Aromatic molecules for use in the treatment of pathological conditions

Abstract

To provide novel aromatic molecules, which can be used in 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 hematologic system, in human and veterinary medicine.SOLUTION: A compound represented by general formula (I) or a salt or solvate thereof is provided. (In the formula, R1 is alkyl, cycloalkyl, or the like; R2 to R5 are each independently H, halogen, cyano, alkyl, or the like; X1 to X4 are each independently N, CR8, or the like; R8 is H, alkyl, or the like; Y is H, OH, alkoxy, or the like; and Z1 and Z2 together form a cyclic residue including carbon atoms bound thereto.)SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to novel compounds and their use as therapeutic agents in humans and veterinary medicine. The compounds of this invention can be used to treat pathological conditions including cancer, skin disorders, muscle disorders, lung disorders, hematopoietic disorders including the blood system, and immune system-related disorders. [Background technology]

[0002] This invention relates to novel molecules that exhibit significant biological activity against human and animal-derived cells. These compounds have been found to affect the growth and survival of cancer cells and primary non-cancerous cells. In particular, molecules capable of completely or partially inhibiting cell proliferation or inducing cell death have been identified. Furthermore, several compounds have been found to affect cellular signaling pathways, particularly the Notch signaling pathway. These molecules have been found to enhance the Notch signaling pathway.

[0003] In other words, the present invention relates to compounds as defined herein that are characterized by antiproliferative activity and can be used for the treatment of benign and malignant hyperproliferative disorders in humans and veterinary medicine. In particular, the present invention relates to compounds as defined herein for the treatment of immune system-related disorders in humans and veterinary medicine, including disorders of the hematopoietic system, including the blood system, and malignancies of both the myeloid and lymphoid systems; malignant and non-malignant disorders of the skin and mucous membranes, including malignant and non-malignant disorders of the muscles, such as keratinization disorders, muscle hyperproliferative disorders such as muscle hyperplasia and muscle hypertrophy; disorders of the neuroendocrine system, including non-melanoma skin cancers including squamous cell carcinoma and basal cell carcinoma; hyperproliferative disorders of the skin and mucous membranes, such as actinic keratosis; cancers and precancerous lesions; hyperproliferative disorders and cancers of the oral cavity and tongue; neuroendocrine system hyperproliferative disorders and cancers such as medullary thyroid cancer; hematopoietic system hyperproliferative disorders and cancers, including leukemia and lymphoma; and hyperproliferative disorders and cancers of the urogenital system, including ovarian cancer, such as cervical cancer, in the lungs, breasts, stomach, etc.

[0004] The biological activity, for example, the antiproliferative activity of the claimed compound, may be attributable to, but is not limited to, Notch signaling-enhancing activity. That is, the present invention also relates to compounds as defined herein characterized by Notch-enhancing activity, which can be used in the treatment of pathological conditions in response to Notch control, such as cancer, skin diseases, muscle disorders, hematopoietic disorders including blood systems, and immune system-related disorders in humans and veterinary medicine. [Overview of the project]

[0005] The compounds of the present invention relate to bis-allyl ethers composed of two six-membered aromatic rings, where one aromatic ring is an unsubstituted or substituted benzyl ring and the other aromatic ring is an unsubstituted or substituted aryl ring, and these optionally contain an N-atom, i.e., optionally six-membered heteroaromatic rings. All such bis-allyl ether structures share the common feature of containing substituents at both para positions of the ether bond, where such substituents on the benzene ring, which cannot be heteroaromatic rings, are preferably nonpolar residues and / or sterically required Such substituents on an aryl ring, which are selected from strict residues and which may optionally be heteroaromatic rings, are preferably selected from structural units containing a large number of heteroatoms.

[0006] The first aspect of the present invention relates to compounds of general formula (I), as well as their salts and solvates.

[0007] [ka]

[0008] (In the formula, R 1 C1-C 12 Preferably C4-C 12 Alkyl, C2-C 12 Preferably C4-C 12 Alkenyl, C2-C 12 Preferably C4-C 12 Alkinyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Tricycloalkyl, -OC1-C 12 Preferably -OC3-C 12 Alkyl, -OC2-C 12 Preferably -OC3-C 12 Alkenyl, -OC2-C 12 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 Preferably -SC3-C 12 Alkyl, -SC2-C 12 Preferably -SC3-C 12 Alkenyl, -SC2-C 12 Preferably -SC3-C 12 Alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 Tricycloalkyl, -NHR 6 Or -NR 6 R 7 (In the formula, R 6 And R 7 Are independently of each other C1-C 12 Preferably C3-C 12 Alkyl, C2-C 12 Preferably C3-C 12 Alkenyl, C2-C 12 Preferably C3-C 12 Alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Selected from tricycloalkyl, or R 6 Is R 7Together with these, they can form a ring structure; where the ring structure containing the N atom is selected from a 3- to 8-membered cyclic structure or a 5- to 12-membered bicyclic structure, and where all such ring structures may further contain one or more heteroatoms independently selected from O, S and N instead of carbon atoms in the ring structure, in particular where such substitutions result in residues containing at least twice as many C atoms as heteroatoms independently selected from O, S and N); Here, R 1 , R 6 and R 7 All alkyl, alkenyl, and alkynyl residues included in the definition are linear or branched, and are unsubstituted or -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 one or more substituents independently selected from 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), and linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); Here, R 1 , R 6 and R 7 If an alkyl, alkenyl, or alkynyl residue included in the definition is substituted with one or more substituents that are =O, then such substitution with =O cannot be one of the groups selected from C=O, S=O, and N=O directly bonded to the aromatic ring; where R 1 , R 6 and R 7All cyclic, bicyclic, and tricyclic structures containing cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition are unsubstituted or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, linear or branched - Substituted with one or more substituents independently selected from C1-C5 alkyl such as CH3, linear or branched -OC1-C5 alkyl such as -OCH3, 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); Here, R 1 , R 6 and R 7 All alkyl, alkenyl, and alkynyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, where such substitution results in a residue containing at least twice as many carbon atoms as heteroatoms independently selected from O, S, and N, where such substitution cannot be one of the groups selected from C=O, S=O, and N=O directly bonded to the aromatic ring; Here, R 1 , R 6 and R 7 All cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, where such substitution results in a residue containing at least the same number of carbon atoms as heteroatoms independently selected from O, S, and N; Here, R 1 , R 6 and R 7All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may be partially or completely halogenated, in particular fluorinated, and more particularly perfluorinated; Here, bicyclic and tricyclic residues include condensation, crosslinking, and spirosystems; And here, R 1Preferably, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, 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, dimethylaminomethyl, dimethylamino Ethyl, diethyl-aminomethyl, ethyl-methyl-aminomethyl, cyclopropyl, methyl-cyclopropyl, ethyl-cyclopropyl, trifluoromethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, preferably norbornyl, bicyclooctyl, bicyclooctenyl, bicyclononyl, methylbicyclononyl, adamantyl, tricyclodecyl, oxylanil, oxetanyl, tetrahydrofuranyl, Methyltetrahydrofuranyl, trimethyltetrahydrofuranyl, tetrahydropyranyl, azilidinyl, N-methylazilidinyl, azetidinyl, N-methylazetidinyl, difluoroazetidinyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thyranyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethylpiperazinyl, dithianly, morpholinyl, N-methylmorpholinyl, thiomorpholinyl L, N-methylthiomorpholinyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methylazaspiroheptyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecyl,N-methyloxazaspirodecyl, azaspirodecyl, N-methylazaspirodecyl, dihydro-oxazinyl, N-methyldihydro-oxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxolanil, imidazolidinyl, N-methylimidazolidinyl, Lu, N, N-dimethylimidazolidinyl, azepanyl, N-methylazepanyl, azaspirohexyl, N-methylazapirohexyl, oxa-azadispirodecyl, N-methyloxa-azadispirodecyl, azadispirodecyl, N-methylazadispirodecyl, oxa-azabicyclooctyl, N-methyloxa-azadispirodecyl, azabicyclooctyl, N-methylazadispirodecyl, azabicycloheptyl, N-methylazadispirodecyl, azabicyclononyl, N-methylazadispirodecyl, azaadamantyl, -O Selected from (adamantyl), oxa-azabicyclononyl, N-methyloxa-azabicyclononyl, oxa-azabicycloheptyl, N-methyloxa-azabicycloheptyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, N,N-dimethyldiazabicyclooctyl, diazabicycloheptyl, N-methyldiazabicycloheptyl, N,N-dimethyldiazabicycloheptyl; 4-oxocyclohexyl; 3-oxocyclopentyl; 2-oxocyclobutyl, 4-oxobicyclo[4.1.0]heptan-1-yl And here, R 1 More preferably, C4-C 12 Alkyl, C4-C 12 Alkenyl, C4-C 12 Selected from alkynyl, cyclic, bicyclic, and tricyclic residues, where alkyl, alkenyl, and alkynyl residues are preferably branched, including:

[0009] [ka]

[0010] R 2 -R 5These are -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 Selected from branched -N(C1-C3 alkyl)(cyclopropyl); Here, R 2 -R 5 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; Here, R 2 -R 5 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, and such substitutions may not be one of the groups selected from C=O and S=O directly bonded to the aromatic ring; Here, R 2 -R 3 Each of these is preferably -H, and R 4 is preferably -H or -F, and R 5 Preferably, the elements 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; Here, the substituent R as defined by the general formula (I) 1 from R 5 to which the 6-membered aromatic ring to which it is attached is preferably selected from the following;

[0011]

Chemical formula

[0012] X 1 -X 4 are each independently N, CR 8 , CR 9 , CR 10 , CR 11 selected from; R 8 -R 11 are each independently -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 -N H(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); Here, all alkyl, alkenyl, alkynyl and cycloalkyl residues included in the definition of R 8 -R<​​​​​​All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N in place of carbon atoms, and such substitution cannot be one of the groups selected from C=O and S=O directly bonded to the aromatic ring; Here, R 8 -R 11 is preferably selected from -H, -F, -Cl, -Br, -CH3, -CF3, -OH, -OCH3, -OCF3, cyclopropyl, oxiranyl, -C(CH3)3, -N(CH3)2, -NH2, -CN, -CH2OCH3, -OCH(CH3)2, -CH2NH2, -CH2N(CH3)2, -CH2OH, -NO2, -CH2-N-morpholinyl; And here, X defined by the general formula (I) 1 -X 4 [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​Here, all aromatic and heteroaromatic residues included in the definition of Y are bonded to the carbon atoms to which Y is bonded via -O- or -S- or -O-CH2- or -O-CH2-CH2- or -S-CH2-CH2- or -O-CH2-O- or -S-CH2-O- or -O-CH2-NH- or -S-CH2-NH- linkers; where the linkers are bonded to the carbon atoms to which Y is bonded via their heteroatoms; Here, the linker included in the definition of Y is unsubstituted or substituted with one or more substituents independently 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 -OCH3, -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); Here, all aromatic and heteroaromatic residues included in the definition of Y are either unsubstituted or substituted with one or more substituents independently 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 -OCH3, -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); Here, all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues included 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); Here, all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and heteroaromatic residues included in the definition of Y may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; Here, all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues included in the definition of Y, as well as the linker, may be partially or completely halogenated, in particular fluorinated, and more particularly perfluorinated; Here, Y is preferably -H, -OH, -OCH3, -OCH2CH3, -O(cyclopropyl), -OC6H5, -OCH2C6H5, -SH, -SCH3, -SCH2CH3, -S(cyclopropyl), -SCH2C6H5, -OS(O)C(CH3)3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3; Z 1 and Z 2 The following are selected from the following bases:

[0015] [ka]

[0016] Here, Z 1 is -H, and here, Z2 -OH, linear or branched -OC1-C6 alkyl, linear or branched -OC2-C6 alkenyl, linear or branched -OC2-C6 alkynyl, -OC3-C6 cycloalkyl, -SH, linear or branched -SC1-C6 alkyl, linear or branched -SC2-C6 alkenyl, linear or branched -SC2-C6 alkynyl, -SC3-C6 cycloalkyl, aromatic and heteroaromatic residues, preferably 5- to 6 membered aromatic rings and 5- to 6 membered heteroaromatic rings, -OS(O)R 12 and -OS(O)2R 12 (In the formula, R 12 (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) (General formula Ia); Here, Z 2 All aromatic and heteroaromatic residues included in the definition are linked to Z via the -O- or -S- or -O-CH2- or -O-CH2-CH2- or -S-CH2- or -S-CH2-CH2- or -O-CH2-O- or -S-CH2-O- or -O-CH2-NH- or -S-CH2-NH- linker. 2 Y is bonded to the carbon atom to which it is bonded; here the linker is bonded to the carbon atom to which Y is bonded by those heteroatoms; here Z 2 The linker included in the definition is 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 -OCH3, -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); Here, Z2 All aromatic and heteroaromatic residues included in the definition are either unsubstituted or substituted with one or more substituents independently 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 -OCH3, -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); Here, Z 2 All alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues included in the definition are linear or branched, and are unsubstituted or -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 as well Alternatively, it may be substituted with one or more substituents independently selected from branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, or linear or branched -N(C1-C3 alkyl)(cyclopropyl); Here, Z 2 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and heteroaromatic residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; Here, Z 2 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues included in the definition, as well as the linker, may be partially or completely halogenated, in particular fluorinated, and more particularly perfluorinated; Here, Z 2 Preferably, these are -OH, -OCH3, -OCH2CH3, -O(cyclopropyl), -OC6H5, -OCH2C6H5, and -SCH2CH3; Or here, Z 1 and Z 2 Together, they equal O or S (general formula Ib); where Z 1 and Z 2 They are preferably equal to O when combined. Or here, Z 1 and Z 2 These combine to form a cyclic residue containing the carbon atoms to which they are bonded (general formula Ic); where the cyclic residue is selected from 3-membered, 4-membered, 5-membered, and 6-membered rings, where all rings may optionally contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; where 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, tert-butyloxycarbonyl, and -CH2C6H5; Here, Z 1 and Z 2 When Y is different from -H, they preferably form a cyclic residue containing the carbon atoms to which they are bonded; where the cyclic residue is selected from 3-membered, 4-membered, 5-membered, and 6-membered rings, where all rings may optionally contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; where 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, tert-butyloxycarbonyl, -CF3, and -CH2C6H5; And here, Z 1 and Z 2These combine to form a three- or four-membered cyclic residue containing a carbon atom to which they are preferably bonded; where this cyclic residue is preferably selected from cyclopropyl, cyclobutyl, oxylanil, oxetanil, azilidinyl, azetidinyl, thietanyl, thiazolidinyl, methylthiazolidinyl, thiazolidinyl-dionyl, methylthiazolidinyl-dionyl, oxazolidinyl, methyloxazolidinyl, oxazolidine-dionyl, and methyloxazolidine-dionyl, where this cyclic residue is optionally preferably substituted with -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3, tert-butyloxycarbonyl, -CF3, and -CH2C6H5;

[0017] [ka]

[0018] Here, Z 1 and Z 2 All cyclic residues included in the definition are partially or completely halos. (It can be ionized, especially fluorinated, and more particularly perfluorinated.) [Modes for carrying out the invention]

[0019] R 1 -R 12 , X 1 -X 4 , Z 1 , Z 2 The following preferred definitions of Y may be applied, either independently or in combination, to all aspects including preferred and certain aspects, all aspects including preferred and certain embodiments, and to all subgenres as defined herein. 1) R 1 It preferably contains four or more carbon atoms, preferably six or more, and more preferably seven or more; 2) R 1 The residue is preferably selected from branched alkyl, alkenyl, and alkynyl residues; 3) R 1The structure is preferably selected from cyclic, bicyclic, and tricyclic structures, where the bicyclic and tricyclic residues include condensation, crosslinking, and spirosystems; 4) R 1 Preferably, it does not contain heteroatoms; 5) R 1 The compound is preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, and tricyclodecyl, and most preferably adamantyl, such as 1-adamantyl and 2-adamantyl; 6)R 1 Preferably, R 1 7)R containing one or more heteroatoms, preferably one, two, or three heteroatoms, independently selected from O, S, and N, instead of the carbon atoms contained in 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); 8)R 2 -R 5 Preferably two, more preferably three substituents independently selected from -H, i.e., R 2 -R 5 Preferably two, more preferably one substituent, independently selected from -H; 9)R 2 -R 5 If two substituents independently selected from are different from -H and are in the ortho position relative to the ether bond, then these two substituents are preferably different from -F, -Cl, -Br, -I, and -NO2, and more preferably different from each other; 10)X 1 -X 4 The composition of the ring atoms, as defined by X, is preferably X 1 -X 4 All of them are CR 8 , CR9 , CR 10 , CR 11 Selected independently from, or X 1 -X 4 One of them is N, and the other three are CR 8 , CR 9 , CR 10 , CR 11 Selected independently from, or X 1 -X 4 Two of them are N, and the other two are CR 8 , CR 9 , CR 10 , CR 11 If selected independently from, then selected from; that is, the aromatic ring or heteroaromatic ring is selected from benzene, pyridine, pyrimidine, pyridazine, and pyrazine; 11)R 8 -R 11 Preferably two, or more preferably three, substituents independently selected from are -H, i.e., R 8 -R 11 Preferably two and more preferably one substituent, independently selected from -H; 12)R 8 -R 11 If two substituents independently selected from are different from -H and are in the ortho position relative to the ether bond, then these two substituents are preferably different from -F, -Cl, -Br, -I, and -NO2, and more preferably different from each other; 13) Y is preferably selected from -OH, -OCH3 and -OCH2CH3.

