioned between petroleum ether and aqueous NaOH 2M. The aqueous layer was extracted twice more, and the combined organic phases were then 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 biaryl ether bromide.

[0990] L) K2CO3 (1.5 eq.) was added to the corresponding 4-substituted phenol (1.2-1.5 eq.) and 1,4-dibromo(hetero)aryl (1 eq.) dissolved in DMSO (0.5 M) under argon atmosphere and stirring, and the mixture was heated between 80° C. and 160° C. until complete conversion. The mixture was returned to room temperature and partitioned between petroleum ether and aqueous NaOH 2M. The aqueous layer was extracted twice more, and the combined organic phases were then 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 bis(hetero)aryl ether bromide.

[0991] M) Under argon atmosphere and stirring, the corresponding bis(hetero)aryl ether bromide (1 equivalent) is dissolved in anhydrous THF (0.2 M), and the resulting solution is cooled to -78°C with a dry ice / acetone bath. Then n- or tert-BuLi (1.1-2.2 equivalents, 1.9-2.5 M, in hexane or pentane) is added dropwise, and the mixture is stirred at this temperature for 30 minutes, and then stirred at -50°C until the starting material is completely consumed (monitored by TLC in pentane). The mixture is then cooled to -78°C, a solution of the corresponding electrophile (2 equivalents, 0.5 M) in anhydrous THF is added, and the reaction is slowly returned to room temperature over 16 hours. The reactants are then partitioned between AcOEt and saturated aqueous NH4Cl, the aqueous layer is extracted twice more, and the combined organic phases are then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt / NEt3) to afford the desired compound.

[0992] N) HCl (0.5M in methanol, 2-6 eq.) is added to the corresponding protected amine compound (1 eq.) dissolved in THF (0.1-0.2 M), and the reaction is stirred until completion. The reaction is then evaporated to dryness to give the desired amine as a hydrochloride salt, or the reaction is partitioned between AcOEt and a saturated NaHCO3 aqueous solution. The aqueous layer is extracted twice more, and the combined organic phases are then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt or petroleum ether / AcOEt / AcOH or DCM / MeOH) to give the desired free amine.

[0993] (0) Under argon atmosphere and stirring, K2CO3 (1.5 eq.) was added to the corresponding 4-substituted phenol (1 eq.) and 4-cyano (hetero)haloaryl (2.5 eq.) dissolved in DMSO (0.5 M), and the mixture was heated between 80° C. and 160° C. until complete conversion. The mixture was returned to room temperature and distributed between petroleum ether and 2M NaOH aqueous solution. The aqueous layer was extracted twice more, and then 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 bis (hetero)aryl ether cyanide.

[0994] P) To the corresponding bis(hetero)aryl ether cyanide (1 eq.) dissolved in THF / MeOH (1:1, 0.1 M) was added NaH (1.1 eq.) at 0°C under argon atmosphere and stirring. After 4 hours, the ice bath was removed, cyanamide (1.5 eq.) was added, and the mixture was stirred for another 16 hours. The reactants were then partitioned between AcOEt and water. The aqueous layer was extracted twice more, and the combined organic phases were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt / MeOH) to give the desired amine.

[0995] Q) To the corresponding bis(hetero)aryl ether alcohol, hydroxamic acid or amide (1 eq) dissolved in THF / DMF (1:0 to 2:8 mixture, 0.2 M) under argon atmosphere and stirring, NaH, NaOAc or Cs2CO3 (1.2-2 eq) was added. After 30 minutes, alkyl(di)halide or acid chloride (1.2-2 eq) was added, and in the case of alkyl(di)bromide, KI (1.2 eq) was added. The mixture was then stirred for another 16 hours at room temperature or at 50°C for another 16 hours in the case of alkyl(di)bromide. The reaction was then partitioned between AcOEt and aqueous HCl (1 M). The aqueous layer was extracted twice more, and the combined organic phases were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt / AcOH) to give the desired amide.

[0996] R) To the corresponding bis(hetero)aryl ether amide (1 eq) dissolved in THF (0.2 M) was added NaBH4 (1.1 eq) at 0°C under argon atmosphere and stirring. After 1 hour, the reaction was then partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted twice more, then 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 amide.

[0997] S) To the corresponding aldehyde (1 eq.) in anhydrous THF (0.2 M) at 0°C was added the corresponding Wittig reagent (1.5 eq.). To the stirred mixture was added dropwise LiHMDS (1.3 et al., 1 M in THF). The reaction was stirred to completion and then partitioned between AcOEt and aqueous HCl (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with saturated aqueous NaHCO3 and then 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 olefin.

[0998] T) is used to add methyl groups to amines:

[0999] To the corresponding free amine (1 eq) in acetonitrile (0.2 M) was added formaldehyde (6 eq, 37% w / w in water) followed by NaBHCN (2 eq). The reaction mixture was stirred until completion and then partitioned between AcOEt and saturated aqueous NaHCO, the aqueous layer was extracted twice more and the combined organic phases were washed with brine, dried over NaSO, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO, gradient DCM / MeOH / NEt) to give the desired compound.

[1000] Regarding the addition of isopropyl groups to amines:

[1001] Five portions of NaBHCN (10 equivalents) were added to the corresponding free amine (1 equivalent) in acetone (0.2 M) every 15 minutes while the pH was maintained at about 5 with acetic acid. The reaction mixture was then partitioned between AcOEt and saturated NaHCO aqueous solution on carbon, the aqueous layer was extracted twice more, and the combined organic phases were then washed with brine, dried over NaSO, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO, gradient DCM / MeOH / NEt) to give the desired compound.

[1002] U) mCPBA (1.2 equivalents) was added to the corresponding amine (1 equivalent) in DCM (0.1M), and the mixture was stirred at room temperature until complete conversion. The reaction mixture was then distributed between AcOEt and NaHCO3 aqueous carbon, the water layer was extracted twice, and then the combined organic phases were washed with salt water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired compound.

[1003] V) To the corresponding nitrile (1 eq.) in ethanol (0.2 M) was added hydroxylamine hydrochloride (2.5 eq.) and sodium hydroxide (2.5 eq.). The reaction was heated to 80° C. overnight, then filtered through celite, concentrated in vacuo, and the residue was purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired compound.

[1004] W) To the corresponding aldehyde (1 eq.) in methanol (0.1 M) was added K2CO3 (2 eq.) ) , then add Ohira-Bestmann reagent (1.1 equivalents), stir the reaction until completion. Then the reaction is distributed between ethyl acetate and sodium bicarbonate. The water layer is extracted twice more, then the combined organic phase is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired alkyne.

[1005] Analyze the data

[1006] The following compounds were synthesized according to the above scheme and characterized by mass spectrometry (Table 93) or NMR (Table 94).

[1007] Table 93:

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040] Table 94:

[1041]

[1042]

[1043] For purposes of illustration, the synthesis and characterization of the following examples are described in detail.

[1044] XPW-0547 4-(4-Butylphenoxy)-N-(methylsulfonyl)benzamide

[1045]

[1046] Under argon atmosphere, 4-(4-butylphenoxy)benzoic acid (104 mg, 0.38 mmol, 1 eq.) suspended in stirred toluene (1.85 mL, 0.2 M) was first added with SOCl2 (67 μL, 0.93 mmol, 2.5 eq.), then DMF (0.3 μL, 3.7 μmol, 1 mol%), and the mixture was heated to 80 °C for 3 h. The reaction mixture was then evaporated to dryness, and the resulting residue was again placed under argon atmosphere and redissolved in THF (1.85 mL, 0.2 M). Trimethylamine (0.13 mL, 0.93 mmol, 2.5 eq.), DMAP (0.45 mg, 3.7 μmol, 1 mol%) and methanesulfonamide (42.3 mg, 0.45 mmol, 1.2 eq.) were added to the solution in sequence, and the suspension was stirred for 16 h. The reaction was then distributed between AcOEt and aqueous hydrochloric acid (1M). The aqueous layer was extracted twice more, and the combined organic phases were then 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 118 mg of 4-(4-butylphenoxy)-N-(methylsulfonyl)benzamide (88%).

[1047] MS:m / z[MH] - , [C 18 H 20 NO4S] - Calculated value = 346.11; measured value is 346.24

[1048] 1 H-NMR(300MHz DMSO-d6)δ12.03(s,1H),7.97(d,J=8.9Hz,2H),7.32-7.24(m,2H),7.08-6.97(m,4H),3.36(s, 3H),2.66-2.56(m,2H),1.58(tt,J=8.8,6.8Hz,2H),1.41-1.24(m,2H),0.92(t,J=7.3Hz,3H).

[1049] 13 C-NMR (75MHz, DMSO-d6) δ166.1,162.1,153.2,139.4,131.4,130.5,126.3,120.4,117.2,41.8,34.6,33.6,22.2,14.3.

[1050] XPW-2890 (6-(4-cyclohexylphenoxy)pyridin-3-yl)(morpholino)methanone

[1051]

[1052] To 6-(4-cyclohexylphenoxy)nicotinic acid (50 mg, 0.17 mmol, 1 eq.) suspended in stirred toluene (0.85 mL, 0.2 M) under argon atmosphere was first added SOCl2 (31 μL, 0.43 mmol, 2.5 eq.), then DMF (0.14 μL, 1.7 μmol, 1 mol%), and the mixture was heated to 80 °C for 3 h. The reaction mixture was then evaporated to dryness, the resulting residue was again placed under argon and redissolved in THF (0.85 mL, 0.2 M). To this solution were added trimethylamine (9.4 μL, 0.68 mmol, 2.5 eq.), DMAP (0.2 mg, 1.7 μmol, 1 mol%), and morpholine (20 μL, 0.23 mmol, 1.5 eq.), and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and aqueous HCl (1 M). The aqueous layer was extracted twice more, then 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 45 mg of (6-(4-cyclohexylphenoxy)pyridin-3-yl)(morpholino)methanone (71%).

[1053] MS:m / z[M+H] + , [C 22 H 27 N2O3] + Calculated value = 367.20; measured value is 367.32

[1054] 1 H-NMR (300MHz, CDCl3) δ8.20(d,J=2.3Hz,1H),7.73(dd,J=8.6,2.2Hz,1H),7.18(d,J=7.7Hz,2H),7.06-6 .92(m,2H),6.87(d,J=8.5Hz,1H),3.63(s,8H),2.50-2.37(m,1H),1.89-1.62(m,5H),1.38-1.08(m,5H).

[1055] 13 C-NMR (75MHz, CDCl3) δ167.7,164.7,151.2,146.6,145.1,139.5,128.1,125.5,121.0,111.3,66.8,53.4,44.0,34.5,26.9,26.1.