[0020] A preferred aspect of the present invention relates to compounds of general formula (I) and their salts and solvates, where R 1 R 1 Selected from residues containing four or more preferably six or more, and more preferably seven or more carbon atoms, which are included in the general definition of And here, R 1 It does not contain heteroatoms, And here, R 1The structure is further more preferably selected from cyclic, bicyclic, and tricyclic structures. , And here, R 1 The more preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and adamantyl, And here, R 1 Most preferably is adamantyl, and R 2 -R 5 , R 8 -R 12 , X 1 -X 4 , Z 1 , Z 2 And Y are as defined in general formula (I), including substituents and preferred definitions.

[0021] A more preferred aspect of the present invention relates to compounds of general formula (I) and their salts and solvates, where R 1 R 1 Selected from residues containing four or more preferably six or more, and more preferably seven or more carbon atoms, which are included in the general definition of And here, R 1 R 1 Instead of carbon atoms contained in, it contains one or more, preferably one to two, heteroatoms independently selected from O, S, and N, And here, R 1 The structure is more preferably selected from annular, biringual, and triringual structures, or here, R 1 These are selected from residues having cyclic, bicyclic, and tricyclic structures. And here, R 1The most more preferred is selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, aza-adamantyl and O-(adamantyl), And here, R 1 The most preferred are tetrahydropyranil, N-methylpiperidinil, morpholinil, 4-oxocyclohexyl, azabicyclooctyl, aza-adamantyl, and O-(adamantyl). and R 2 -R 12 , X 1 -X 4 , Z 1 , Z 2 And Y are as defined in general formula (I), including substituents and preferred definitions.

[0022] A more preferred aspect of the present invention relates to compounds of general formula (I) that fall within the scope of the subgroups defined herein, as well as their salts and solvates.

[0023] S.1 Z 1 and Z 2 Z is defined in general formula (I), including substituents and preferred definitions, provided that Z 1 and Z 2 If they are never together = O or = S, In that case, R 1 -R 12 , X 1 -X 4 And Y are as defined in general formula (I), including substituents and preferred definitions.

[0024] S.2 Y is as defined in general formula (I), including substituents and preferred definitions, provided that Y is different from -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group. In that case, R 1 -R 12 , X 1 -X 4 , Z 1 and Z 2 It is defined in general formula (I), including substituents and preferred definitions.

[0025] S.3 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, R 1 C1-C 12 Preferably C1-C6 alkyl, C2-C 12 Preferably C2-C6 alkenyl, C2-C 12 Preferably C2-C6 alkynyl, C3-C 8-Cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Tricycloalkyl, -OC1-C 12 Preferably -OC1-C6 alkyl, -OC2-C 12 Preferably -OC2-C6 alkenyl, -OC2-C 12 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 Preferably -SC1-C6 alkyl, -SC2-C 12 Preferably -SC2-C6 alkenyl, -SC2-C 12Preferably -SC2-C6 alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 Tricycloalkyl, -NHR 6 Or -NR 6 R 7 (In the formula, R 6 and R 7 They are C1-C, which are independent of each other. 12 Preferably C1-C6 alkyl, C2-C 12 Preferably C2-C6 alkenyl, C2-C 12 Preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Selected from tricycloalkyl, or R 6 R 7 They can combine to form a ring structure; where 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 all such ring structures may further include one or more heteroatoms independently selected from O, S and N in place of the carbon atoms included in the ring structure; Here, all C1-C 12 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, norbornyl, and adamantyl residues are linear or branched and are referred to herein as side substituents, including C5-C, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, norbornyl. 12 Bicycloalkyl, C7-C 12 C8-C containing bicycloalkenyl and adamantyl 14Substituted with one or more substituents independently selected from 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); and where all the C1-C 12 Alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, adamantyl, or norbornyl residues may further optionally contain one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS; and all C9-C 12 Alkenil, C9-C 12 Alkinyl, -OC1-C 12 Alkyl, -OC2-C 12 Alkenyl, -OC2-C 12 Alkinyl, -SC1-C 12 Alkyl, -SC2-C 12 Alkenyl, -SC2-C 12 Alkinyl, and R 6 and R 7 All residues included in the definition are linear or branched, unsubstituted or referred to herein as side substituents, and include -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14Substituted with one or more substituents independently selected from 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), and linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); Here, all -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl residues, as well as R 6 and R 7 All cycloalkyl and cycloalkenyl residues included in the definition and the selection of named side substituents, as well as R 1 , R 6 and R 7 All bicyclic and tricyclic structures containing bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition are, on the premise that they are different from adamantyl and norbornyl, unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, linear or branched -CH3, -OC1-C5 alkyl such as linear or branched -OCH3, linear or branched -NH(C1-C5 alkyl), linear or branched -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(cyclopropyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); Here, R 6 and R 7All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; And here, R 1 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, provided that the combination of such heteroatoms at the terminal site is R 1 If not explicitly included in the definition, it differs from -CN, -NCO, -NCS, and -N3 residues; Here, R 1 , R 6 and R 7 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may be partially or completely halogenated, in particular fluorinated, and more particularly perfluorinated; Here, bicyclic and tricyclic residues include condensation, crosslinking, and spirosystems; In that case, R 2 -R 5 , R 8 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0026] S.4 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, R 2-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); Here, all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C4 cycloalkyl residues are substituted with one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, the C5-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, R 2 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are one or more hematophores independently selected from O, S, and N instead of carbon atoms. It may contain terror atoms; and R 3 -R 5These are 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); Here, R 3 -R 5 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; Here, R 3 -R 5 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 , R 6 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0027] S.5 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 1 CR 8 And, and R 8-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); Here, all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C4 cycloalkyl residues are substituted with one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, the C5-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R 9 -R 11 and X 2 -X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0028] S.6 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 2CR 8 And, and R 8 -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, linear or selected from 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); Here, all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C4 cycloalkyl residues are substituted with one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, the C5-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R 9 -R 11 , X 1 , X 3 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0029] S.7 Z 1 and Z 2When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 3 CR 8 And, and R 8 -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); Here, all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C4 cycloalkyl residues are substituted with one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, the C5-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R 9 -R 11 , X 1 , X 2 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0030] S.8 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 4 CR 8 And, and R 8 -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-C4 alkyl, linear or branched C2-C4 alkenyl, linear or selected from 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); Here, all C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, and C3-C4 cycloalkyl residues are substituted with one or more substituents independently selected from -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, the C5-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2; Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R 9 -R 11 and X 1 -X3 It is defined in general formula (I), including substituents and preferred definitions.

[0031] S.9 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 1 , X 2 and X 3 Each of these is N, In that case, R 1 -R 11 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0032] S.10 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 1 , X 2 and X 4 Each of these is N, In that case, R 1 -R 11 and X 3 It is defined in general formula (I), including substituents and preferred definitions.

[0033] S.11 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 1 , X 3 and X 4 Each of these is N, In that case, R 1 -R 11 and X2 It is defined in general formula (I), including substituents and preferred definitions.

[0034] S.12 Z 1 and Z 2 When they come together, they are either =O or =S, and Y is -OH or a linear unsubstituted or branched unsubstituted -OC1-C6 alkyl group, In that case, X 2 , X 3 and X 4 Each of these is N, In that case, R 1 -R 11 and X 1 It is defined in general formula (I), including substituents and preferred definitions.

[0035] S.13 R 1 R is defined in general formula (I), including substituents and preferred definitions, provided that R 1 Instead of carbon atoms, one independently selected from O, S, and N The above heteroatoms are included, provided that the combination of heteroatoms at the terminal site is different from that of -CN, -NCO, and -NCS residues, In that case, R 2 -R 12 , X 1 -X 4 , Y, Z 1 and Z 2 It is defined in general formula (I), including substituents and preferred definitions.

[0036] S.14 Z 1 and Z 2 Z is defined in general formula (I), including substituents and preferred definitions, provided that Z 1 and Z 2 If they do not come together to equal O, In that case, R 1 -R 12 , X1 -X 4 And Y are as defined in general formula (I), including substituents and preferred definitions.

[0037] S.15 Y is as defined in general formula (I), including substituents and preferred definitions, provided that Y is different from -OH or -OC1-C6 alkyl or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, R 1 -R 12 , X 1 -X 4 , Z 1 and Z 2 It is defined in general formula (I), including substituents and preferred definitions.

[0038] S.16 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, R 1 C1-C 12 Preferably C1-C6 alkyl, C2-C 12 Preferably C2-C6 alkenyl, C2-C 12 Preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Tricycloalkyl, -OC1-C 12 Preferably -OC1-C6 alkyl, -OC2-C 12 Preferably -OC2-C6 alkenyl, -OC2-C 12 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 Preferably -SC1-C6 alkyl, -SC2-C 12 Preferably -SC2-C6 alkenyl, -SC2-C 12 Preferably -SC2-C6 alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 Tricycloalkyl, -NHR 6 Or -NR 6 R 7 (In the formula, R 6 and R 7 They are C1-C, which are independent of each other. 12 Preferably C1 -C6 alkyl, C2-C 12 Preferably C2-C6 alkenyl, C2-C 12 Preferably C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Selected from tricycloalkyl, or R 6 R 7 They can come together to form a ring structure; where the ring structure containing the N atom is selected from a 3- to 8-membered cyclic structure or a 5- to 12-membered bicyclic structure, and where all such ring structures may further include one or more heteroatoms independently selected from O, S and N in place of the carbon atoms included in the ring structure; Here, all C1-C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkinyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl and C8-C 14 Tricycloalkyl residues are linear or branched and are referred to herein as side substituents, and include -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Substituted with one or more substituents independently selected from tricycloalkyl, linear or branched -OC4-C5 alkyl, -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); and where all the C1-C 12 Alkyl, C2-C12 Alkenyl, C2-C 12 Alkinyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl and C8-C 14 The tricycloalkyl residue may further contain one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, and -NCS; and all -OC1-C 12 Alkyl, -OC2-C 12 Alkenyl, -OC2-C 12 Alkinyl, -SC1-C 12 Alkyl, -SC2-C 12 Alkenyl, -SC2-C 12 Alkinyl, and R 6 and R 7 All alkyl, alkenyl, and alkynyl residues included in the definition are linear or branched, unsubstituted or referred to herein as side substituents, and include -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and C5-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Substituted with one or more substituents independently selected from 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), and linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); Here, all -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 Bicycloalkyl, -OC7-C 12Bicycloalkenyl, -OC8-C 14 Tricycloalkyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 Bicycloalkyl, -SC7-C 12 Bicycloalkenyl, -SC8-C 14 Tricycloalkyl residues, and R 6 and R 7 All cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition and in the selection of named side substituents are unsubstituted or -C1-C5 alkyl such as -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, linear or branched -CH3, -OC1-C5 alkyl such as linear or branched -OCH3, linear or branched -NH(C1-C5 alkyl), linear or branched -N(C1-C5 alkyl)(C1-C Substituted with one or more substituents independently selected from -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), and linear or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl), such as -NH(cyclopropyl); Here, R 6 and R 7 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; And here, R 1 All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, provided that the combination of such heteroatoms at the terminal site is R 1If not explicitly included in the definition, it differs from -CN, -NCO, -NCS, and -OC1-C3 alkyl residues; Here, bicyclic and tricyclic residues include condensation, crosslinking, and spirosystems; In that case, R 2 -R 5 , R 8 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0039] S.17 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, R 2-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); Here, R 2 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; Here, R 2 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 , R 3 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0040] S.18 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 1 CR 8 and and R 8 This is 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); Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, NHCH3, and N(CH3)2; Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R 9 -R 11 and X 2 -X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0041] S.19 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 2 CR 8 and and R 8 This is 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); Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, NHCH3, and N(CH3)2. Substituted with one or more selected substituents; Here, R8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R 9 -R 11 , X 1 , X 3 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0042] S.20 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 3 CR 8 and and R 8This is 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); Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, NHCH3, and N(CH3)2; Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R 9 -R 11 , X 1 , X 2 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0043] S.21 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 4 CR 8 and and R 8 -Cl, -Br, -I, CN, -NCO, -NCS, -OH, -NH2, -NO2, selected from 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); Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, NHCH3, and N(CH3)2; Here, R 8 All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; In that case, R 1 -R 7 , R9 -R 11 and X 1 -X 3 It is defined in general formula (I), including substituents and preferred definitions.

[0044] S.22 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 3 is N In that case, R 1 -R 11 , X 1 , X 2 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0045] S.23 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 4 is N In that case, R 1 -R 11 and X 1 -X 3 It is defined in general formula (I), including substituents and preferred definitions.

[0046] S.24 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 1 and X 2 Each of these is N In that case, R 1 -R 11 , X 3 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0047] S.25 Z1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 1 and X 3 Each of these is N In that case, R 1 -R 11 , X 2 and X 4 It is defined in general formula (I), including substituents and preferred definitions.

[0048] S.26 Z 1 and Z 2 When combined, they are either O or S, and Y is -OH, -OC1-C6 alkyl, or -OC3-C6 cycloalkyl, Here, all of the -OC1-C6 alkyl residues are linear or branched and are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I and -OC1-C3 alkyl groups. And here, all of the -OC3-C6 cycloalkyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, And here, all of the alkyl and cycloalkyl residues may optionally be halogenated or perhalated. In that case, X 1 and X 4 Each of these is N In that case, R 1 -R 11 , X 2 and X 3 It is defined in general formula (I), including substituents and preferred definitions.

[0049] S.27 R 1 R is defined in general formula (I), including substituents and preferred definitions, provided that R 1 If it is different from a C3-C8 cycloalkyl group, Here, the C3-C8 cycloalkyl residue is either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, C1-C3 alkyl, and -OC1-C3 alkyl. Here, the C3-C8 cycloalkyl residue may be optionally perhalated. And here, the C3-C8 cycloalkyl residue is defined in general formula (I). C1-C on the same carbon atom as the phenyl ring bond 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Substituting with substituents selected from alkynyl, C3-C8 cycloalkyl, or C5-C8 cycloalkenyl, Here, 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 groups. Here, all of the cycloalkyl and cycloalkenyl residues are either unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, C1-C3 alkyl and -OC1-C3 alkyl. And here, all of the alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues may optionally be perhalated. In that case, R 2 -R 12 , X 1 -X 4 , Y, Z 1 and Z 2 It is defined in general formula (I), including substituents and preferred definitions.

[0050] In one embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, where R 1 It is adamantyl, And here, Z 1 and Z 2 This is defined as in general formula (I), including general formula (Ia), general formula (Ib), and general formula (Ic), including substituents and preferred definitions, except in the case of general formula (Ib), Z 1 and Z 2 They don't come together to equal O. And here, R 12 It is defined in general formula (Ia), including substituents and preferred definitions, And here, R 2 -R 5 , R 8 -R 11 , X 1 -X 4 And Y, including substituents and preferred definitions, are as defined in general formula (I), And here, the compounds share the following structure (I-1)

[0051] [ka]

[0052] And hereby, the compound of structure (I-1) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-0014, XPA-0140, XPA-0154, XPA-0168, XPA-0182, XPA-0196, XPA- 0210, XPA-0238, XPA-0518, XPA-0644, XPA-0658, XPA-0672, XPA-1278, XPA-1280 ,XPA-1308,XPA-1311,XPA-1312,XPA-1316,XPA-1318,XPA-1326,XPA-1327,XPA -1328, XPA-1329, XPA-1330, XPA-1331, XPA-1333, XPA-1336 and XPA-1338.

[0053] In a further embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, where R 1 is adamantyl, and here, X 2 CR 8 dea R 8 is -Br, And here, Z 1 and Z 2 R is defined in general formula (I), including general formula (Ia), general formula (Ib), and general formula (Ic), including substituents and preferred definitions, and here, R 12 It is defined in general formula (Ia), including substituents and preferred definitions, And here, R 2 -R 5 , R 9 -R 11 , X 1 , X 3 , X 4And Y, including substituents and preferred definitions, are as defined in general formula (I), And here, the compounds share the following structure (I-2)

[0054] [ka]

[0055] And hereby, the compounds of structure (I-2) are preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-1299, XPA-1300, XPA-1320, XPA-1321, XPA-1326, and XPA-1327.

[0056] In a further embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, where R 1 It is adamantyl, Here, R 5 R is defined in general formula (I), including substituents and preferred definitions, provided that R 5 Unlike -H, And here, Z 1 and Z 2 R is defined in general formula (I), including general formula (Ia), general formula (Ib), and general formula (Ic), including substituents and preferred definitions, and here, R 12 It is defined in general formula (Ia), including substituents and preferred definitions, And here, R 2 -R 4 , R 8 -R 11 , X 1 -X4 And Y, including substituents and preferred definitions, are as defined in general formula (I), And here, the compounds share the following structure (I-3)

[0057] [ka]

[0058] And hereby, the compounds of structure (I-3) are for use in humans and veterinary medicine, particularly in medical uses as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, as well as for immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders, and It is preferable for use in the treatment of cancers including hematopoietic and blood system cancers such as leukemia and lymphoma, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-1270, XPA-1272, XPA-1274, XPA-1276, XPA-1278, XPA-1280, XPA-1284, and XPA-1286.