[1056] XPW-0636N-Cyano-4-(4-cyclohexylphenoxy)benzamide

[1057]

[1058] Under argon atmosphere, 4-(4-cyclohexylphenoxy)benzoic acid (60 mg, 0.2 mmol, 1 eq.) suspended in stirred toluene (0.8 mL, 0.2 M) was first added SOCl2 (37 μL, 0.0.5 mmol, 2.5 eq.), then DMF (0.15 μL, 2.0 μmol, 1 mol%), and the mixture was heated to 80 ° C for 3 hours. The reaction mixture was then evaporated to dryness, the resulting residue was placed under argon atmosphere again, and redissolved in THF (0.8 mL, 0.2 M). Trimethylamine (57 μL, 0.5 mmol, 2.5 eq.), DMAP (0.24 mg, 2.0 μmol, 1 mol%) and cyanamide (12.6 mg, 0.3 mmol, 1.5 eq.) were added to the solution in sequence, and the suspension was stirred for 16 hours. The reactants were then partitioned between AcOEt and aqueous hydrochloric acid (1 M). The aqueous layer was extracted twice more, then 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 15.4 mg of N-cyano-4-(4-cyclohexylphenoxy)benzamide (24%).

[1059] MS:m / z[MH] - , [C 20 H 19 N2O2] - Calculated value = 319.15; measured value is 319.28

[1060] 1 H-NMR, (300MHz, CDCl3) δ7.93 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.23-6.8 5(m,4H),3.37(brs,1H),2.59-2.51(m,1H)1.91-1.63(m,5H),1.57-1.12(m,5H).

[1061] 13 C-NMR, (75MHz, CDCl3) δ166.5,161.8,152.7,144.2,130.8,128.4,124.8,119.9,117.1,110.0,43.1,34.0,26.3,25.5.

[1062] XPW-0675N-Hydroxy-4-(4-(2-methoxyethyl)phenoxy)-N-methylbenzamide

[1063]

[1064] To 4-(4-(2-methoxyethyl)phenoxy)benzoic acid (125 mg, 0.46 mmol, 1 eq.) suspended in stirred toluene (2.3 mL, 0.2 M) under argon, SOCl2 (84 μL, 1.15 mmol, 2.5 eq.) was first added, followed by DMF (0.35 μL, 4.6 μmol, 1 mol%), and the mixture was heated to 80 °C for 3 h. The reaction mixture was then evaporated to dryness, and the resulting residue was again placed under argon and redissolved in THF (2.3 mL, 0.2 M). Trimethylamine (144 μL, 1.13 mmol, 2.5 eq.), DMAP (0.56 mg, 4.6 μmol, 1 mol%), and N-methylhydroxylamine hydrochloride (58 mg, 0.69 mmol, 1.5 eq.) were added in sequence to the solution, and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and aqueous hydrochloric acid (1 M). The aqueous layer was extracted twice more, then 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 103.1 mg of N-hydroxy-4-(4-(2-methoxyethyl)phenoxy)-N-methylbenzamide (74%).

[1065] MS:m / z[M+H] + , [C 17 H 20 NO4] + Calculated value = 302.14; measured value is 302.17

[1066] 1 H-NMR, (300MHz, CDCl3) δ10.00(s,1H),7.73-7.61(m,2H),7.37-7.20(m,2H),7.07- 6.82(m,4H),3.55(t,J=6.8Hz,2H),3.26(s,3H),3.25(s,3H),2.82(t,J=6.8Hz,2H).

[1067] 13 C-NMR, (75MHz, CDCl3) δ168.6,159.2,154.3,135.6,131.2,130.9,129.5,119.9,117.1,73.2,58.3,37.9,35.1.

[1068] XPW-0832N'-Cyano-6-(4-cyclohexylphenoxy) nicotinamide

[1069]

[1070] To 6-(4-cyclohexylphenoxy)nicotinonitrile (41 mg, 0.15 mmol, 1 eq.) dissolved in THF / MeOH (1:1, 1.5 mL, 0.1 M) was added NaH (6.6 mg, 0.17 mmol, 1.1 eq., 60% in oil) at 0°C under argon atmosphere and stirring. After 4 hours, the ice bath was removed, cyanamide (9.5 mg, 0.23 mmol, 1.5 eq.) was added, and the mixture was stirred for another 16 hours. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more, and the combined organic phases were then washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt / MeOH) to give 32 mg of N'-cyano-6-(4-cyclohexylphenoxy)nicotinimide (67%).

[1071] MS:m / z[M+H] + , [C 20 H 22 N3O] + Calculated value = 320.18; measured value is 320.27

[1072] 1 H-NMR(300MHz,DMSO-d6)δ7.79(d,J=8.9Hz,2H),7.25-7.17(m,2H),7.07-6.94 (m,4H),3.83(s,2H),2.63-2.41(m,1H),1.94-1.55(m,5H),1.48-1.16(m,5H).

[1073] 13 C-NMR (75MHz, DMSO-d6) δ152.9,144.9,129.3,129.3,128.4,124.4,120.1,117.4,116.4,113.3,77.5,44.0,34.6,26.9,26.1.

[1074] XPW-0902: N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide

[1075]

[1076] Under argon atmosphere and stirring, (3r,5r,7r)-1-(4-(4-bromophenoxy)phenyl)adamantane (100 mg, 0.26 mmol, 1 equivalent) was dissolved in anhydrous THF (1.3 mL, 0.2 M), and the resulting solution was cooled to -78°C with a dry ice / acetone bath. Then, the mixture was added dropwise. n BuLi (0.11 mL, 0.26 mmol, 1.0 eq., 2.3 M in pentane) was added and the mixture was stirred at this temperature for 30 minutes and then at -50 °C for another 30 minutes. The mixture was then cooled back to -78 °C. A solution of 2-methyl-N-(2,2,2-trifluoroethylidene)propane-2-sulfenamide (79 mg, 0.39 mmol, 1.5 eq.) in THF (0.39 mL, 1 M) was added dropwise and the reaction was stirred for 1 hour and then allowed to slowly return to room temperature overnight. The reaction was then partitioned between AcOEt and saturated aqueous NH4Cl. The aqueous layer was extracted twice more and the combined organic phases were then 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 81 mg of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfenamide (62%).

[1077] MS:m / z[M+H] + , [C 28 H 35 F3NO2S] + Calculated value = 506.23; measured value is 506.70

[1078] 1 H NMR (400MHz, CDCl3) δ7.38-7.32(m,4H),7.03-6.95(m,4H),4.83(qd,J=7.1,3.5Hz,1H),3.88( d,J=3.5Hz,1H),2.10(p,J=3.5Hz,3H),1.91(d,J=2.9Hz,6H),1.83-1.68(m,6H),1.23(s,9H).

[1079] 13C NMR (101MHz, CDCl3) δ159.29,153.59,147.36,130.78,126.31,125.24,124.53(q,J=281 .3Hz),119.39,117.93,59.87(q,J=30.4Hz),56.31,43.33,36.76,35.91,28.95,22.41.

[1080] 19 F NMR (376MHz, CDCl3) δ-74.56 (d, J=7.2Hz).

[1081] XPW-3052 3-(6-(4-((adamantan-1-yl)phenoxy)pyridin-3-yl)oxetane-3-amine

[1082]

[1083] To a solution of N-(3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)oxetane-3-yl)-2-methylpropane-2-sulfinamide (31 mg, 0.065 mmol, 1 eq) in THF (0.32 mL, 0.2 M) was added HCl (0.8 mL, 0.5 M in MeOH, 6 eq) and the reaction was stirred until completion. The reaction was then partitioned between AcOEt and aqueous NaHCO3 (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient DCM / MeOH) to afford 17.4 mg of 3-(6-(4-((adamantan-1-yl)phenoxy)pyridin-3-yl)oxetane-3-amine (71%).

[1084] MS:m / z[M+H] + , [C 24 H 29 N2O2] + Calculated value = 377.22; measured value is 377.34

[1085] 1H-NMR, (300MHz, DMSO-d6) δ8.33(dd,J=2.6,0.7Hz,1H),8.02(dd,J=8.6,2.6Hz,1H),7.50-7.36(m,2H),7.14-6.96(m ,3H),4.70(d,J=6.3Hz,2H),4.64(d,J=6.3Hz,2H),2.65(brs,2H),2.18-1.99(m,3H),1.96-1.83(m,6H),1.75(s,6H).

[1086] 13 C-NMR, (75MHz, DMSO-d6) δ162.6,152.3,147.4,144.9,138.0,136.4,126.4,121.0,111.3,85.7,57.6,43.2,36.6,35.9,28.8.

[1087] XPW-4642N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfenamide

[1088]

[1089] To a solution of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (360 mg, 0.71 mmol, 1 eq) in THF (7.2 mL, 0.1 M) was added Cs2CO3 (464 mg, 1.42 mmol, 2 eq). After 30 min, iodomethane (0.089 mL, 1.42 mmol, 2 eq) was added. The mixture was then heated at 50 °C for another 16 h. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more, then 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 300 mg of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N,N-dimethylpropane-2-sulfenamide (81%).

[1090] MS:m / z[M+H] + , [C 29 H 37 F3NO2S] + Calculated value = 520.25; measured value is 520.69

[1091] 1 H NMR (400MHz, CDCl3) δ7.42 (d, J=8.6Hz, 2H), 7.37-7.32 (m, 2H), 7.02-6.96 (m, 4H), 4.92 (q, J= 8.6Hz,1H),2.71(s,3H),2.11(s,3H),1.91(d,J=2.9Hz,6H),1.85-1.71(m,6H),1.20(s,9H).

[1092] 19 F NMR (376MHz, CDCl3) δ-67.23 (d, J=8.2Hz).

[1093] XPW-0028: 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride

[1094]

[1095] To N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N,2-dimethylpropane-2-sulfenamide (300 mg, 0.58 mmol, 1 eq) dissolved in THF (5.8 mL, 0.1 M) was added HCl (2.3 mL, 1.15 mmol, 0.5 M in MeOH, 2 eq) and the reaction was stirred until completion. The reaction was then evaporated to dryness to give 255 mg of 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (quantitative).

[1096] MS:m / z[M+H] + , [C 25 H 29 F3NO] + Calculated value = 416.22; measured value is 416.69

[1097] 1H NMR (400MHz, CDCl3) δ11.04(brs,2H),7.62(d,J=8.5Hz,2H),7.43-7.33(m,2H),7.08(d,J=8.4Hz,2H),7 .05-6.96(m,2H),4.71-4.36(m,1H),2.69(s,3H),2.14(s,3H),1.94(d,J=2.9Hz,6H),1.88-1.73(m,6H).