[0059] In a further embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, where R 1 R is defined in general formula (I), including substituents and preferred definitions, and where R 1 These are unsubstituted or substituted C6-C8 cycloalkyl, C6-C8 cycloalkenyl, and C6-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Selected from tricycloalkyl, where R 1 Any carbon atom contained therein can be independently substituted with a heteroatom selected from O, S, and N as defined in general formula (I), And here, Z 1 and Z 2This is defined in general formula (I), including general formulas (Ia), (Ib), and (Ic), including substituents and preferred definitions, where in the case of general formula (Ib), Z 1 and Z 2 They don't come together to equal O. And here Y is as defined in general formula (I), including substituents and preferred definitions, except that Y is optionally different from -H. And here, R 12 It is defined in general formula (Ia), including substituents and preferred definitions, And here, R 2 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structures (I-4)

[0060] [ka]

[0061] And hereby, the compounds of structure (I-4) are preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-0006, XPA-0007, XPA-0008, XPA-0009, XPA-0014, XPA-0132, XPA-0140, XPA-0146, XPA-0154, PA-0174, XPA-0182, XPA-0188, XPA-0196, XPA-0210, XPA-0230, XPA-0238, XPA-0510, XPA-0518, XPA-0644, XPA-0658, XPA-0672, XPA -1266, XPA-1277, XPA-1278, XPA-1279, XPA-1280, XPA-1281, XPA-1282, XPA-1293, XPA-1296, XPA-1297, XPA-1308, XPA-1309, XPA-1 310, XPA-1311, XPA-1312, XPA-1313, XPA-1315, XPA-1316, XPA-1317, XPA-1318, XPA-1325, XPA-1326, XPA-1327, XPA-1328, XPA-132 9. Examples include XPA-1330, XPA-1331, XPA-1333, XPA-1336, XPA-1338, and XPA-1884.

[0062] In a further embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, where Y and Z 1 These are -H respectively, and here, X 1 CR 11 X 2 CR 8 X 3 CR 9 X 4 CR 10 And, And here, R 1 These are unsubstituted or substituted C6-C8 cycloalkyl, C6-C8 cycloalkenyl, and C6-C 12 Bicycloalkyl, C7-C 12 Bicycloalkenyl, C8-C 14 Selected from tricycloalkyl, where R 1Any carbon atom contained therein can be independently substituted with a heteroatom selected from O, S, and N as defined in general formula (I), And here, R 5 R is defined in general formula (I), including substituents and preferred definitions, where R 5 R is in the ortho position relative to the ether bond, however, 5 Unlike -H, And here, R 12 It is defined in general formula (Ia), including substituents and preferred definitions, And, R 2 -R 4 , R 6 -R 11 and Z 2 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ia-1)

[0063] [ka]

[0064] And hereby, the compound of structure (Ia-1) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, and cancers of the neuroendocrine system. Examples include compounds XPA-1277, XPA-1278, XPA-1279, XPA-1280, XPA-1293, XPA-1296, and XPA-1297.

[0065] In a further embodiment, the present invention relates to compounds of general formula (Ia) and their salts and solvates, where Y and Z 1 These are -H respectively, and here, X1 is N, and X 2 CR 8 X 3 CR 9 X 4 CR 10 And, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 R comprises six or more carbon atoms that are optionally and independently substituted with heteroatoms selected from O, S, and N as defined in general formula (I), wherein R optionally contains any of the substituents. 1 This includes either no heteroatoms or one or two heteroatoms independently selected from O, S, and N. And here, Z 2 and R 12 It is defined in general formula (Ia), including substituents and preferred definitions, And here, R 2 -R 10 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ia-2)

[0066] [ka]

[0067] And hereby, the compounds of structure (Ia-2) are preferred for use in human and veterinary medicine, in particular for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, and cancers of the neuroendocrine system. Examples include compounds XPA-0510, XPA-0518, XPA-1281, XPA-1327, XPA-1333, XPA-1338, and XPA-1884.

[0068] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they are = O, Y is -OH, and here R 2 , R 3 and R 4 These are each -H, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 R comprises five or more carbon atoms, preferably six or more, and includes any substituent. 1 It does not contain atoms other than C and H, And here, R 5 R is defined in general formula (I), including substituents and preferred definitions, where R 5 R is in the ortho position relative to the ether bond, however, 5 Unlike -H, And, R 8 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-1)

[0069] [ka]

[0070] And hereby, the compound of structure (Ib-1) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, as well as for use in the treatment of immune system-related disorders, skin diseases, hyperproliferative disorders, and cancers including hematopoietic and blood system cancers such as leukemia and lymphoma, and cancers of the tongue. Examples include compounds XPA-1273, XPA-1274, XPA-1275, XPA-1276, and XPA-1292.

[0071] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they are = O, Y is -OH, and here R 2 , R 3 and R 4 These are each -H, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 It contains nine or more carbon atoms that are arbitrarily and independently substituted with heteroatoms selected from O, S, and N, as defined in general formula (I). And here, R 5 R is defined in general formula (I), including substituents and preferred definitions, where R 5 R is in the ortho position relative to the ether bond, however, 5 Unlike -H, And, R 6 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-2)

[0072] [ka]

[0073] And herein, the compound of structure (Ib-2) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, as well as for use in the treatment of immune system-related disorders, skin diseases, hyperproliferative disorders, and cancers including hematopoietic and blood system cancers such as leukemia and lymphoma, and cancers of the tongue. Examples include compounds XPA-1274 and XPA-1276.

[0074] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they are = O, Y is -OH, and here R 2 , R 3 and R 4 These are each -H, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 R is selected from ring, biring and triring structures, and here, 1 It comprises six or more carbon atoms that are arbitrarily and independently substituted with heteroatoms selected from O, S, and N, as defined in general formula (I). And here, R 5 R is defined in general formula (I), including substituents and preferred definitions, and where R 5 R is in the ortho position relative to the ether bond, however, 5 Unlike -H, And, R 6 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-3)

[0075] [ka]

[0076] And herein, the compound of structure (Ib-3) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, as well as for use in the treatment of immune system-related disorders, skin diseases, hyperproliferative disorders, and cancers including hematopoietic and blood system cancers such as leukemia and lymphoma, and cancers of the tongue. Examples include compounds XPA-1273, XPA-1274, XPA-1275, XPA-1276, and XPA-1292.

[0077] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they equal O, and here X 4 is N, and here Y is as defined in general formula (I), including substituents and preferred definitions, where Y is different from -H. And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 The structure is selected from ring, biring, and triring structures, or includes ring, biring, or triring structures, provided that R is optionally included. 1 It contains five or more carbon atoms that are arbitrarily and independently substituted with heteroatoms selected from O, S, and N, as defined in general formula (I). And, R 2 -R 11 and X 1 -X 3 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-4)

[0078] [ka]

[0079] And hereby, the compounds of structure (Ib-4) are preferred for use in human and veterinary medicine, in particular for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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 leukemia and lymphoma, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, ovary, and cancers of the neuroendocrine system. Examples include compounds XPA-1302, XPA-1303, XPA-1304, XPA-1305, XPA-1306, XPA-1322, XPA-1323, and XPA-1324.

[0080] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they equal O, and here X 2 CR 9 X 3 CR 10 And R 9 and R 10 These are -H respectively, and here, X 4 CR 8 And R 8 R is defined in general formula (I), including substituents and preferred definitions, where R 8 Unlike -H, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 R comprises six or more carbon atoms that are arbitrarily and independently substituted with heteroatoms selected from O, S, and N as defined in general formula (I), and where R contains any of the substituents. 1This may be a compound that does not contain heteroatoms or contains one, two, or three heteroatoms independently selected from O, S, and N. And here Y is as defined in general formula (I), including substituents and preferred definitions, except that Y is different from -H. And here, R 2 -R 7 , R 11 and X 1 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-5)

[0081] [ka]

[0082] And hereby, the compound of structure (Ib-5) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, as well as for use in 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, and cancers of the tongue and breast. Examples include compounds XPA-1334 and XPA-1335.

[0083] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they equal O, and here X 2 CR 8 And R 8 It is selected from -Br and -I, And here Y is as defined in general formula (I), including substituents and preferred definitions, where Y is different from -H, And here, R 1R is defined in general formula (I), including substituents and preferred definitions, where R 1 R comprises six or more carbon atoms that are arbitrarily and independently substituted with heteroatoms selected from O, S, and N as defined in general formula (I), provided that any substituent is present in R 1 It either contains no heteroatoms or contains one, two, three, or four heteroatoms independently selected from O, S, and N. And, R 2 -R 7 , R 9 -R 11 , X 1 , X 3 and X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-6)

[0084] [ka]

[0085] And hereby, the compound of structure (Ib-6) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, as well as for use in 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 cancers of the skin, tongue, and breast. Examples include compounds XPA-1299, XPA-1300, XPA-1320, and XPA-1321.

[0086] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they equal O, and here X 2 CR 8 And R 8 is -Br, And here, R1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 It comprises six or more carbon atoms that are arbitrarily and independently substituted with heteroatoms selected from O, S, and N, as defined in general formula (I). And, R 2 -R 7 , R 9 -R 11 , X 1 , X 3 , X 4 And Y, including substituents and preferred definitions, are as defined in general formula (I), And here, the compounds share the following structure (Ib-7)

[0087] [ka]

[0088] And hereby, the compound of structure (Ib-7) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, as well as for use in 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 cancers of the skin, tongue, and breast. Examples include compounds XPA-1299, XPA-1300, XPA-1301, XPA-1320, XPA-1321, and XPA-1344.

[0089] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they are = O, and here Y is -H, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 As defined in general formula (I), O, S It comprises six or more carbon atoms that are arbitrarily and independently substituted with heteroatoms selected from and N, and where R 1 The structure can be selected from ring, biring, and triring structures, however, R can be optionally selected. 1 Unlike unsubstituted cyclohexyl, And, R 2 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-8)

[0090] [ka]

[0091] And hereby, the compounds of structure (Ib-8) are preferred for use in human and veterinary medicine, in particular for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, cancers of the skin, tongue, lung, stomach, breast, and neuroendocrine system cancers. Examples include compounds XPA-0020, XPA-0028, XPA-0280, XPA-0511, XPA-0512, XPA-0524, XPA-0532, XPA-1283, XPA-1284, XPA-1285, XPA-1286, XPA-1298, XPA-1337, and XPA-1339.

[0092] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z 2 Together they are = O, and here Y is -H, And here, R 5 R is defined in general formula (I), including substituents and preferred definitions, where R5 R is in the ortho position relative to the ether bond, and here, 5 Unlike -H, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 R is selected from cyclic, bicyclic, and tricyclic structures, or includes cyclic, bicyclic, or tricyclic structures, provided that it optionally includes any of the substituents. 1 This may contain no heteroatoms or one, two, three, or four heteroatoms independently selected from O, S, and N. And, R 2 -R 4 , R 6 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-9)

[0093] [ka]

[0094] And hereby, the compounds of structure (Ib-9) are preferred for use in human and veterinary medicine, in particular for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, cancers of the skin, tongue, lung, stomach, breast, and cancers of the neuroendocrine system. Examples include compounds XPA-1283, XPA-1284, XPA-1285, XPA-1286, and XPA-1298.

[0095] In a further embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, where Z 1 and Z2 Together they equal O, And here, R 1 R is defined in general formula (I), including substituents and preferred definitions, where R 1 R is an unsubstituted or substituted cycloalkyl group, where any ring carbon atom may be independently substituted with a heteroatom selected from O, S, and N as defined in general formula (I), and where R contains any of the substituents. 1 is comprised of one or more heteroatoms independently selected from O, S, and N, where Y is as defined in general formula (I), including substituents and preferred definitions, where Y is different from -H, and further, however optionally Y is different from -OCH3. And, R 2 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ib-10)

[0096] [ka]

[0097] And hereby, the compound of structure (Ib-10) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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, and cancers of the skin, oral mucosa, tongue, lung and breast. Examples include compounds XPA-0035, XPA-0036, XPA-0037, XPA-0063, XPA-0064, XPA-0065, XPA-0079, XPA-0541, XPA-0569, XPA-1267, and XPA-1268.

[0098] In a further embodiment, the present invention relates to compounds of general formula (Ic) and their salts and solvates, where Z 1 and Z 2 They come together to form a cyclic residue containing carbon atoms to which they bond, and here, Z 1 and Z 2 The compound is defined in general formula (Ic), including substituents and preferred definitions, where the cyclic residue is a four-membered ring, and where the cyclic residue preferably contains one heteroatom selected from O, S, and N instead of a carbon atom, and / or where the cyclic residue is preferably substituted as defined in general formula (I), provided that the cyclic residue is optionally not perhalated. And here Y is as defined in general formula (I), including substituents and preferred definitions, where Y is different from -H, And, R 1 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ic-1)

[0099] [ka]

[0100] And hereby, the compounds of structure (Ic-1) are preferred for use in human and veterinary medicine, in particular for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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 leukemia and lymphoma, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-0132, XPA-0140, XPA-0146, XPA-0154, XPA-0160, XPA-0168, XPA-0174, XPA-0182, XPA-0188, XPA-0196, XPA-0210, XPA-0230, XPA-0238, XPA-0644, XPA-0658, XPA-0672, XPA-1308, XPA-1309, XPA-1310, XPA-1311, XPA-1312, XPA-1313, XPA-1315, XPA-1316, XPA-1317, XPA-1318, and XPA-1331.

[0101] In a further embodiment, the present invention relates to compounds of general formula (Ic) and their salts and solvates, where Z 1 and Z 2 They come together to form a cyclic residue containing carbon atoms to which they bond, and here, Z 1 and Z 2 The substituents and preferred definitions are as defined in general formula (Ic), And here Y is as defined in general formula (I), including substituents and preferred definitions, where Y is different from -H, and further, however Y is optionally different from -OH and -OCH3, And, R 1 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ic-2)

[0102] [ka]

[0103] And hereby, the compound of structure (Ic-2) is preferred for use in human and veterinary medicine, particularly for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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 leukemia and lymphoma, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-0132, XPA-0140, XPA-0146, XPA-0154, XPA-0160, XPA-0168, XPA-0174, XPA-0182, XPA-0188, XPA-0196, XPA-0210, XPA-0230, XPA-0238, XPA-0644, XPA-0658, XPA-0672, XPA-1308, XPA-1309, XPA-1310, XPA-1311, XPA-1312, XPA-1313, XPA-1315, XPA-1316, XPA-1317, XPA-1318, and XPA-1331.

[0104] In a further embodiment, the present invention relates to compounds of general formula (Ic) and their salts and solvates, where Z 1 and Z 2 They come together to form a cyclic residue containing carbon atoms to which they bond, and here, Z 1 and Z 2 It is defined in general formula (Ic), including substituents and preferred definitions, where the cyclic residue is not perhalated. And here, Y is -OH, And here, R 1 It is defined in general formula (I), including substituents and preferred definitions, provided that R is optionally included. 1 It contains two or more carbon atoms, And, R 2 -R 11 and X 1 -X 4It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ic-3)

[0105] [ka]

[0106] And hereby, the compounds of structure (Ic-3) are preferred for use in human and veterinary medicine, in particular for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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 leukemia and lymphoma, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-0132, XPA-0140, XPA-0174, XPA-0182, XPA-0644, XPA-1308, XPA-1309, XPA-1312, and XPA-1313.

[0107] In a further embodiment, the present invention relates to compounds of general formula (Ic) and their salts and solvates, where Z 1 and Z 2 They come together to form a cyclic residue containing carbon atoms to which they bond, and here, Z 1 and Z 2 This includes substituents and preferred definitions. Furthermore, as defined in general formula (Ic), however, the cyclic residue may differ from oxiranil. And here, Y is -OCH3, And, R 1 -R 11 and X 1 -X 4 It is defined in general formula (I), including substituents and preferred definitions, And here, the compounds share the following structure (Ic-4)

[0108] [ka]

[0109] And hereby, the compounds of structure (Ic-4) are preferred for use in human and veterinary medicine, in particular for medical use as described in the present invention, preferably in immune system-related applications including immunotherapy and other immunotherapies as defined in the present invention, and for use in 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 leukemia and lymphoma, cancers of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancers of the neuroendocrine system. Examples include compounds XPA-0146, XPA-0154, XPA-0188, XPA-0196, XPA-0230, XPA-0238, XPA-0658, XPA-1310, XPA-1311, XPA-1315, and XPA-1316.

[0110] In some embodiments, the following compounds, shown in Tables 1 to 3, are expressly excluded from the scope of the invention.

[0111] The compounds in Table 1, specifically identified by their CAS registry numbers, were identified by the inventors skilled in the art. In embodiments in which these compounds are included in general formula (I) or any of the subgeneral formulas 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, these compounds are not known for any medical use. That is, the present invention encompasses any medical use of the compounds in Table 1.

[0112] [Table 1-1]

[0113] [Table 1-2]

[0114] [Table 1-3]

[0115] [Table 1-4]

[0116] The compounds in Table 2, specifically identified by their CAS registry numbers, were identified by the inventors skilled in the art. In embodiments in which these compounds are included in general formula (I) or any of the subgeneral formulas defined herein, they are expressly excluded from the scope of the invention with respect to compound protection. To the best of the inventors' knowledge, these compounds are not known for any medical use as defined in the invention. That is, the compounds in Table 2 are expressly included in the scope of the invention with respect to medical uses as defined in the invention, particularly in the treatment of non-malignant or malignant hyperproliferative diseases.

[0117] [Table 2]

[0118] The compounds in Table 3, specifically identified by their CAS registry numbers, were identified by the inventors skilled in the art. In embodiments in which these compounds are included in general formula (I) or any of the subgeneral formulas defined herein, they are expressly excluded from the scope of the invention with respect to compound protection. Furthermore, these compounds are known to the inventors for medical uses, and such uses may, in some embodiments, be included in the medical uses defined herein. That is, the compounds in Table 3 may be expressly excluded from the scope of the invention with respect to compound protection and certain medical uses in some embodiments defined herein.

[0119] [Table 3-1]

[0120] [Table 3-2]

[0121] Specific examples of compounds that fall within the scope of compounds included in the pending application PCT / EP2018 / 054686 have been confirmed in this application to have novel medical applications and, in particular, to possess growth inhibitory properties against keratinocytes and cells and malignant cells selected from cutaneous T-cell lymphoma and acute promyelocytic leukemia. In other words, these compounds, together with their salts and solvates, are particularly suitable for the treatment of hyperproliferative skin diseases as defined herein, as well as hematopoietic disorders, including vascular and immune system-related disorders such as cutaneous T-cell lymphoma and acute promyelocytic leukemia as defined herein.

[0122] Specific examples of compounds that fall within the scope of compounds included in the pending application PCT / EP2018 / 054686 have been further identified in this application as having novel medical applications and possessing growth inhibitory properties against cells and malignant cells selected from T-cell leukemia, B-cell leukemia, gastric cancer, breast cancer, ovarian cancer, epidermal squamous cell carcinoma, oral and lingual squamous cell carcinoma, lung squamous cell carcinoma, acute myeloid leukemia, and muscle cells. In other words, these compounds, together with their salts and solvates, are particularly suitable for the treatment of hematopoietic diseases, including blood disorders such as T-cell leukemia, B-cell leukemia, gastric cancer, breast and ovarian cancer, epidermal carcinomas such as non-melanoma skin cancer, oral cancer, tongue cancer, lung cancer, acute myeloid leukemia, and hyperproliferative muscle diseases, as defined herein.

[0123] Tables 4 and 5 show novel medical uses identified herein for specific compounds that fall within the scope of compounds contained in the pending application PCT / EP2018 / 054686, where such medical uses are selected from the treatment of hyperproliferative cutaneous diseases (A), cutaneous T-cell lymphoma (B), acute promyelocytic leukemia (C), T-cell leukemia (D), B-cell leukemia (E), gastric cancer (F), breast cancer (G), ovarian cancer (H), epidermal carcinoma (I), tongue cancer (J), lung cancer (K), acute myeloid leukemia (L), oral cancer (M), and hyperproliferative muscular diseases (N) as defined herein.

[0124] The following compounds, as listed in PCT / EP2018 / 054686, are specifically claimed for the indicated medical use.

[0125] [Table 4]

[0126] The following compounds, as listed in PCT / EP2018 / 054686, are specifically claimed for the indicated medical use.

[0127] [Table 5]

[0128] Tables 6 to 29 show specific examples of compounds that fall within the range of formula (I). The intermediate is denoted as "XPA-I".

[0129] [Table 6]

[0130] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0131] [Table 7]

[0132] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0133] [Table 8]

[0134] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0135] [Table 9]

[0136] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0137] [Table 10]

[0138] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0139] [Table 11]

[0140] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0141] [Table 12]

[0142] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0143] [Table 13]

[0144] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0145] [Table 14]

[0146] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0147] [Table 15]

[0148] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0149] [Table 16]

[0150] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0151] [Table 17]

[0152] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0153] [Table 18]

[0154] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0155] [Table 19]

[0156] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0157] [Table 20]

[0158] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0159] [Table 21]

[0160] The table above lists each of the compounds specifically shown therein, as well as their salts and solvents. Japanese items constitute individual descriptions.

[0161] [Table 22]

[0162] The table above provides individual descriptions of the compounds specifically shown therein, as well as their salts and solvates, and the intermediates used in the synthesis of the compounds specifically shown therein, as well as their salts and solvates. Such intermediates, as well as their salts and solvates, are also part of the present invention and are within the framework of the process for producing the final compound.

[0163] [Table 23]

[0164] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates, and of the intermediates used in the synthesis of the compounds specifically shown, as well as their salts and solvates. Such intermediates, as well as their salts and solvates, are also part of the present invention and are within the framework of the process for producing the final compound.

[0165] [Table 24]

[0166] The table above provides individual descriptions of the compounds specifically shown therein, as well as their salts and solvates.

[0167] [Table 25]

[0168] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates, and of the intermediates used in the synthesis of the compounds specifically shown, as well as their salts and solvates. Such intermediates, as well as their salts and solvates, are also part of the present invention and are within the framework of the process for producing the final compound.

[0169] [Table 26]

[0170] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0171] [Table 27]

[0172] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0173] [Table 28]

[0174] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0175] [Table 29]

[0176] The table above provides individual descriptions of each of the compounds specifically shown therein, as well as their salts and solvates.

[0177] This also includes isomers of the aforementioned compounds, such as enantiomers or diastereomers or mixtures of isomers, salts, especially pharmaceutically acceptable salts, and solvates.

[0178] [Further Definitions] "C1-C 12The term "alkyl" includes all isomers of the corresponding saturated aliphatic hydrocarbon group containing 1 to 12 carbon atoms; this includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, iso-pentyl, 2-methylbutan-2-yl, 3-methylbutan-2-yl, all hexyl isomers, all heptyl isomers, all octyl isomers, all nonyl isomers, all decyl isomers, all undecyl isomers, and all dodecyl isomers. "C2-C 12 The term “alkenyl” encompasses all isomers of the corresponding unsaturated olefinic hydrocarbon group containing 2 to 12 carbon atoms linked by one or more double bonds (i.e., including); 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. "C2-C 12 The term “alkynyl” includes all isomers of the corresponding unsaturated acetylene hydrocarbon group containing 2 to 12 carbon atoms linked by one or more triple bonds (i.e., including); this includes ethynyl, all propynyl isomers, all butynyl isomers, all pentynyl isomers, all hexynyl isomers, all heptynyl isomers, all octinyl isomers, all noninyl isomers, all desynyl 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. The term "C3-C8 cycloalkyl" refers to a corresponding saturated hydrocarbon group containing 3 to 8 carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C5-C8 cycloalkenyl" implies that at least one of them is sp 3It is hybrid and contains corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups comprising 5 to 8 carbon atoms arranged in a monocyclic ring structure and linked by one or more double bonds (i.e., including); this includes all cyclopentenyl isomers, all cyclohexenyl isomers, all cycloheptenyl isomers, and all cyclooctenyl isomers. "C5-C 12 The term "bicycloalkyl" includes a corresponding saturated hydrocarbon group containing 5 to 12 carbon atoms arranged in a bicyclic ring structure; where these bicyclic ring structures include condensation, crosslinking, and spiro systems. "C7-C 12 The term “bicycloalkenyl” includes corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups that are arranged in a bicyclic ring structure and contain 7 to 12 carbon atoms linked by one or more double bonds (i.e., including); where these bicyclic ring structures include condensation, bridging, and spiro systems. "C8-C 14 The term "tricycloalkyl" refers to a corresponding saturated hydrocarbon group containing 8 to 14 carbon atoms arranged in a tricyclic ring structure; where these tricyclic ring structures include condensation, crosslinking, and spiro systems. R 1 The terms “cyclic,” “bicyclic,” “tricyclic,” “cycloalkyl,” “cycloalkenyl,” “bicycloalkyl,” “bicycloalkenyl,” and “tricycloalkyl” mean that such cyclic, bicyclic, or tricyclic residues are directly bonded by a chemical bond to the aromatic ring to which R1 is attached. 1 The terms "cyclic," "bicyclic," "tricyclic," "cycloalkyl," "cycloalkenyl," "bicycloalkyl," and "tricycloalkyl" refer to substituents such as cyclic, bicyclic, or tricyclic residues that are chemically bonded by R 1 This means that it is directly bonded to one of the C, N, O, or S atoms contained in it; for example, "R 1 "It is cyclohexyl" means that the cyclohexyl residue is R 1 This means that it is bonded to the aromatic ring to which it is bonded; "R1 is methyl, and R 1 " is substituted with cyclohexyl" means that the resulting -CH2 (cyclohexyl) residue is R 1 This means that it is bonded to the aromatic ring to which it is bonded. When a carbon atom is substituted with a heteroatom selected from O, N, or S, the number of substituents on each heteroatom is adjusted according to its valence. For example, the -CR2- group can have -NR-, -NR2 + -, -O-, or -S- groups may be substituted. The term "perhalogenation" relates to the thorough halogenation of a carbon scaffold; the corresponding residues include the corresponding perfluorinated, perchlorinated, perbrominated, and periodinated groups. Preferably, the term "perhalogenation" relates to a perfluorinated or perchlorinated group, more preferably a perfluorinated group.

[0179] The following includes definitions of terms used in this specification. The first definition provided for a base or term in this specification applies throughout this specification, either individually or as part of another base, unless otherwise indicated. The compounds of the present invention may also form salts, which is also within the scope of the invention. References to the compounds of the present invention herein, unless otherwise indicated, are understood to include references to their salts. As used herein, the term “salt” refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Zwitterions (internal or inner salts) are included in the term “salt” as used herein (and may be formed, for example, when substituents include an acidic moiety such as a carboxyl group and an amino group). Quaternary ammonium salts, such as alkylammonium salts, are also included herein. Salts of compounds may be formed, for example, by reacting the compound with an equal amount of acid or base in an aqueous medium, such as a medium on which the salt precipitates, or in an aqueous medium with subsequent lyophilization. Exemplary salts resulting from the addition of acid include acetates (such as those formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid), adipines, alginates, ascorbicates, aspartates, benzoates, benzenesulfons, bisulfates, borates, butyrates, citrates, camphorates, camphor sulfons, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfons, fumarates, glucoheptanates, glycerophosphates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobroms, and iodine. This includes hydrochlorides, chlorates, bromates, iodates, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectins, persulfates, 3-phenylpropionates, phosphates, picrinates, pivaphosphates, propions, salicylates, succinates, sulfates (such as those formed by sulfuric acid), sulfonates (such as those described herein), tartrates, thiocyans, tosylates, toluenesulfonates, undecanoates, and the like. Exemplary salts resulting from the addition of a base (e.g., formed when 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, dicyclohexylamine, hydravamin, N-methyl-D-glucamine, N-methyl-D-glucamide, and tert-butylamine, and salts with amino acids such as arginine and lysine. The basic nitrogen-containing group may be quaternized with reagents 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, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), and aralkyl halides (e.g., benzyl and phenethyl bromides). The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” means a derivative of a disclosed compound in which the parent compound is modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in the form of free acids or bases with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof; generally, ether, ethyl acetate, ethanol, isopropanol or acetate. A non-aqueous medium such as tonitrile is preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, PA., 1985, p.1418 and Journal of Pharmaceutical Science 1977, 66(2), each of which is incorporated herein by reference in its entirety. The phrase "pharmaceutically acceptable" is used herein to mean a compound, material, composition and / or dosage form that, within the bounds of sound medical judgment, is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications, and that is commensurate with a reasonable benefit / risk ratio. Furthermore, in the case of compounds of the present invention containing a chiral carbon atom or atropisomer bond, the present invention relates to D-type, L-type and D,L mixtures, and also to diastereomer forms when one or more chiral carbon atoms or atropisomer bonds are present. These compounds of the present invention, which contain a chiral carbon atom or atropisomer bond and generally occur as racemates, can be separated into optically active isomers by known methods, for example, using an optically active acid. However, it is also possible to use optically active starting materials from the outset, in which case the corresponding optically active or diastereomer compound is obtained as the final product. The compounds of the present invention also include tautomers. Tautomers arise from the exchange of a single bond with an adjacent double bond, accompanied by the simultaneous transfer of a proton. Tautomers include prototropic tautomers, which are the protonated states of isomers having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H- and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers may be in equilibrium or sterically fixed into one form by appropriate substitution. The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods relating to how to prepare optically active forms from optically active starting materials are known in the art, such as by the division of racemic mixtures or by stereoselective synthesis. Many geometric isomers, such as olefins and C=N double bonds, may also exist in the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomers. The compounds of the present invention may also contain all isotopes of the atoms that occur in the intermediate or final compound. Isotopes consist of atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. The present invention also includes solvates and hydrates of the compounds of the present invention, as well as solvates and hydrates of pharmaceutically acceptable salts thereof. As used herein, the term “compound” is intended to include all stereoisomers, geometric isomers, tautomers, rotatomers, and isotopes of the given structure, unless otherwise indicated. In some embodiments, the compound may be provided as a prodrug. As used herein, the term “prodrug” refers to a compound that, upon administration to a subject, undergoes a chemical transformation by metabolism or a chemical process to produce the compound of the present invention or a salt and / or solvate thereof. In some embodiments, the compounds of the present invention and their salts are substantially isolated. “Substantially isolated” means that the compounds are at least partially or substantially separated from the environment in which they were formed or detected. Partial isolation is, for example, in the present invention. The compounds may include compositions rich in the compounds. Substantial separation may include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds of the present invention or salts thereof.

[0180] [Pharmaceutical Methods] The compounds of the present invention have been found to possess pharmacologically important properties that make them therapeutically usable. The compounds of the present invention can be used alone, in combination with each other, or in combination with other active compounds. In some embodiments, the compounds of the present invention may exhibit growth-inhibiting properties during the overgrowth process. The antiproliferative activity of the compounds in formulas (1a), (lb), and (Ic) was investigated in cells or cell lines derived from the hematopoietic system, including bone marrow cell compartments and lymphoid cell compartments (T cells and B cells), the neuroendocrine system, the cervix, breast, ovary, lung, gastrointestinal tract, and mucosal epithelium, as well as cutaneous epithelium and muscle. For this purpose, 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 representative dermal keratinocytes (HPEK), and C2C12 cells were seeded in 96-well plates suitable for fluorescence assay (CORNING #3598) at the following initial cell counts. For HL-60, 1000 cells per well; for NB-4, 1000 cells per well; for HH, 5000 cells per well; for RPMI-8402, 5000 cells per well; for TANOUE, 1500 cells per well; for TT, 9000 cells per well; for HeLa, 2000 cells per well; for MDA-MB-231, 3000 cells per well; for FU-OV-1, 3000 cells per well; for L0U-NH91, 4000 cells per well; for 23132 / 87, 2000 cells per well; for CAL-27, 2000 cells per well; for BHY, 1500 cells per well; for SCC-25, 1500 cells per well; for A-431, 700 cells per well; for HPEK, 1000 cells per well; for C2C12, 500 cells per well. Cells were treated for 5 days with the indicated final concentration of the compound (diluted from a 1000x stock solution in DMSO to a final DMSO concentration of 0.1% v / v in H2O (Water for Injection, WFI, Fishers Scientific #10378939)) or with an empty carrier containing 0.1% v / v DMSO as a control. On day 5 after the start of treatment, cells were subjected to the alamarBlue® proliferation assay (Bio-Rad Serotec GmbH, BUF012B) according to the manufacturer's protocol.Readouts were performed using a fluorescence mode multiwell plate reader with filters applied for excitation at 560 nm (bandwidth 10 nm) and emission at 590 nm (bandwidth 10 nm). Control treatments for growth inhibition with commercially available compounds such as methotrexate (MTREX) and resveratrol (RES) were included in all plates. Some of the test compounds of the present invention were obtained as their salts and applied directly. Corresponding cases are shown in the "Specifications" column of Tables 30 to 62, and the complete molecular formulas are shown in Table 63. The assay was performed with two or more replications of independent single experiments, each including six replications for all conditions. For each individual plate, the measured fluorescence intensity values ​​for the compound-treated conditions were normalized to the corresponding equally weighted arithmetic mean of the fluorescence intensity values ​​of the six DMSO-treated control wells to obtain relative values ​​to a baseline level of 1.0. Two independent outlier analyses were performed following the Peirce and Chauvenet method (Ross, Journal of Engineering Technology 2003, 1-12). Outliers identified by at least one method were excluded from the calculation. However, within a single experiment, the value was less than one out of six for each compound. The weighted arithmetic mean (AVE) of each compound was used. W The standard deviation corresponding to the weighted arithmetic mean was calculated from the normalized values ​​of all independent reproductions of a single experiment, each containing six reproductions. The standard deviation was calculated according to the method described by am Main and Thun, and combined with Gaussian error propagation associated with the calculations performed for normalization. The resulting standard deviation is referred to herein as the "combined standard deviation". If there was significant variation in the normalized, equally weighted arithmetic mean obtained from two independent reproductions, the number of independent reproductions was increased to three or more. For four or more independent reproductions, a second outlier analysis was applied to all normalized, equally weighted arithmetic means according to the Peirce-Chauvenet method described above. In some embodiments, the compounds of the present invention may be growth inhibitors in overgrowth processes, including malignant and non-malignant overgrowth processes. In one embodiment, several compounds of the present invention were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia cells), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC3. HL-60 cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered an HL-60 cell growth inhibitor if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, 0.7, 0.6, 0.4, and 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, similar to the calculation performed for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a), (1b), and (1c), respectively, were identified as growth inhibitors of HL-60 cells. The HL-60 growth inhibitors identified to date are those listed in Tables 30 and 31. The entries in Tables 30 and 31 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0181] [Table 30-1]

[0182] [Table 30-2]

[0183] [Table 31]

[0184] The data in Table 30 pertains to novel compounds, while the data in Table 31 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of NB-4 cells (human acute promyelocytic leukemia cells) available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 207. NB-4 cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered an NB-4 cell growth inhibitor if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1b) and (1c), respectively, were identified as NB-4 cell growth inhibitors. The NB-4 growth inhibitors identified to date are those listed in Tables 32 and 33. The entries in Tables 32 and 33 are, without considering their respective standard deviations, therefore They are classified by the corresponding weighted arithmetic mean of compounds that fall within the indicated activity range.