[1098] XPW-0182;

[1099] N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N-methylhydroxylamine

[1100]

[1101] To 1-(4-(4-(3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (50 mg, 0.12 mmol, 1 eq) in DCM (1.2 mL, 0.1 M) was added mCPBA (35 mg, 0.144 mmol, 70%, 1.2 eq) and the mixture was stirred at room temperature for 30 min. The reaction mixture was then partitioned between AcOEt and saturated aqueous NaHCO3 on carbon, the aqueous layer was extracted twice more, and the combined organic phases were then 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 44.5 mg of N-(1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N-methylhydroxylamine (86%).

[1102] 1 H NMR (400MHz, CDCl3) δ7.41-7.33(m,4H),7.05-6.96(m,4H),4.32(q,J=7.6Hz, 1H),2.87(s,3H),2.16-2.07(m,3H),1.92(d,J=2.9Hz,6H),1.85-1.67(m,6H).

[1103] 19 F NMR (376MHz, CDCl3) δ-67.82 (d, J=7.5Hz).

[1104] 13C NMR(101MHz, CDCl3)δ159.24,153.61,147.38,131.35,126.33,124.40,124.18(q,J= 282.5Hz),119.37,117.73,74.70(q,J=29.0Hz),50.31,43.34,36.76,35.92,28.96.

[1105] XPW-0042: 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N,N-dimethylethane-1-amine

[1106]

[1107] To 1-(4-(4-(3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N-methylethane-1-amine hydrochloride (20 mg, 0.05 mmol, 1 eq) in acetonitrile (0.25 mL, 0.2 M) was added formaldehyde (0.025 mL, 0.29 mmol, 6 eq, 37% w / w in water) followed by NaBH3CN (6.1 mg, 0.10 mmol, 2 eq). The reaction mixture was stirred until complete and then partitioned between AcOEt and saturated aqueous NaHCO3 on carbon, the aqueous layer was extracted twice more and the combined organic phases were then washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient DCM / MeOH) to afford 15 mg of 1-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoro-N,N-dimethylethane-1-amine (75%).

[1108] MS:m / z[M+H] + , [C 26 H 31 F3NO] + Calculated value = 430.27; measured value is 430.71

[1109] 1 H NMR (400MHz, CDCl3) δ7.39-7.28(m,4H),7.04-6.93(m,4H),3.95(q,J=8.7H z,1H),2.36(s,6H),2.10(s,3H),1.91(d,J=2.9Hz,6H),1.85-1.69(m,6H).

[1110] 19F NMR (376MHz,CDCl3)δ-67.30.

[1111] XPW-0314 2-(4-(4-cyclohexylphenoxy)phenyl)-2-(dimethylamino)acetonitrile

[1112]

[1113] To a stirred solution of 4-(4-cyclohexylphenoxy)benzaldehyde (50 mg, 0.18 mmol, 1 eq.) in toluene (0.90.9 mL, 0.2 M) under argon was added dimethylamine (0.18 mL, 0.36 mmol, 2 eq.) followed by TMSCN (0.05 mL, 0.36 mmol, 2 eq.) and the reaction was stirred for 16 h. The reaction was then partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted twice more and the combined organic phases were then 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 29 mg of 2-(4-(4-cyclohexylphenoxy)phenyl)-2-(dimethylamino)acetonitrile (48%).

[1114] MS:m / z[M+H] + , [C 22 H 27 N2O] + Calculated value = 335.21; measured value is 335.31

[1115] 1 H-NMR, (300MHz, CDCl3) δ7.46-7.32(m,2H),7.16-7.07(m,2H),6.99-6.82(m,4H),4.75(s, 1H),2.43(ddt,J=11.7,8.2,5.0Hz,1H),2.27(s,6H),1.87-1.61(m,5H),1.42-1.24(m,5H).

[1116] 13 C NMR (75 MHz, CDCl3) δ158.5,154.2,143.8,129.3,128.1,119.3,118.3,115.0,62.5,43.9,41.7,34.6,26.9,26.1.