[0185] [Table 32-1]

[0186] [Table 32-2]

[0187] [Table 33]

[0188] The data in Table 32 pertains to novel compounds, while the data in Table 33 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of HH cells (human cutaneous T-cell lymphoma cells) available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 707. The HH cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered an HH cell growth inhibitor if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, 0.7, 0.6, 0.4, and 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. According to the method described above, the formulas defined herein by formulas (1b) and (1c), respectively. Several molecules falling within the compound range have been identified as HH cell growth inhibitors. The HH growth inhibitors identified to date are those listed in Tables 34 and 35. Entries in Tables 34 and 35 are classified by the corresponding weighted arithmetic mean of the compounds falling within the indicated activity range, without considering their respective standard deviations.

[0189] [Table 34]

[0190] [Table 35]

[0191] The data in Table 34 pertains to novel compounds, while the data in Table 35 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. 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), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 290. RPMI-8402 cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered a growth inhibitor of RPMI-8402 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a), (1b), and (1c), respectively, were identified as growth inhibitors of RPMI-8402 cells. The RPMI-8402 growth inhibitors identified to date are those listed in Tables 36 and 37. The entries in Tables 36 and 37 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0192] [Table 36-1]

[0193] [Table 36-2]

[0194] [Table 36-3]

[0195] [Table 37]

[0196] The data in Table 36 pertains to novel compounds, while the data in Table 37 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of TANOUE cells (human B-cell leukemia cells), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 399. TANOUE cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). The compound exhibits normalized fluorescence at a reference concentration of 20 μM, after adding the corresponding binding standard deviations. A compound is considered a growth inhibitor of TANOUE cells if the weighted arithmetic mean of the intensity values ​​is 0.9 or less relative to the overall reference level of 1.0, and especially if it is 0.8 or less, 0.7 or less, 0.6 or less, 0.4 or less, and 0.2 or less. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding combined standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a), (1b), and (1c), respectively, were identified as TANOUE cell growth inhibitors. The TANOUE growth inhibitors identified to date are those listed in Tables 38 and 39. The entries in Tables 38 and 39 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0197] [Table 38-1]

[0198] [Table 38-2]

[0199] [Table 39]

[0200] The data in Table 38 pertains to novel compounds, while the data in Table 39 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of MDA-MB-231 cells (human breast cancer cells), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 732. MDA-MB-231 cells were cultured at 37°C and 0% CO2 in Leibovitz's L-15 medium (without phenol red) (Fisherscientific, #11540556) containing 10% fetal bovine serum (Fisherscientific, #15517589). The compound, at a reference concentration of 20 μM, has a weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations, which is 0.9 or less relative to the overall reference level of 1.0, and particularly 0.8 or less. Values ​​of 0.7 or less, 0.6 or less, 0.4 or less, and 0.2 or less are considered to be growth inhibitors of MDA-MB-231 cells. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding combined standard deviation for DMSO values ​​is 1.10 -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a), (1b), and (1c), respectively, were identified as growth inhibitors of MDA-MB-231 cells. The MDA-MB-231 growth inhibitors identified to date are those listed in Tables 40 and 41. The entries in Tables 40 and 41 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0201] [Table 40-1]

[0202] [Table 40-2]

[0203] [Table 41]

[0204] The data in Table 40 pertains to novel compounds, while the data in Table 41 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of FU-OV-1 cells (human ovarian cancer cells), 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). A compound is considered a growth inhibitor of FU-OV-1 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1b) and (1c), respectively, were identified as growth inhibitors of FU-OV-1 cells. The FU-OV-1 growth inhibitors identified to date are those listed in Tables 42 and 43. The entries in Tables 42 and 43 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0205] [Table 42]

[0206] [Table 43]

[0207] The data in Table 42 pertains to novel compounds, while the data in Table 43 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. 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), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 393. LOU-NH91 cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). The compound, at a reference concentration of 20 μM, has a weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations, which is 0.9 or less relative to the overall reference level of 1.0, and particularly 0.8 or less. Values ​​of 0.7 or less, 0.6 or less, 0.4 or less, and 0.2 or less are considered growth inhibitors of LOU-NH91 cells. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding combined standard deviation for DMSO values ​​is 1.10 -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1b) and (1c), respectively, were identified as growth inhibitors of LOU-NH91 cells. The LOU-NH91 growth inhibitors identified to date are those listed in Tables 44 and 45. The entries in Tables 44 and 45 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0208] [Table 44]

[0209] [Table 45]

[0210] The data in Table 44 pertains to novel compounds, while the data in Table 45 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of 23132 / 87 cells (human gastric adenocarcinoma cells), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 201. The 23132 / 87 cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered a growth inhibitor of 23132 / 87 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a), (1b), and (1c), respectively, were identified as growth inhibitors of 23132 / 87 cells. The 23132 / 87 growth inhibitors identified to date are those listed in Tables 46 and 47. The entries in Tables 46 and 47 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0211] [Table 46]

[0212] [Table 47]

[0213] The data in Table 46 pertains to novel compounds, while the data in Table 47 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. 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), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 446. CAL-27 cells were cultured at 37°C and 5% CO2 in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered a growth inhibitor of CAL-27 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly less than or equal to 0.8, 0.7, 0.6, 0.4, and 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a) and (1b), respectively, were identified as CAL-27 cell growth inhibitors. The CAL-27 growth inhibitors identified to date are those listed in Table 48. The entries in Table 48 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0214] [Table 48]

[0215] In one embodiment, several compounds of the present invention were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells), available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 404. The BHY cells were cultured at 37°C and 5% CO2 in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). If the compound inhibits BHY cell growth when, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is 0.9 or less relative to the overall reference level of 1.0, and especially when it is 0.8 or less, 0.7 or less, 0.6 or less, 0.4 or less, and 0.2 or less. It is considered a harmful agent. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as well as the calculation performed for the test compound. The corresponding combined standard deviation for DMSO values ​​is 1.10 -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a), (1b), and (1c), respectively, were identified as BHY cell growth inhibitors. The BHY growth inhibitors identified to date are those listed in Tables 49 and 50. The entries in Tables 49 and 50 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0216] [Table 49]

[0217] [Table 50]

[0218] The data in Table 49 pertains to novel compounds, while the data in Table 50 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. 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), 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). A compound is considered a growth inhibitor of SCC-25 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formula (1b) were identified as growth inhibitors of SCC-25 cells. The SCC-25 growth inhibitors identified to date are those listed in Tables 51 and 52. The entries in Tables 51 and 52 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0219] [Table 51]

[0220] [Table 52]

[0221] The data in Table 51 pertains to novel compounds, while the data in Table 52 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of A-431 cells (human epidermal squamous cell carcinoma cells), available from Cell Lines Service GmbH (CLS) under accession number 300112. The A-431 cells were cultured at 37°C and 5% CO2 in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered an A-431 cell growth inhibitor if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a) and (1b), respectively, were identified as growth inhibitors of A-431 cells. The A-431 growth inhibitors identified to date are those listed in Tables 53 and 54. The entries in Tables 53 and 54 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0222] [Table 53]

[0223] [Table 54]

[0224] The data in Table 53 pertains to novel compounds, while the data in Table 54 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of human epidermal keratinocyte progenitor cells (HPEKp, pooled) available from CELLnTEC Advanced Cell Systems AG under accession number HPEKp. HPEKp cells were cultured at 37°C and 5% CO2 in CnT-Prime epithelial culture medium (CELLnTEC, #CnT-PR, a well-defined low-calcium formulation, completely free of animal or human-derived components) without the addition of any additional components. The compound, at a reference concentration of 10 μM, has a weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations, which is 0.9 or less, and particularly 0.8 or less, relative to the overall reference level of 1.0. Values ​​of 0.7 or less, 0.6 or less, 0.4 or less, and 0.2 or less are considered to be HPEKp cell growth inhibitors. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding combined standard deviation for DMSO values ​​is 1.10 -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a) and (1b), respectively, were identified as HPEKp cell growth inhibitors. The HPEKp growth inhibitors identified to date are those listed in Tables 55, 56, and 57. The entries in Tables 55, 56, and 57 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0225] [Table 55-1]

[0226] [Table 55-2]

[0227] [Table 55-3]

[0228] [Table 56]

[0229] [Table 57-1]

[0230] [Table 57-2]

[0231] The data in Table 55 pertains to novel compounds, while the data in Tables 56 and 57 pertains to PC This relates to novel medical applications of compounds disclosed in T / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of C2C12 cells (mouse myoblasts) available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 565. The C2C12 cells were cultured at 37°C and 5% CO2 in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered a growth inhibitor of C2C12 cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a) and (1b), respectively, were identified as C2C12 cell growth inhibitors. The C2C12 growth inhibitors identified to date are those listed in Tables 58 and 59. The entries in Tables 58 and 59 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0232] [Table 58-1]

[0233] [Table 58-2]

[0234] [Table 59]

[0235] The data in Table 58 pertains to novel compounds, while the data in Table 59 pertains to novel medical applications of compounds disclosed in PCT / EP2018 / 054686. In one embodiment, several compounds of the present invention were found to inhibit the growth of TT cells (human medullary thyroid carcinoma cells) available from the American Type Culture Collection (ATCC) under accession number ATCC-CRL-1803. The TT cells were cultured at 37°C and 5% CO2 in F-12K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589). A compound is considered a growth inhibitor of TT cells if, at a reference concentration of 20 μM, the weighted arithmetic mean of normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, 0.7, 0.6, 0.4, and 0.2. The overall reference level was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements, as was done for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a), (1b), and (1c), respectively, were identified as TT cell growth inhibitors. The TT growth inhibitors identified to date are those listed in Table 60. The entries in Table 60 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0236] [Table 60]

[0237] In one embodiment, several compounds of the present invention were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells) available from the American Type Culture Collection (ATCC) under accession number ATCC-CCL-2. The HeLa cells were cultured in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2. A compound is considered a HeLa cell growth inhibitor if, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values ​​after adding the corresponding binding standard deviations is less than or equal to 0.9 relative to the overall reference level of 1.0, particularly if it is less than or equal to 0.8, less than or equal to 0.7, less than or equal to 0.6, less than or equal to 0.4, and less than or equal to 0.2. The overall reference level is the same as the calculation performed for the test compound. It was calculated as the weighted arithmetic mean of all normalized values ​​from DMSO control measurements. The corresponding combined standard deviation for DMSO values ​​is 1.10 -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formula (1c) were identified as HeLa cell growth inhibitors. The HeLa growth inhibitors identified to date are those listed in Table 61. The entries in Table 61 are classified by the corresponding weighted arithmetic mean of the compounds falling within the indicated activity range, without considering their respective standard deviations.

[0238] [Table 61]

[0239] In some embodiments, the compounds of the present invention may be modulators, particularly enhancers of notch signaling. Intercellular communication via Notch signaling (reviewed in Kopan et al., Cell 2009, 137, 216-233; Bray, Nat. Rev. Mol. Cell Biol. 2016, 17, 722-735) begins with a first step mediated by two types of transmembrane proteins. Notch receptors are distributed throughout the cell membrane of signal-receiving cells, while Notch ligands cover the membrane of signal-sending cells. Mechanistically, Notch signaling is activated by receptor-ligand interactions, which leads to the proteolytic release of the intracellular domain (NICD) of the membrane-bound Notch receptor into the signal-receiving cell. Subsequent translocation of the NICD to the nucleus leads, in turn, to the transcriptional activation of specific cell-type-specific genes. Notch-mediated changes in the cell's previous gene expression program manifest as corresponding cellular changes that represent the cell's response to Notch signaling. The activation level of Notch signaling can be reliably quantified in vitro by measuring the expression level of Notch-specific target genes. This can be achieved by quantifying the corresponding mRNA or protein of a specific Notch target gene. Alternatively, cells can be genetically modified to have a luciferase gene as an artificial Notch target gene, which is expressed in a Notch activity-dependent manner. In this setup, the Notch signaling level can be quantified by measuring the bioluminescence value derived from luciferase. A Notch-reporter assay, i.e., a luciferase-based luminescence readout, was used here to quantify the ability of the claimed compounds to enhance Notch signaling in the cell line. For this purpose, HeLa cells available from the American Type Culture Collection (ATCC) under accession number ATCC-CCL-2 were transfected using FuGENE® HD (Promega, #E2311) as the transfection reagent to express a membrane-tethered form of the constitutively active intracellular domain of the human Notch I receptor (h Notch IΔE) in an expression vector (BPS Bioscience, Notch Pathway) for activating the Notch signaling cascade. HeLa cells were transiently transfected for 24 hours with firefly luciferase expressed under the control of a Notch-responsive promoter for monitoring Notch signaling (BPS Bioscience, Notch Pathway Reporter Kit #60509, CSL luciferase reporter vector from component A, not pre-mixed with sea urchin luciferase vector), and sea urchin luciferase constitutively expressed in a Notch signaling-independent manner, including measurement of cell count per sample (Promega, pRL-SV40, #E2231). 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) with cells properly attached to plates in a total volume of 7 mL of medium at a cell density of 80-90%. For each transfected dish, a transfection mix was prepared by adding 40 μL of h-notch lΔE expression vector (100 ng / μL), 80 μL of CSL luciferase reporter vector (40 ng / μL), 4 μL of pRL-SV40-sea oyster luciferase vector (10 ng / μL), and in the final step, 18.1 μL of FuGENE® HD to 238 μL of Opti-MEM (Fisherscientific, #10149832). After adding FuGENE® HD, the transfection mix was allowed to stand at room temperature for 15 minutes, and then evenly distributed into the culture dishes. Twenty-four hours after transfection, the transfected cells were carefully detached from the dish using 0.5 mM EDTA in PBS and seeded at 10,000 cells per well in a 96-well plate (CORNING, #3610) suitable for reading luminescence.The cells were then incubated for 20 hours with the test compound at a final concentration of 10 μM (diluted from a 10 mM stock solution in DMSO to a final DMSO concentration of 0.1% v / v in H2O (Water for Injection, WFI, Fishers Scientific #10378939)) or with an empty carrier containing 0.1% v / v DMSO as a control. The cells were then washed once with PBS and lysed with 30 μL per well of Passive Lysis Buffer (Promega, #E194A, a component of the Dual-Luciferase® reporter assay system, #E1910) by gently shaking the plate in an orbital plate shaker for 20 minutes at room temperature. Immediately after lysis, the values ​​of firefly ciferase and then sea ciferase were measured sequentially from the same well using a luminescence reader, immediately after applying 15 μL of each of the corresponding enzyme substrates (Promega, Dual-Luciferase® reporter assay system, #E1910) required to generate the luminescence signal. The suitability of the assay for monitoring Notch signaling was controlled by including a commonly accepted commercially available Notch inhibitor, namely DAPT, as a negative control, and the 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 similarly tested at 10 μM. Within each single experiment, measurements were performed with six replicates for each compound. For all compounds, this experiment was repeated with at least three independent replicates. Notch reporter luciferase values ​​were normalized by division through the corresponding individual Notch-independent Notch values ​​to eliminate the influence of absolute cell number variability between samples. For each individual plate, a second normalization was performed against the equally weighted arithmetic mean (abbreviated here as AVE) of the six relevant Notch normalized DMSO control values ​​within the single experiment to obtain a relative value to the baseline level of 1.0. Statistical calculations were performed in the same manner as in the growth assay described above. For this purpose, the method of Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12) was used. Therefore, two independent outlier analyses were performed. Outliers identified by at least one method were excluded from the calculation, but there were no more than one out of six values ​​for each compound within a single experiment. The weighted arithmetic mean AVE for each compound was also excluded. W The standard deviation corresponding to the weighted arithmetic mean was calculated from the double-normalized values ​​of all independent reproductions of a single experiment, each including six reproductions. The standard deviation corresponding to the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Muehlig, Taschenbuch der Mathematik, 5th edition 2001 (in German), published by Verlag Harri Deutsch, Frankfurt am Main and Thun) and combined with Gaussian error propagation associated with the calculations performed for normalization. The resulting standard deviation is referred to herein as the "combined standard deviation". If there was significant variability in the double-normalized, equally weighted arithmetic mean obtained from three independent reproductions, the number of independent reproductions was increased to four or more. In the case of four or more independent reproductions, a second outlier analysis was applied to all double-normalized, equally weighted arithmetic means according to the Peirce-Chauvenet method described above. A compound is considered a notch signaling enhancer if its weighted arithmetic mean of luminescence values, after subtracting the corresponding binding standard deviation, is 1.1 or higher relative to the overall reference level of 1.0, particularly if it is 1.2 or higher, 1.3 or higher, 1.4 or higher, 1.5 or higher, 1.7 or higher, or 2.0 or higher. The overall reference level was calculated as the weighted arithmetic mean of all double-normalized values ​​from DMSO control measurements, similar to the calculation performed for the test compound. The corresponding binding standard deviation for DMSO values ​​is 1.10. -2 It is less than. Following the method described above, several molecules falling within the range of compounds defined herein by formulas (1a) and (1b), respectively, were identified as notch signaling enhancers. The notch enhancers identified to date are those listed in Table 62. The entries in Table 62 are classified by the corresponding weighted arithmetic mean of the compounds that thus fall within the indicated activity range, without considering their respective standard deviations.

[0240] [Table 62-1]

[0241] [Table 62-2]

[0242] According to the method described above, several other molecules were not identified as enhancers of notch signaling. In some cases, growth inhibition properties correlate with notch enhancement properties, while in other cases, growth inhibition properties do not correlate with notch enhancement properties. The biological activity of the claimed compound may be attributable to, but is not limited to, Notch signaling-enhancing activity. The Notch-regulating properties of the claimed compound can be used as an alternative to, or in combination with, mechanisms that produce antiproliferative effects in medical treatments, preferably in the treatment of hyperproliferative disorders, including cancer and non-malignant hyperproliferative disorders.

[0243] In one aspect, the present invention relates to the treatment of skin, skin appendages, mucous membranes, mucosal appendages, cornea, and all types of epithelial tissue. The term “skin” refers to tissues including the epidermis and dermis. The term “mucous membrane” refers to mucous membranes and submucosal tissues including oral mucosa, nasal mucosa, ocular mucosa, ear mucosa, respiratory mucosa, genital mucosa, urinary tract 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 or eccrine sweat glands, and mammary glands. In one embodiment, the present invention relates to the treatment of non-melanoma skin cancers and precancerous lesions such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), sebaceous carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, actinic keratosis (AK), or Bowen's disease (BD), as well as other squamous cell carcinomas and precancerous lesions, such as cutaneous SCC, lung SCC, head and neck SCC, oral SCC, tongue SCC, esophageal SCC, cervical SCC, periorbital SCC, thyroid SCC, penile SCC, vaginal SCC, prostate SCC, and bladder SCC. In further embodiments, the present invention relates to the treatment of skin and mucous membrane disorders involving keratosis (keratosis) and / or abnormal keratinocyte proliferation, such as psoriasis, Darier's disease, lichen planus, lupus erythematosus, ichthyosis, or senile warts. In further embodiments, the present invention relates to warts and HPV (human papillomavirus)-related warts, papillomas, HPV-associated papillomas, papillomatosis and HPV-associated papillomatosis, such as Verruca (plantar warts), Verruca plana (flat warts / planar warts), Verruca filiformis (filamentous warts), mosaic warts, perungual warts, subungual warts, oral warts, genital warts, fibroepithelial papilloma, intraductal papilloma, intratubular papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibroangiopapiloma, plexus papilloma, nasal papilloma, pharyngeal papilloma, papillomatosis cutaneous carcinoid, papillomatosis cutaneous lymphoid injection, confluent and reticular This relates to the treatment of papillomas or laryngeal papillomas (respiratory papillomas), herpes-related diseases such as oral herpes, genital herpes, herpes zoster, corneal herpes or Kaposi's sarcoma, and skin and mucous membrane diseases associated with and / or caused by viral infections, such as HPV-related cancers of the cervix, vulva, penis, vagina, anus, oropharynx, tongue and oral cavity, as well as skin and mucous membrane cancers. In further embodiments, the present invention relates to the treatment of atopic dermatitis. In further embodiments, the present invention relates to the treatment of acne. In further embodiments, the present invention relates to the treatment of skin wounds, in which the wound healing process is accelerated. In further embodiments, the present invention relates to the treatment of cancers associated with and / or caused by viral infections, i.e., tumor virus infections, such as cancers associated with HBV and HCV (hepatitis viruses B and C), such as liver cancer; cancers associated with EBV (Epstein-Barr virus), such as Burkitt lymphoma, Hodgkin and non-Hodgkin lymphoma and gastric cancer; cancers associated with HPV (human papillary carcinoma virus), such as cervical cancer; cancers associated with HHV (human herpesvirus), such as Kaposi's sarcoma; and cancers associated with HTLV (human T-lymphotrophic virus), such as T-cell leukemia and T-cell lymphoma. A further 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 vascular system, and in particular to pathological conditions of immune cells belonging to the congenital or acquired immune system. Examples include myeloid malignancies, including acute and chronic types of leukemia, such as chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), and acute promyelocytic leukemia (APL); or acute and chronic types of leukemia and lymphoma, such as T-cell acute lymphoblastic leukemia (T-ALL), T-cell preacute lymphoblastic leukemia (pre-T-ALL), cutaneous T-cell lymphoma, chronic lymphocytic leukemia (CLL), including T-cell CLL (T-CLL) and B-cell CLL (B-CLL), T-cell Examples include lymphatic malignancies, including prolymphocytic leukemia (PLL), including PLL (T-PLL) and B-cell PLL (B-PLL); B-cell acute lymphoblastic leukemia (B-ALL); B-cell preacute lymphoblastic leukemia (pre-B-ALL); cutaneous B-cell lymphoma; Hodgkin lymphoma; non-Hodgkin lymphoma; mantle cell lymphoma; myeloma; or hematopoietic disorders, including blood disorders such as acute lymphoblastic and acute myeloid mixed lineage leukemia with MLL gene translocation. A further aspect of the present invention relates to therapeutic use in immune system-related applications. As used herein, the term “immune system-related application” applies to interventions on the proliferation, differentiation, and / or activation of hematopoietic cell lineages, including the vascular system, for the purpose of modulating (immunomodulation) the immune response. As used herein, the term “immune system-related application” also applies to interventions on the cellular and non-cellular microenvironment of the site of action of immune cells for the purpose of supporting and / or enabling the performance of immune cells. In particular, interventions as defined herein by the term “immune system-related application” relate to immune cells belonging to the innate or acquired immune system. In other words, the compounds of the present invention may be used in immunotherapy, either alone or in combination with other immunotherapeutic methods or compounds, as immunological adjuvants, for example, as vaccine adjuvants or as adjuvants to immunotherapy. As used herein, the term “immunotherapy” is applied to activated immunotherapy in patients without immunodeficiency or with acquired or congenital immunodeficiency, as immune resuscitation that enhances the function of the immune system in response to pathogens such as cancer cells or pathologically transformed endogenous cells. As used herein, the term “other immunotherapies” applies to vaccination, antibody therapy, cytokine therapy, the use of immune checkpoint inhibitors and immune response stimulants, and autotransplantation of genetically modified or non-modified immune cells, which may be stimulated by intercellular signaling, or signaling molecules, or antigens, or antibodies, i.e., adoptive immune cell transfer. The methods of use of the present invention in immune system-related applications and other immunotherapies relate to in vivo, in vitro, and ex vivo applications, respectively. Specific examples include the activation and / or enhancement of peripheral T lymphocytes, including T helper cells and cytotoxic T cells, to stimulate the immune response, particularly cytokine proliferation and / or production and / or secretion, and / or to amplify cytotoxic agents at antigen recognition to amplify the immune response; the activation and / or enhancement of B lymphocytes to amplify the stimulation of the immune response, particularly proliferation and / or antibody production and / or secretion; and the enhancement of the immune response by increasing the number of specific immune cell subtypes to increase the number of immune cells belonging to T and B cell lines, particularly marginal zone B cells, cytotoxic T cells, or T helper (Th) subsets, particularly Thl, Th2, Thl7, and regulatory T cells, by regulating cell fate determination during differentiation and / or immune cell development; or use as an immune adjuvant, such as a vaccine adjuvant. Yet another aspect of the present invention relates to the treatment of muscular diseases, including diseases of skeletal muscle, cardiac muscle, and smooth muscle. In one embodiment, the present invention relates to the treatment of muscular dystrophy (MD). Specific examples include Duchenne MD, Becker MD, congenital MD, limb-girdle MD, facioscapulohumeral MD, Emery-Dreyfus MD, distal MD, myotonic MD, or oculopharyngeal MD. In further embodiments, the present invention relates to the treatment of myoblastoma, rhabdomyosarcoma and other muscle hyperproliferative disorders, as well as muscle hyperplasia and muscle hypertrophy. In further embodiments, the compounds of the present invention may be used, for example, for muscle regeneration after pathological muscle degeneration or atrophy caused by trauma, muscle ischemia, or inflammation in age-related muscle atrophy, or muscle atrophy associated with diseases such as myositis and fibromyositis or polio. Another aspect concerns the treatment of neuroendocrine disorders, such as neuroendocrine small cell carcinoma, neuroendocrine large cell carcinoma, and carcinoid tumors, including neuroendocrine tumors of the pituitary gland, neuroendocrine tumors of the adrenal gland, medullary thyroid carcinoma (MTC), C-cell hyperplasia, anaplastic thyroid carcinoma (ATC), parathyroid adenoma, intrathyroidal nodule, islet carcinoma, hyalinized trabecular neoplasm, paraganglioma, pulmonary carcinoid tumor, neuroblastoma, gastrointestinal carcinoid, goblet cell carcinoid, pancreatic carcinoid, gastrinoma, glucagenoma, somatic cell statinoma, VIPoma, insulinoma, non-functional islet cell tumor, multiple endocrine neoplasia type 1, or pulmonary carcinoid. Another aspect concerns the treatment of lung disorders, including lung cancers such as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), including squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. Another aspect is glioma, mixed glioma, glioblastoma multiforme, astrocytoma, undifferentiated astrocytoma, glioblastoma, oligodendroglioma, undifferentiated oligodendroglioma, undifferentiated oligoastrocytoma, ependymoma, undifferentiated ependymoma, myxopapillary ependymoma, subependymoma, brainstem glioma, optic glioma, as well as forebrain tumors, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic adenocyte carcinoma, pancreatic pseudopapillary neoplasm, intraductal papillary mucinous neoplasm, pancreatic This invention relates to the treatment of hyperproliferative diseases, cancers, or precancerous lesions of the brain, pancreas, breast, ovaries, liver, thyroid, genitourinary tract, gastrointestinal tract, and endothelial tissues, including visceral mucinous cystadenocarcinoma, pancreatic blastoma and pancreatic intraepithelial neoplasm, hepatocellular carcinoma, fibrous hepatocellular carcinoma, papillary thyroid carcinoma and follicular thyroid carcinoma, cervical cancer, hormone receptor-positive breast cancer and hormone receptor-negative breast cancer, ovarian cancer, gastric cancer, and angiosarcoma. The methods of use of the present invention relate to in vivo, in vitro, and ex vivo applications, respectively. As used herein, the terms “to treat” or “to cure” mean: 1) inhibiting a disease; for example, inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the symptoms or condition of a disease, condition or disorder (i.e., preventing further progression of the symptoms and / or condition); and (2) bringing a disease into remission; for example, bringing a disease, condition or disorder into remission in an individual experiencing or exhibiting the symptoms or condition of a disease, condition or disorder (i.e., reversing the symptoms and / or condition), such as reducing the severity of the disease; and (3) slowing the progression of a disease. The above applies. The term "treatment" also includes post-treatment care. In some embodiments, administration of the compound of the present invention or a pharmaceutically acceptable salt thereof is effective in preventing disease, for example, in individuals who may have a predisposition to disease, condition, or disorder but have not yet experienced or shown the pathology or symptoms of the disease. The compounds of the present invention may be used in human and veterinary medicine, including the treatment of companion animals such as horses, dogs, cats, rabbits, guinea pigs, fish such as carp, and birds such as falcons; as well as livestock such as cattle, poultry, pigs, sheep, goats, donkeys, yaks, and camels.