Claims

1. A compound according to the general 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-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, 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-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 Bicycloalkyl, -OC7-C 12 Bicycloalkenyl, -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-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 Tricycloalkyl, -NHR 7 or -NR 7 R 8 , where R 7 and R 8 Independently selected from: 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-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 tricycloalkyl, or wherein R 7 Can be used with R 8 Together forming a ring structure, wherein the ring structure containing the N atom is selected from a 3- to 8-membered ring structure or a 5- to 12-membered bicyclic structure, and wherein all of the ring structures may additionally contain one or more heteroatoms independently selected from O, S and N to replace the carbon atoms contained in the ring structure, in particular wherein such replacement results in a residue containing at least twice the number of C atoms independently selected from O, S and N; Included in R 1 , R 7 and R 8 All alkyl, alkenyl and alkynyl residues in the definition are straight-chain or branched and are unsubstituted or substituted by one or more independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Substituted with tricycloalkyl, linear or branched -OC1-C5 alkyl such as -OCH3, -OC3-C5 cycloalkyl such as -O(cyclopropyl), linear or branched -NH(C1-C5 alkyl), linear or branched -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl) such as -NH(cyclopropyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); When included in R 1 , R 7 and R 8 When the alkyl, alkenyl and alkynyl residues in the definition are substituted by one or more substituents being =O, such substitution with =O cannot result in one of the groups selected from C=O, S=O and N=O being directly bonded to the aromatic ring; Included in R 1 , R 7 and R 8 All cyclic structures, bicyclic structures and tricyclic structures in the definition of include cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -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); Included in R 1 , R 7 and R 8 All alkyl, alkenyl and alkynyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms, and wherein such substitution results in the residue containing at least twice the number of C atoms as 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=O, S=O and N=O being directly bonded to the aromatic ring; Included in R 1 , R 7 and R 8 All cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms, and wherein such replacement results in the residue containing at least the same number of C atoms as the number of heteroatoms independently selected from O, S and N; Included in R 1 , R 7 and R 8 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definition of may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated; Among them, bicyclic and tricyclic residues include fused, bridged, and spirocyclic systems; R 2 –R 5 Independently selected from -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); Included in R 2 –R 5 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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; Included in R 2 –R 5 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N in substitution of a carbon atom, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; X 1 –X 4 are independently selected from N, CR 9 , CR 10 , CR 11 , CR 12 ; R 9 -R 12 Independently selected from -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); Included in R 9 -R 12 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition are 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; Included in R 9 -R 12 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may contain one or more heteroatoms independently selected from O, S and N in substitution of a carbon atom, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; Where R 9 -R 12 Preferably selected from -H, -F, -Cl, -Br, -CH3, -CF3, -OH, -OCH3, -OCF3, cyclopropyl, oxirane, -C(CH3)3, -N(CH3)2, -NH2, -CN, -CH2OCH3, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2OH, -NO2, -CH2-N-morpholinyl; R 6 =-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 Bicycloalkyl, C7–C 12 Bicycloalkenyl, C8–C 14 tricycloalkyl groups and aromatic and heteroaromatic residues, preferably 6-membered aromatic rings and 5- to 6-membered heteroaromatic rings; and wherein bicyclic and tricyclic residues include fused, bridged, and spiro ring systems; Included in R 6 The cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definition of are optionally linked to R via a C1 alkylene or C2 alkylene or C3 alkylene linker. 6 The combined N; Included in R 6 All aromatic and heteroaromatic residues in the definition of are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, straight or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), straight or branched -NH(C1-C3 alkyl), straight or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight or branched -N(C1-C3 alkyl)(cyclopropyl); Included in R 6 all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues and alkylene linkers in the definition of are linear or branched and unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, =O, 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); Included in R 6 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaryl residues and alkylene linkers in the definition of may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms; Where R 6 Preferred are -H, -CH3, -CH2CH3, n-propyl, isopropyl, cyclopropyl, -CF3 and -CF2CF3, benzyl, tert-butyl, phenyl, cyclohexyl, 1-phenylethyl, 2,2-dimethyl-1-phenylpropyl, (1-naphthyl)-methyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, tetrahydropyranyl; Included in R 2 –R 6 and R 9 –R 12 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definition of may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated; Y=-H, linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, -OH, linear or branched -OC1-C6 alkyl, linear or branched -OC2-C6 alkenyl, linear or branched -OC2-C6 alkynyl, -OC3-C6 cycloalkyl, -OC5-C6 cycloalkenyl, -CN, aromatic and heteroaromatic residues, preferably six-membered aromatic rings and five- to six-membered heteroaromatic rings, -S(O)R 13 and -S(O)2R 13 , where R 13 Selected from linear or branched C1-C6 alkyl, linear or branched C2-C6 alkenyl, linear or branched C2-C6 alkynyl, C3-C6 cycloalkyl, C5-C6 cycloalkenyl, -CF3 and -C6H4CH3; wherein all cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues included in the definition of Y may be optionally linked to the N to which Y is bound via a C1 alkylene, or C2 alkylene, or C3 alkylene, or -O-, or -O-CH2-, or -O-CH2-CH2- linker; wherein all aromatic and heteroaromatic residues contained in the definition of Y are unsubstituted or substituted with substituents selected from -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); wherein all alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues and alkylene linkers contained in the definition of Y are linear or branched and unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, =O, 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 and heteroaryl residues and alkylene linkers included in the definition of Y may contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms; wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues and alkylene linkers comprised in the definition of Y may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated; Where Y can be 6 Together, they form a ring structure, wherein the ring structure containing the N atom of Formula I is selected from a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 5- to 12-membered bicyclic residue, an 8- to 14-membered tricyclic residue, and a heteroaromatic residue, wherein all of the rings, bicyclics, tricyclics, and heteroaromatic residues may additionally contain one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in the ring structure, and wherein all of the rings, bicyclics, tricyclics, and heteroaromatic residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3, -CF3, morpholinyl; and wherein bicyclic and tricyclic residues include fused, bridged, and spiro ring systems; Z 1 and Z 2 Selected from the following groups: Where Z 1 is selected from linear or branched C1-C3 alkyl, preferably -CH3, cyclopropyl, oxiranyl, N-methyl-aziridine, thiirane, -CN, -N3, -CF3, -CF2CF3, and wherein Z 2 Independently selected from -H and linear or branched C1-C3 alkyl, preferably -CH3, -CF3, -CF2CF3 (Ia); or where Z 1 and Z 2 Together = O, = S, = NR 14 (Ib); where R 14 Selected from -H, -OH, -OCH3, -CN, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, linear or branched C1-C3 alkyl, preferably -CH3, cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5, -CH2C6H5; or where Z 1 and Z 2 The carbon atoms to which they are attached together form a cyclic residue (Ic); wherein the cyclic residue is selected from a three-membered ring, a four-membered ring, a five-membered ring and a six-membered ring, wherein all rings optionally may contain one or more heteroatoms independently selected from O, S and N to replace the carbon atoms contained in the ring structure; wherein all rings are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3; This is included in Z 1 and Z 2 All alkyl and cyclic residues in the definition of may be partially or fully halogenated, in particular fluorinated, more in particular perfluorinated.

2. A compound according to formula (Ia) as claimed in claim 1 or a salt or solvate thereof.

3. A compound according to formula (Ib) as claimed in claim 1 or a salt or solvate thereof.

4. A compound according to formula (Ic) as claimed in claim 1 or a salt or solvate thereof.

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

6. The compound according to any one of claims 1 to 5 And where R 1 is selected from the group consisting of 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 norbornyl, dicyclooctyl, dicyclooctenyl, dicyclononyl, methylbicyclononyl, adamantyl, tricyclodecyl, oxiranyl, oxetanyl, tetrahydrofuranyl, methyltetrahydrofuranyl, trimethyltetrahydrofuranyl, tetrahydropyranyl, aziridinyl, N-methylaziridine, azetidinyl, N-methylazetidinyl, difluoroazetidinyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thiirane, thiene, tetrahydrothiophenyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethylpiperazinyl, dithianyl, morpholinyl, N-methylmorpholinyl, thiomorpholinyl, N-methyl Thiomorpholinyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methylazaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecanyl, N-methyloxa-azaspirodecanyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecanyl, N-methylazaspirodecanyl, dihydro-oxazinyl, N-methyldihydro-oxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxolanyl, imidazolidinyl, N-methylimidazolidinyl, N,N -dimethylimidazolidinyl, azepanyl, N-methylazepanyl, azaspirohexyl, N-methylazepanyl, oxa-azadispirodecanyl, N-methyloxa-azadispirodecanyl, azadispirodecanyl, N-methylazepanyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N-methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N-methylazabicyclononyl, azaadadamantyl, -O(adamantyl), oxa-azabicyclononyl, N-methyloxa-azabicyclononyl, oxaazabicycloheptyl, N-methyldiazabicycloheptyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, 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 according to any one of claims 1 to 6, Where R 1 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 according to any one of claims 1 to 7, Where R 2 -R 3 Each is -H, R 4 Preferably -H or -F, and / or R 5 It is -H, -F, -Cl, -Br, -CH3, -CF3, -CH=CH2, -C≡CH, -CH2OH, -CH2NHCH3, -OH, -OCH3, -OCF3, cyclopropyl, oxirane, -CH2-N-morpholinyl, -C(CH3)3, -CH2OCH3, -NO2, -CN, -NH2, -N(CH3)2, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2.

9. The compound according to any one of claims 1 to 8, Wherein the substituent R as defined in the general formula (I) 1 To R 5 The six-membered aromatic ring is selected from 10. The compound according to any one of claims 1 to 9 Wherein as defined in the general formula (I) containing X 1 -X 4 The six-membered aromatic ring is selected from:

11. The compound according to any one of claims 1 to 10 wherein Y is -H, -CH3, -CH2CH3, n-propyl, isopropyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, -CF3, -CF2CF3, -OH, -OCH3, -OCH2CH3, -OCH2(cyclopropyl), -CN, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, -S(O)2C6H4CH3, -OCH2C6H5, and -OC6H5; and for R 6 =-H or -CH3 or benzyl, then Y is preferably -OH, -OCH3, -OCH2CH3, -OCH2(cyclopropyl).

12. The compound according to any one of claims 1 to 11 Wherein Y and R 6 The ring structures together containing the N atom are selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, difluoropiperidinyl, morpholinyl, morpholinylazetidinyl, hydroxyazetidinyl, azetidinonyl, azetidinyl, difluoroazetidinyl, azaspirohexyl, azaspiroheptyl, difluoroazaspiroheptyl, hydroxyazaspiroheptyl, methylhydroxyazaspiroheptyl, trifluoromethylhydroxyazaspiroheptyl, azaspirooctyl, azaspirononyl, oxa-azaspiroheptyl, oxa-azaspirooctyl, oxa-azaspirononyl, thia-azaspiroheptyl, oxazolidinyl, tetrahydro-oxazinyl, isoxazolidinyl, oxazinane, isoxazolidine, piperazine.

13. The compound according to any one of claims 1 to 12 Wherein Y and R 6 The ring structures containing the N atom together are selected from:

14. The compound according to any one of claims 1 to 13 Where Z 1 is -CH3, -CF3, -CN, cyclopropyl; and / or wherein Z 2 Preferred are -H, -CH3 and -CF3; for example:

15. The compound according to any one of claims 1 to 13 Where Z 1 and Z 2 Preferably, =O, =NR 14 ; where R 14 Preferably selected from -H, -CH3, cyclopropyl, -OH, -OCH3, -CN:

16. The compound according to any one of claims 1 to 13 Where Z 1 and Z 2 The carbon atoms to which they are attached together form a 3-membered or 4-membered cyclic residue; wherein the cyclic residue is preferably selected from cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridine, azetidinyl ring and thietanyl; and wherein the cyclic residue is optionally preferably substituted by -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3 substitution; and wherein the cyclic residue is even more preferably selected from:

17. The compound according to any one of claims 1 to 16 wherein Y is selected from the residues included in the general definition of Y which, together with the oxygen atom, are bound to the N to which Y is bound.

18. The compound according to any one of claims 1 to 17 Where R 1 Selected from R 1 The general definition of includes residues which contain 4 or more, preferably 6 or more, even more preferably 7 or more carbon atoms and in which R 1 Contains no heteroatoms.