[0244] [Pharmaceutical composition] The present invention further provides pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof for use in medicine, for example, in human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier. The compounds of the present invention, or their salts, solvates, or prodrugs in effective dosages, are used in addition to physiologically acceptable carriers, diluents, and / or adjuvants for the preparation of pharmaceutical compositions. The dosage of the active compound may vary depending on the route of administration, the patient's age and weight, the nature and severity of the disease being treated, and similar factors. The daily dose can be given as a single dose administered at one time, or it can be divided into two or more daily doses, typically 0.001–2000 mg. A daily dose of 0.1–500 mg, for example, 0.1–100 mg, is particularly preferred. Appropriate forms of administration include infusion and infusion, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardiac, epidural, intracerebral, intraventricular, intraosseous, intraarticular, intraocular, intravitreous, intrathecal, intravaginal, intracavitary, intrabladder, subcutaneous, intradermal, transmucosal, inhalation, intranasal, oral, sublingual, and intrafocal formulations, including intestinal, oral, rectal, and parenteral formulations, and topical or systemic. It is particularly preferable to use oral, parenteral, for example, intravenous or intramuscular, or intranasal formulations of the compound of the present invention, such as dried powder or sublingual formulations. Conventional herbal drug formulations, such as tablets, sugar-coated tablets, capsules, dispersible powders, granules, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashes, foams, pastes, tinctures, skin patches and tapes, time-release drug delivery systems, electrophoretic skin delivery systems including implants and devices, and occlusion or combinations with jet injectors, liposomes and transfersome vesicles, vapors, sprays, syrups, juices, or intravenous and ophthalmic formulations may be used. Solid pharmaceutical forms may contain inactive ingredients and carrier materials such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginic acid, gelatin, guar gum, magnesium stearate, aluminum stearate, methylcellulose, talc, highly dispersed silicic acid, silicone oil, higher 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); formulations suitable for oral administration may contain additional flavorings and / or sweeteners as needed. Liquid pharmaceutical forms may be sterilized and / or, where appropriate, may contain auxiliary substances such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols, and / or viscosity modifiers to adjust or buffer osmotic pressure. Examples of such additives are tartaric acid and citrate buffer, ethanol, and chelating agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers such as liquid polyethylene oxide, microcrystalline cellulose, carboxymethylcellulose, polyvinylpyrrolidone, dextran, or gelatin are suitable for adjusting viscosity. Examples of solid carriers are starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular weight fatty acids (such as stearic acid), gelatin, agar, These are solid high molecular weight polymers such as calcium phosphate, magnesium stearate, animal and vegetable fats, and polyethylene glycol. Oily suspensions for parenteral or topical application may be vegetable, synthetic, or semi-synthetic oils, such as liquid fatty acid esters having 8 to 22 carbon atoms in the fatty acid chain in each case, including palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brassic acid, erucic acid, or oleic acid, esterified with monohydric to trihydric alcohols having 1 to 6 carbon atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol, or glycerol. Examples of such fatty acid esters include commercially available migliol, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG-6 capric acid, caprylic / capric acid esters of saturated aliphatic alcohols, polyoxyethylene glycerol trioleate, ethyl oleate, especially artificial ducktail gland fat, isopropyl coconut fatty acid esters, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, and waxy fatty acid esters such as polyol fatty acid esters. Silicone oils of different viscosities, or aliphatic alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetyl stearyl alcohol or oleyl alcohol, or fatty acids such as oleic acid are also suitable. It is also possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil. Suitable solvents, gelatinizers, and solubilizers are water or water-miscible solvents. Examples of suitable substances include alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycol, phthalates, adipates, propylene glycol, glycerol, di or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and cyclohexanone. Cellulose ethers such as hydroxypropyl methylcellulose, methylcellulose, or ethylcellulose, or soluble starch, which can dissolve or swell in both water and organic solvents, may be used as film-forming agents. Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, in particular, ionic polymers such as sodium carboxymethylcellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginic acid as sodium salts, gum arabic, xanthan gum, guar gum or carrageenan are used. The following may be used as further formulation aids: glycerol, paraffins of different viscosities, triethanolamine, collagen, allantoin and novantisolic acid. The use of surfactants, emulsifiers, or wetting agents, such as sodium lauryl sulfate, aliphatic alcohol ether sulfate, di-sodium-N-lauryl-beta-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbate (e.g., Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, cetyltrimethylammonium chloride, or mono / dialkyl polyglycol ether orthophosphate monoethanolamine salts, may also be required in the formulation. Stabilizers such as montmorillonite or colloidal silicic acid, such as tocopherol or butylhydroxyanisole, or preservatives such as p-hydroxybenzoic acid esters, to stabilize the emulsion or prevent the degradation of active substances such as antioxidants, may also be used to prepare the desired formulation. Formulations for parenteral administration may exist in the form of individual dose units, such as ampoules or vials. Preferably, a solution of the active compound, preferably an aqueous solution, and especially an isotonic solution. Suspensions are also used. These injection forms may be available as ready-to-use formulations, or they may be prepared directly before use by mixing the active compound, such as a lyophilized form, with the desired solvent or suspension, and, where appropriate, other solid carrier materials. Intranasal preparations may exist as aqueous or oily solutions or aqueous or oily suspensions. They may also exist as lyophilized products prepared before use with a suitable solvent or suspension. Inhalable formulations may exist as powders, solutions, or suspensions. Preferably, the inhalable formulation is in powder form, as a mixture of the active ingredient and a suitable formulation aid, such as lactose. The formulations are manufactured, divided, and sealed under conventional antimicrobial and sterile conditions. As described above, the compounds of the present invention may be administered as combination therapy, as sequential therapy, or as concurrent combination therapy, together with further activators, for example, therapeutically active compounds useful in the treatment of the above-described disorders. These therapeutically active compounds include nucleosides and nucleic acid base analogs, such as cytarabine, gemcitabine, azathioprine, mercaptopurine, fluorouracil, thioguanine, azacitidine, capecitabine, and doxifluridine; platinum-based drugs, such as cisplatin, oxaliplatin, carboplatin, and nedaplatin; anthracyclines, such as doxorubicin, epirubicin, barurubicin, idarubicin, daunorubicin, subbarbicin, picanthrone, and mitoxantrone; peptide antibiotics, such as actinomycin and bleomycin; and Killing agents, such as mechloretamine, chlorambucil, melphalan, nitrosourea, dacarbazine, temozolomide, and cyclophosphamide; mitotic inhibitors including taxanes and vinca alkaloids, such as docetaxel, paclitaxel, abraxane, cabazitaxel, vinblastine, vindesine, vinorelbine, and vincristine; topoisomerase inhibitors, such as irinotecan, topotecan, teniposide, and etoposide; other cell proliferation inhibitors, such as hydroxyurea and methotrexate; proteosome inhibitors, such as bortezomib and ixazomib;and other targeted therapeutic agents such as kinase inhibitors, cell cycle inhibitors, and regulators, namely inhibitors and activators of signaling pathways including growth factor signaling, cytokine signaling, NF-kappa B signaling, AP1 signaling, JAK / STAT signaling, EGFR signaling, TGF-beta signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g., erlotinib, lapatinib, dasatinib Imatinib, afatinib, vemurafenib, dabrafenib, nilotinib, cetuximab, trametinib, palbociclib, cobimetinib, cabozantinib, pegaptanib, crizotinib, olaparib, panitumumab, cabozantinib, ponatinib, regorafenib, entrectinib, ranibizumab, ibrutinib, trastuzumab, rituximab, alemtuzumab, gefitinib, bevacizumab, lenvatinib, bosutinib, axitinib, pazopanib, everolimus, temsirolimus, ruxolitinib Tofacitinib, sorafenib, sunitinib, afrivercept, vandetanib; bismodegib and sonidecib; 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, and rasofoxy Fen, toremifene, bicalutamide, flutamide, anastrozole, letrozole and exemestane; histone deacetylase inhibitors, e.g., vorinostat, romidepsin, panobinostat, belinostat and thidamide; and ingenol mebutate; and other Notch enhancers not included in the compounds of the present invention, e.g., valproic acid, resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocholalin, N-methylhemeansidine chloride and Notch signaling; Immunotherapy agents including immune checkpoint inhibitors such as imiquimod, ipilimumab, atezolizumab, ofatumumab, rituximab, nivolumab, and pembrolizumab; anti-inflammatory agents including glucocorticoids; and non-steroidal anti-inflammatory drugs such as cortisol preparations, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolone-hexaacetonide, mometasone fluate, clobetasol propionate, acetylsalicylic acid, salicylic acid and other salicylic acid esters, diflunisal, ibuprofen The active ingredients may include, but are not limited to, dexuibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, loxoprofen, flurbiprofen, oxaprozin, indomethacin, ketolac, tolmetin, diclofenac, etodolac, aceclofenac, nabumetone, sulindac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, parecoxib, etoricoxib, and firocoxib; and ACE inhibitors; and beta-blockers; and myostatin inhibitors; and PDE-5 inhibitors; and antihistamines. For combination therapy, the active ingredients may be formulated as a composition containing several active ingredients in a single-dose form, and / or as a kit containing individual active ingredients in separate dose forms. The active ingredients used in combination therapy may be co-administered or administered individually. The compounds of the present invention may be administered as antibody-drug conjugates. The compounds of the present invention may be administered in combination with surgical procedures, cryotherapy, electrodessication, radiotherapy, photodynamic therapy, laser therapy, chemotherapy, targeted therapy, immunotherapy, gene therapy, antisense therapy, cell-based transplantation therapy, stem cell therapy, physical therapy, and occupational therapy.

[0245] [Chemical synthesis] Abbreviation

[0246] [Table 63]

[0247] [General considerations] The compounds listed in Tables 63 and 64 were identified using a pre-coated silica TLC sheet and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, toluene, triethylamine, or acetic acid as eluents, preferably two or three solvent mixtures thereof. UV light at wavelengths of 254 or 366 nm. Light and / or common staining solutions such as phosphomolybdate, potassium permanganate, or ninhydrin were used to visualize the compounds. The reactions were also monitored in this manner for completion. Unless otherwise specified, reactions were carried out under an inert atmosphere. Dry solvents were used where necessary. All reactions were stirred using stirring plates and magnetic stirring rods. The compounds listed in Table 63 were further identified by mass spectrometry using formic acid as the mobile phase for cation detection, while no additives were used for anions. Ammonium carbonate was used when ionization was difficult in negative mode for molecules. Representative compounds and compounds showing insufficient ionization by mass spectrometry were also identified by nuclear magnetic resonance spectroscopy (Table 64). Chemical shifts (δ) were reported as parts per million (ppm) compared to the nearest residual solvent peak of 0.01 ppm for protons and 0.1 ppm for carbon (Reference: CHCI3[ 1 H: 7.26 ppm, 13 C:77.2ppm], DMSO[ 1 H: 2.50 ppm, 13 C: 39.5 ppm). The coupling constant (J) was reported in Hz at the nearest 0.1 Hz. Peak multiplicity was shown as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (heptet), m (multiplet), and br (broad).

[0248] [Synthesis of the listed compounds] The aforementioned compounds of the present invention, which fall within the range of Formula I, can be synthesized and purified by those skilled in the art, and are preferably synthesized according to the general procedures (A to N) described herein, as shown in Scheme 1.

[0249] [ka]

[0250] Scheme 1: General Synthesis Scheme A) To the corresponding monosubstituted or disubstituted phenols (1.0-1.5 equiv) and 4-alkyl ester halo(hetero)aryls (1 equiv) dissolved in DMSO (0.5 M) under argon with stirring, K2CO3 (1.5 equiv) was added, and the mixture was stirred at room temperature or heated between 40°C and 160°C until the mixture was completely converted. The mixture was allowed to return to room temperature, and The organic phase was partitioned between an organic solvent, preferably petroleum ether and water. The aqueous layer was extracted twice more, and the combined organic phase was then washed with NaOH (aq, 2M) followed by brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt, DCM / MeOH, or petroleum ether / AcOEt / NEt3) to obtain the desired bi(hetero)aryl ether ethyl ester.

[0251] B) The corresponding bi(hetero)aryl ether alkyl ester (1 equiv) was dissolved in dry THF (0.2 M) under argon with stirring, and the resulting solution was cooled to 0°C in an ice bath. Then DIBAL-H (2.5 equiv, 1.2 M in toluene) was added dropwise, and the mixture was stirred until it was completely converted at that temperature. The reaction product was quenched by the Feeser method, filtered, concentrated under vacuum, and the residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired alcohol.

[0252] C) Depending on the scale and substrate, one of these procedures was used. MnO2 (2-4 equiv) was added to the corresponding alcohol (1 equiv) dissolved in DCM (0.2 M) with vigorous stirring. The resulting suspension was stirred at room temperature or 40°C until complete conversion occurred. The reaction mixture was then diluted with AcOEt, filtered through Celite, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired aldehyde.

[0253] Desmartin periodinane (1.2 equivs) was added to the dissolved corresponding alcohol (1 equiv) in DCM or DMSO (0.2 M) with vigorous stirring. The resulting suspension was stirred at room temperature until completely converted. The solution was diluted with AcOEt and quenched with aq.sat.NaHCO3 to separate the phases. The aqueous layer was extracted two more times, and the combined organic phases were then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the aldehyde of interest.

[0254] To a solution of oxalyl chloride (2 equivs) in DCM (0.2 M) at -78°C, dry DMSO (4 equivs) was added, and the mixture was stirred for 30 minutes. Then, a solution of the corresponding alcohol (1 equiv) in DCM (0.2 M) was added, followed by freshly distilled NEt3 (8 equivs). The resulting solution was stirred for 1 hour and then slowly allowed to return to room temperature. The solution was diluted with AcOEt, quenched with aq HCl 1 M, and the phases were separated. The aqueous layer was extracted two more times, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the target aldehyde.

[0255] D) To the corresponding bi(hetero)aryl ether alkyl ester (1 equiv) dissolved in EtOH or THF (0.5 M), NaOH aq 2 M (2 equivs) was added, and the reaction was stirred until the reaction was complete. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted two more times, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) or recrystallization (cyclohexane, AcOEt, EtOH or aq HCl) to obtain the desired carboxylic acid.

[0256] E) To the corresponding 4-substituted phenol (1 equiv) and 1,4-dibromoaryl (2.5 equiv) dissolved in DMF (0.2 M), Cs2CO3 (2 equiv), CuI (10 mol%) and tBuXPos (20 mol%) were added. The mixture was degassed using the freeze-pump-thaw method, placed under argon, vigorously stirred, and refluxed for 72 hours (1 The mixture was heated to 65°C. The mixture was returned to room temperature and partitioned between petroleum ether and 2M NaOH aq. The aqueous layer was extracted two more times, and the combined organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired biaryl ether bromide.

[0257] F) Under argon with stirring, the corresponding 4-substituted phenols (1,2-1,5 equiv) and 1,4-dilomo(hetero)aryls (1 equiv) were dissolved in DMSO (0.5 M), to which K2CO3 (1,5 equiv) was added, and the mixture was heated between 80°C and 160°C until the mixture was completely converted. The mixture was allowed to return to room temperature and partitioned between petroleum ether and NaOH aq 2 M. The aqueous layer was extracted two more times, and the combined organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired bi(hetero)aryl ether bromide.

[0258] G) The corresponding bi(hetero)aryl ether bromide (1 equiv) was dissolved in dry THF (0.2 M) under argon with stirring, and the resulting solution was cooled to -78°C in a dry ice / acetone bath. Then, n- or t-BuLi (1.1-2.2 equiv, 1.9-2.5 M in hexane or pentane) was added dropwise, and the mixture was left stirring at that temperature for 30 minutes, then at -50°C until the starting materials were completely consumed (monitored by TLC in pentane). The mixture was then cooled back to -78°C, and the solution of the corresponding electrophile (2 equiv, 0.5 M) in dry THF was added, and the reaction was slowly brought back to room temperature over 16 hours. The reaction was then partitioned between AcOEt and NH4C1 aq.sat., the aqueous layer was extracted two more times, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt / NEt3) or recrystallized in a suitable solvent to obtain the target compound.

[0259] H) Depending on the scale and substrate, one of these procedures was used. The corresponding bis(hetero)aryl ether carboxylic acid (1 equiv) suspended in toluene (0.2 M) was first mixed with SOCl2 (2.5 equiv), then DMF (1 mol%), and the mixture was heated at 80°C for 3 hours. The reaction mixture was then evaporated to dryness, and the resulting residue was again placed under argon. It was redissolved in a solution of the corresponding alcohol (0.2 M) or the corresponding alcohol (1.5 equiv) in DCM (0.2 M). Triethylamine (2.5 equiv) was added, and the suspension was stirred for 16 hours. The reaction product was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired ester.

[0260] To the corresponding bis(hetero)aryl ether carboxylic acid (1 equiv) suspended in the corresponding alcohol (0.2 M) or DCM (0.2 M), SOCl2 (2.5 equiv) was added, followed by the corresponding alcohol (1.5 equiv) as needed, and the mixture was stirred for 3 hours. The reaction product was then partitioned between AcOEt and aq.sat.NaHCO3. The aqueous layer was extracted two more times, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired ester.

[0261] I) To the corresponding alcohol (1 equiv) in dry THF (0.2 M), NaH (1.2-2 equiv, 60% in oil) was added at 0°C, and the mixture was stirred at room temperature for 15-30 minutes. Next, the corresponding alkyl halide or acyl anhydride (1.5-2 equiv) was added to the mixture, or KI (1.2-2 equiv) in the case of alkyl bromide, and the mixture was stirred at room temperature or at 50°C for 16 hours in the case of alkyl bromide. The reaction product was then partitioned between AcOEt and HCl aq (1M). The aqueous layer was extracted two more times, and the combined organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired ether or ester.

[0262] J) The corresponding aldehyde (1 equiv) in dry THF (0.2 M) was mixed with the corresponding Wittig reagent (1.5 equiv) at 0°C. LiHMDS (1.3 equiv, 1 M in THF) was added dropwise to this stirred mixture. The reaction was stirred until the reaction was complete, and then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted two more times, and the combined organic phase was then washed with aq.sat.NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the target olefin.

[0263] To the corresponding olefin (1 equiv) in DCM (0.2 M) at 0°C, NaHCO3 (2 equivs) and a solution of mCPBA (1.2 equivs) in DCM (1 M) were added. The mixture was then slowly allowed to return to room temperature over 16 hours. The mixture was then partitioned between AcOEt and aq.sat.NaHCO3, the aqueous layer was extracted twice more, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the desired compound.

[0264] ZnEt2 (2 equiv, 1.5 M in toluene) was added dropwise to 0°C DCM (0.2 M). The reaction mixture was then stirred for 30 minutes. CH2I2 (4 equiv) was then added dropwise, and the resulting mixture was stirred for a further 30 minutes. Next, a solution of TFA (0.2 equiv) and 1,4-dioxane (1 equiv) in DCM (1 M) was added dropwise, and the resulting mixture was stirred for a further 30 minutes. The corresponding olefin (1 equiv) in DCM (1 M) was then added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was then partitioned between DCM and aq. HCl 1 M, the aqueous layer was extracted twice more, and the combined organic phase was washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain the target compound.

[0265] M) The corresponding BOC protective amine (1equiv) is 1,4-dioxane and aq 1M It was dissolved in a mixture of HCl (0.2 M, 4:1 mixture). The reaction mixture was then stirred at 80°C until the reaction was complete. It was then partitioned between AcOEt and aq.sat.NaHCO3, the aqueous layer was extracted twice more, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain a clean free amine.

[0266] N) The corresponding free amine (1 equiv) in acetonitrile (0.2 M) was to be mixed with formaldehyde (6 equivs, 37% w / w in water), followed by NaBH3CN (2 equivs). The reaction mixture was stirred until the reaction was complete, then partitioned between AcOEt and aq.sat.NaHCO3. The aqueous layer was extracted twice more, and the combined organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient DCM / MeOH / NEt3) to obtain the target compound. [Examples]

[0267] [Analysis Data] The following compounds were synthesized according to the protocol described above and characterized by mass spectrometry (Table 63) or NMR (Table 64).

[0268] [Table 64-1]

[0269] [Table 64-2]

[0270] [Table 64-3]

[0271] [Table 64-4]

[0272] [Table 64-5]

[0273] [Table 65-1]

[0274]

Table 65-2

[0275] For the sake of explanation, the synthesis and properties of the following examples will be described in detail.

[0276] XPA-0006: [4-(4-Cyclohexylphenoxy)phenyl)methanol

[0277]

Chemical formula

[0278] Ethyl 4-(4-cyclohexylphenoxy)benzoate (4.82 g, 14.86 mmol, 1 equiv) was dissolved in dry THF (74.3 mL, 0.2 M) under stirring under argon, and the resulting solution was cooled to 0 °C in an ice bath. Then, DIBAL-H (31.9 mL, 37.15 mmol, 2.5 equiv, 1.2 M in tetrahydrofuran) was added dropwise, and the mixture was stirred at that temperature until complete conversion. The reaction was quenched by the Fisher method, filtered, concentrated under vacuum, and then the residue was purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 4.07 g of (4-(4-cyclohexylphenoxy)phenyl)methanol (97%).

[0279] MS: m / z[M-OH] + , calc for [C 19 H 21 O] + = 265.16 ; found 265.11 1 1H-NMR(300 MHz, CDCl3) δ 7.38-7.28 (m, 2H), 7.23-7.12 (m, 2H), 7.02-6.87 (m, 4H), 4.65 (s, 2H), 2.56-2.40 (m, 1H), 2.00-1.71 (m, 5H), 1.51-1.15 (m, 5H). 13 13C-NMR(75MHz, CDCl3) δ 157.3, 154.9, 143.3, 135.4, 128.7, 128.0, 118.8, 118.6, 65.0, 43.9, 34.7, 26.9, 26.2.