19. The compound of claim 18, wherein R 1 It comprises a ring structure, a bicyclic structure and a tricyclic structure.

20. The compound of claim 18 or 19, wherein R 1 Selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and adamantyl.

21. A compound as described in any one of claims 1 to 17, wherein R 1 Select from R 1 The general definition of includes residues which contain 4 or more, preferably 6 or more, even more preferably 7 or more carbon atoms and in which R 1 Contains one or more, preferably 1 to 2, heteroatoms independently selected from O, S and N to replace R 1 The carbon atoms contained in .

22. The compound of claim 21, wherein R 1 Selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicyclohexyl, N-methylazabicyclohexyl, oxa-azabicyclohexyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azaadamantyl and -O(adamantyl).

23. A compound as described in any one of claims 1 to 22, wherein the compound has the following structure (I-1) And where Z 1 and Z 2 As defined in Formula (I), including Formula (Ia), Formula (Ib) and Formula (Ic), including substitutions and preferred definitions, optionally with the proviso that in the case of Formula (Ib) Z 1 and Z 2 Together is different from =O, And where R 14 As defined in formula (Ib), including substitution and preferred definitions, And among them, Y, R 2 -R 6 , R 9 -R 13 or X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions.

24. The compound of any one of claims 1 to 23, wherein the compound has the following structure (I-4): Where R 6 As defined in formula (I), including substitution and preferred definitions, provided that R 6 Different from -H, And where Z 1 and Z 2 As defined in Formula (I), including Formula (Ia), Formula (Ib) and Formula (Ic), including substitutions and preferred definitions, And where R 14 As defined in formula (Ib), including substitution and preferred definitions, And where R 1 -R 5 , R 7 -R 12 and X 1 -X 4 As defined in formula (I), including substitutions and preferred definitions.

25. The compound according to any one of claims 1 to 24, wherein the compound has the following structure (Ib-1): Where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 contains 6 or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I), and wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, And where R 5 As defined in formula (I), including substitution and preferred definitions, provided that R 5 Different from -H, And where Z 1 , Z 2 and R 14 As defined in formula (Ib), including substitution and preferred definitions, And where R 2 -R 4 , R 6 -R 13 and X 1 -X 4 and Y are as defined in formula (I), including substitutions and preferred definitions.

26. A compound as described in any one of claims 1 to 25, wherein the compound has the following structure (Ib-2): Where R 1 As defined in formula (I), including substitution and preferred definitions, wherein R 1 contains six or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I), and wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, And where Z 1 , Z 2 and R 14 As defined in formula (Ib), including substitution and preferred definitions, And where R 2 -R 13 , X 1 -X 4 and Y are as defined in formula (I), including substitutions and preferred definitions.

27. A compound as described in any one of Tables 6 to 54, or a salt or solvate thereof.

28. A compound as claimed in any one of claims 1 to 27 for use in medicine, such as in human or veterinary medicine.

29. A compound as claimed in any one of claims 1 to 27 for use in treating a condition associated with, associated with and / or caused by dysfunctional Notch signalling.

30. A compound as claimed in any one of claims 1 to 27 for use as an enhancer of Notch signalling.

31. A compound as claimed in any one of claims 1 to 27 for use in the treatment of a hyperproliferative disorder, including malignant and non-malignant hyperproliferative disorders.

32. A compound as described in any one of claims 1 to 27 for use in the treatment of diseases of the skin, mucosa, skin and mucosal appendages, cornea and epithelial tissues and malignant, non-malignant and hyperproliferative conditions, including cancers such as non-melanoma skin cancers including squamous cell carcinoma and basal cell carcinoma and precancerous lesions including actinic keratosis, skin and / or mucosal conditions with keratinization defects and / or abnormal keratinocyte proliferation, viral infections, atopic dermatitis and acne-related, associated and / or caused skin and / or mucosal diseases, and for promoting wound healing of the skin and mucosa.

33. A compound as described in any one of claims 1 to 27 for use in the treatment of hyperproliferative disorders, cancers or precancerous lesions of the skin, oral mucosa, tongue, lung, stomach, breast, cancers of the neuroendocrine system such as medullary thyroid cancer, brain cancer, pancreatic cancer, liver cancer, thyroid cancer and genitourinary tract cancers, including cancers of the cervix and ovary.

34. A compound as claimed in any one of claims 1 to 27 for use in the treatment of malignant and non-malignant muscle diseases, including muscular dystrophy, or for muscle regeneration, or for muscle hyperproliferative disorders, such as muscle hyperplasia and muscle hypertrophy.

35. A compound as described in any one of claims 1 to 27 for use in the treatment of immune system related disorders, including disorders of the hematopoietic system, including the blood system, such as cancers of the hematopoietic and hematological systems, such as leukemias and lymphomas, such as myeloid malignancies, for example acute and chronic myeloid leukemias and acute and chronic promyelocytic leukemias, and malignancies of the lymphoid system, for example acute and chronic T-cell leukemias and acute and chronic B-cell leukemias, and cutaneous T-cell lymphomas.

36. A compound as claimed in any one of claims 1 to 27 for use in therapeutic immune system related applications, including immunotherapy and other immunotherapy methods, such as use as an immune adjuvant or vaccine adjuvant.

37. A method of treating a hyperproliferative disorder, said method comprising administering to a subject, particularly a human subject, in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 27.

38. A method for treating a disorder associated with, accompanied by and / or caused by dysfunctional Notch signaling, the method comprising treating a subject, particularly a human subject, in need thereof with an effective amount of a compound according to any one of claims 1 to 27.

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