[0280] XPA-0028: 4-(4-(Adamantan-1-yl)phenoxy)benzaldehyde

[0281]

Chem.

[0282] MnO2 (1.56 g, 17.9 mmol, 2 - 4 equiv) was added to (4-(4-(adamantan-1-yl)phenoxy)phenyl)methanol (1.49 g, 4.47 mmol, 1 equiv) dissolved in DCM (22.5 mL, 0.2 M) under vigorous stirring, and the resulting suspension was heated to 40 °C and left until completely converted. Then, the reaction mixture was diluted with AcOEt, filtered through celite, and concentrated under vacuum. Subsequently, the residue was purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 1.1 g of 4-(4-(adamantan-1-yl)phenoxy)benzaldehyde (74%).

[0283] MS: m / z [M+H] + , calc for [C 23 H 25 O2] + = 333.18; found 333.26 1 1H-NMR(300MHz, CDCl?3) δ 9.91(s, 1H), 7.90 - 7.72(m, 2H), 7.47 - 7.33(m, 2H), 7.13 - 6.97(m, 4H), 2.19 - 2.05(m, 3H), 1.97 - 1.86(m, 6H), 1.87 - 1.64(m, 7H). 13C-NMR(75MHz,CDCl3) δ 190.8, 163.6, 152.6, 148.3, 131.9, 131.1, 126.6, 120.0, 117.4, 43.3, 36.7, 36.0, 28.9.

[0284] XPA-0060: 4-(4-(2-(dimethylamino)ethyl)phenoxy)benzoic acid ester

[0285] [ka]

[0286] 4-(2-(dimethylamino)ethyl)phenol (5.16 g, 31.25 mmol, 1.25 equiv) and 4-ethyl fluorobenzoate (4.2 g, 25 mmol, 1 equiv) were dissolved in DMSO (50 mL, 0.5 M) under argon with stirring, to which K2CO3 (5.2 g, 37.5 mmol, 1.5 equiv) was added, and the mixture was heated to 120°C until completely converted. The mixture was allowed to cool to room temperature and partitioned between an organic solvent, preferably petroleum ether, and water. The aqueous layer was extracted twice more, and the combined organic phase was then washed with NaOH (aq, 2 M) and then brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt / NEt3) to obtain 6.27 g of 4-(4-(2-(dimethylamino)ethyl) Ethyl phenoxybenzoate (80%) was obtained.

[0287] MS: m / z[M+H] + , calc for [C 19 H 24 NO3] + = 314.18; found 314.27 1H-NMR(300MHz,CDCl3) δ 7.96-7.84(m,2H), 7.27-7.08(m,2H), 6.98-6.79(m,4H), 4.28(q,J=7.1Hz,2 H), 2.85-2.67(m,2H), 2.58-2.41(m,2H), 2.26(s,6H), 1.31(t,J=7.1Hz,3H). 13 C-NMR(75MHz,CDCl3) δ 166.2, 161.9, 153.9, 136.4, 131.6, 130.1, 124.7, 120.1, 117.1, 61.4, 60.8, 45.4, 33.5, 14.4.

[0288] XPA-0063: 4-(4-(tetrahydro-2H-pyran-4-yl)phenoxy)ethyl benzoate

[0289] [ka]

[0290] 4-(tetrahydro-2H-pyran-4-yl)phenol (0.85 g, 4.75 mmol, 1 equiv) and ethyl 4-fluorobenzoate (0.80 g, 4.75 mmol, 1 equiv) were dissolved in DMSO (15 mL, 0.5 M) under argon with stirring, to which K2CO3 (0.98 g, 7.13 mmol, 1.5 equiv) was added, and the mixture was heated to 120°C until completely converted. The mixture was allowed to return to room temperature and partitioned between an organic solvent, preferably petroleum ether, and water. The aqueous layer was extracted twice more, and the combined organic phase was then washed with NaOH (aq, 2 M) and then brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 1.01 g of 65% ethyl 4-(4-(tetrahydro-2H-pyran-4-yl)phenoxy)benzoate.

[0291] MS: m / z[M+H] + , calc for [C 20 H 23 O4]+ = 327.16; found 327.24 1 H-NMR(300MHz,CDCl3) δ 7.96-7.90(m,2H), 7.24-7.12(m,2H), 6.97-6.87(m,4H), 4.29(q,J=7.1Hz,2H), 4.09-3.95(m, 2H), 3.54-3.39(m,2H), 2.70(tq,J=10.2,5.4Hz,1H), 1.84-1.63(m,4H), 1.31(t,J=7.1Hz,3H). 13 C NMR(75MHz,CDCl3) δ 166.2, 161.9, 154.0, 142.1, 131.6, 128.2, 124.8, 120.1, 117.2, 68.4, 60.8, 41.0, 34.1, 14.4.

[0292] XPA-0064: 4-(4-(1-methylpiperidine-4-yl)phenoxy)ethyl benzoate

[0293] [ka]

[0294] 4-(1-methylpiperidine-4-yl)phenol (0.84 mg, 4.38 mmol, 1 equiv) and ethyl 4-fluorobenzoate (0.74 g, 4.38 mmol, 1 equiv) were dissolved in DMSO (8.76 mL, 0.5 M) under argon with stirring, to which K2CO3 (0.91 g, 6.57 mmol, 1.5 equiv) was added, and the mixture was heated to 120°C until completely converted. The mixture was allowed to cool to room temperature and partitioned between an organic solvent, preferably petroleum ether, and water. The aqueous layer was extracted twice more, and the combined organic phase was then washed with NaOH (aq, 2 M) and then brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient DCM / MeOH) to obtain 1.0 g of ethyl 4-(4-(1-methylpiperidine-4-yl)phenoxy)benzoate (67%).

[0295] MS: m / z[M+H] + , calc for [C 21 H 26 NO3] + = 340.19; found 340.35 1 H-NMR (300MHz, CDCl3) δ 7.92(d,J=8.9Hz,2H), 7.29-7.09(m,2H), 7.00-6.80(m,4H), 4.28(q,J=7.1Hz,2H), 3.06-2.86(m,2H), 2.5 1-2.36(m,1H), 2.29(s,3H), 2.14-1.95(m,2H), 1.78(ddd,J=10.5,7.2,3.4Hz,4H), 1.31(t,J=7.1Hz,3H). 13 C-NMR (75MHz, CDCl3) δ 166.2, 161.9, 153.9, 142.4, 131.6, 128.3, 124.7, 120.0, 117.1, 60.8, 56.3, 46.3, 41.3, 33.4, 14.4.

[0296] XPA-0036:4-(4-(1-メチルピペリジン-4-イル)フェノキシ)benzoic acid

[0297]

change

[0298] Ethyl 4-(4-(1-methylpiperidine-4-yl)phenoxy)benzoate (0.25 g, 0.73 mmol, 1 equiv) was dissolved in EtOH (5 mL, 0.5 M), to which 2 M NaOH aq (0.73 mL, 1.46 mmol, 2 equiv) was added, and the reaction mixture was stirred until the reaction was complete. The reaction mixture was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted two more times, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then repeatedly recrystallized from 1 M HCl to obtain 219.5 mg of 4-(4-(1-methylpiperidine-4-yl)phenoxy)benzoate-HCl salt (96%).

[0299] MS: m / z[M+H] + , calc for [C 19 H 22 NO3] + = 312.16; found 312.19 1 H-NMR(300MHz, DMSO-d6) δ 12.60(brs,1H), 11.02(brs,1H), 7.99-7.90(m,2H), 7.33(d,J=8.2Hz,2H), 7.10(d,J=8.4Hz,2H) , 7.05-6.95(m,2H), 3.55-3.27(m,2H), 3.20-2.99(m,2H), 2.92-2.70(m,4H), 2.19-1.83(m,4H). 13 C-NMR(300MHz, DMSO-d6) δ 167.2, 161.6, 154.1, 141.0, 132.1, 128.9, 125.6, 120.6, 117.5, 53.9, 42.9, 38.1, 30.3.

[0300] XPA-I-0018:(3r,5r,7r)-1-(4-(4-bromophenoxy)phenyl)adamantane

[0301] [ka]

[0302] 4-(1-adamentyl)phenol (2 g, 8.76 mmol, 1 equiv) and 1,4-dibromobenzene (5.16 g, 21.90 mmol, 2.5 equiv) were dissolved in DMF (44 ml, 0.2 M), to which Cs2CO3 (5.7 g, 17.51 ​​mmol, 2 equiv), CuI (83.4 mg, 0.44 mmol, 10 mol%) and tBuXPos (744 mg, 1.752 mmol, 20 mol%) were added. The mixture was degassed using the freeze-pump-thaw method, placed under argon, vigorously stirred, and refluxed (165°C) for 72 hours. The mixture was returned to room temperature and partitioned between petroleum ether and NaOH aq 2M. The aqueous layer was extracted two more times, and the combined organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Next, the residue was purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 2.33 g (69%) of the target (3r,5r,7r)-1-(4-(4-bromophenoxy)phenyl)adamantane.

[0303] 1 H NMR(400MHz,CDCl3) δ 7.43-7.38(m,2H), 7.35-7.30(m,2H), 6.97-6.91(m,2H), 6.90-6.84(m,2H), 2.10(s,3H), 1.90(d,J=2.9Hz,6H), 1.84-1.69(m,6H). 13 C NMR(101MHz,CDCl3) δ 156.4, 154.2, 147.0, 132.6, 126.3, 120.2, 118.7, 115.2, 43.3, 36.8, 35.9, 29.0.

[0304] XPA-I-0020:2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-bromopyridine

[0305] [ka]

[0306] 4-(1-adamentyl)phenol (2.89 g, 12.66 mmol, 1.5 equiv) and 1,4- phenol were dissolved in DMSO (42 ml, 0.5 M) under stirring under argon. Diromopyridine (2 g, 8.44 mmol, 1 equiv) was mixed with K2CO3 (2.92 g, 21.1 mmol, 1.5 equiv) and heated at 80°C until the mixture was completely converted. The mixture was allowed to cool to room temperature and partitioned between petroleum ether and 2 M NaOH aq. The aqueous layer was extracted twice more, and the combined organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then recrystallized in hexane to obtain 1.9 g (59%) of 2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-bromopyridine.

[0307] MS: m / z[M+H] + , calc for [C 21 H 23 BrNO] + = 384.10 / 386.09; found 384.21 / 386.20 1 H NMR(400MHz,CDCl3) δ 8.23(d,J=2.5Hz,1H), 7.74(dd,J=8.7,2.6Hz,1H), 7.42-7.34(m,2H), 7.10-7.02(m,2H), 6. 81(d,J=8.7Hz,1H), 2.16-2.03(m,3H), 1.92(d,J=2.9Hz,6H), 1.79(dd,J=11.5,8.4Hz,6H). 13 C NMR(101MHz,CDCl3) δ 162.8, 151.4, 148.4, 148.0, 141.8, 126.3, 120.4, 113.3, 113.0, 43.3, 36.8, 36.0, 29.00.

[0308] XPA-0140:3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)oxetan-3-ol

[0309] [ka]

[0310] (3r,5r,7r)-1-(4-(4-bromophenoxy)phenyl)adamantane (0.5 g, 1.30 mmol, 1 equiv) was dissolved in dry THF (6.5 ml, 0.2 M) under argon with stirring, and the resulting solution was cooled to -78°C in a dry ice / acetone bath. Then, n-BuLi (1.1 equiv, 2.1 M in hexane) was added dropwise, and the mixture was stirred at that temperature for 30 minutes, then at -50°C until the starting materials were completely consumed (monitored by TLC in pentane). The mixture was then cooled back to -78°C, and a solution of 3-oxetanone in dry THF (0.17 ml, 2 equiv, 0.5 M) was added, and the reaction was slowly allowed to return to room temperature over 16 hours. Next, the reaction product was partitioned between AcOEt and NH4Cl aq.sat., the aqueous layer was extracted two more times, and the combined organic phase was then washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 350 mg (71%) of 3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)oxetan-3-ol.

[0311] MS: m / z[M-OH] + , calc for [C 25 H 27 O2] + = 359.49; found 359.59 1 H NMR(400MHz,CDCl3) δ 7.50-7.60(m,2H), 7.40-7.30(m,2H), 7.10-7.05(m,2H), 7.00-6.90(m,2 H), 5.00-4.90(m,4H), 2.45(s,3H), 2.20-2.10(m,6H), 1.85-1.75(m,6H). 13C NMR(101MHz,CDCl3) δ 157.5, 154.4, 146.9, 136.7, 126.2, 126.0, 118.7, 118.6, 85.6, 75.8, 43.3, 36.8, 35.9, 29.0.

[0312] XPA-1303: 5-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)pyrimidine-2-carboxylate ethyl

[0313] [ka]

[0314] 5-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)pyrimidine-2-carboxylic acid (0.94 g, 2.68 mmol, 1 equiv, exceptionally obtained in procedure A by cleavage of the ester group under reaction conditions) suspended in ethanol (13.4 ml, 0.2 M) was combined with SOCl2 (0.49 ml, 6.7 mmol, 2.5 equiv) and the mixture was stirred for 3 hours. The reaction product was then partitioned between AcOEt and aq.sat.NaHCO3. The aqueous layer was extracted twice more, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 1 g (98%) of ethyl 5-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)pyrimidine-2-carboxylic acid.

[0315] MS: m / z[M+H] + , calc for [C 23 H 27 N2O3] + = 379.20; found 379.63 1H NMR(400MHz,CDCl3) δ 8.55(s,2H), 7.46-7.37(m,2H), 7.07-6.98(m,2H), 4.51(q,J=7.2Hz,2H), 2.10( q,J=3.2Hz,3H), 1.91(d,J=2.9Hz,6H), 1.85-1.70(m,6H), 1.45(t,J=7.1Hz,3H). 13 C NMR(101MHz,CDCl3) δ 162.85, 153.96, 151.77, 150.32, 149.27, 146.50, 127.02, 119.06, 62.63, 43.22, 36.66, 36.09, 28.87, 14.30.

[0316] XPA-0146: 3-(4-(4-cyclohexylphenoxy)phenyl)-3-methoxyoxetane

[0317] [ka]

[0318] 3-(4-(4-cyclohexylphenoxy)phenyl)oxetan-3-ol (25 mg, 0.08 mmol, 1 equiv) in dry THF (0.4 ml, 0.2 M) was mixed with NaH (6.10 mg, 0.15 mmol, 2 equiv, 60% in oil) at 0°C, and the mixture was stirred at room temperature for 15-30 minutes. Then, MeI (0.01 ml, 0.15 mmol, 2 equiv) was added to the mixture, and the whole was stirred at room temperature for 16 hours. The reaction product was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 21.4 mg (82%) of 3-(4-(4-cyclohexylphenoxy)phenyl Xy)phenyl)-3-methoxyoxetane was obtained.

[0319] MS: m / z[M-OMe] +, calc for [C 21 H 23 O2] + = 307.17; found 307.46 1 H NMR (400MHz, CDCl3) δ 7.40-7.34(m,2H), 7.21-7.16(m,2H), 7.05-7.00(m,2H), 6.99-6.93(m,2H ), 4.91(d,J=6.7Hz,2H), 4.83(d,J=6.7Hz,2H), 3.13(s,3H), 2.49(ddt,J= 11.7,6.6,3.7Hz,1H), 1.87(ddt,J=15.6,8.4,2.6Hz,4H), 1.75(dtt,J=12 .6,3.1,1.6Hz,1H), 1.50-1.33(m,4H), 1.25(dtt,J=11.3,8.0,4.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ 157.6, 154.5, 143.6, 133.8, 128.1, 127.4, 119.2, 118.3, 80.9, 80.6, 51.6, 43.9, 34.6, 26.9, 26.1.

[0320] XPA-1284:4-(4-シクロヘキシル-2-ビニルフェノキシ)benzoic acid エチル

[0321]

change

[0322] Methyltriphenylphosphonium bromide (456.13 mg, 1.27 mmol, 1.5 equiv) was added at 0°C to ethyl 4-(4-cyclohexyl-2-formylphenoxy)benzoate (300 mg, 0.85 mmol, 1 equiv) in dry THF (4.25 ml, 0.2 M). LiHMDS (1.1 ml, 1.1 mmol, 1.3 equiv, 1 M in THF) was added dropwise to this stirred mixture. The reaction was stirred until the reaction was complete, and then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more, and the combined organic phase was then washed with aq.sat.NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. Next, the residue was purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 153 mg (51%) of ethyl 4-(4-cyclohexyl-2-vinylphenoxy)benzoate.

[0323] 1 H NMR(400MHz,CDCl3) δ 8.00-7.95(m,2H), 7.45(d,J=2.2Hz,1H), 7.12(dd,J=8.3,2.2Hz,1H), 6.93-6 .86(m,3H), 6.82(dd,J=17.7,11.1Hz,1H), 5.76(dd,J=17.7,1.3Hz,1H), 5.23( dd,J=11.1,1.3Hz,1H), 4.35(q,J=7.1Hz,2H), 2.59-2.46(m,1H), 1.89(td,J= 9.8,5.2Hz,4H), 1.77(d,J=12.9Hz,1H), 1.47-1.33(m,7H), 1.32-1.19(m,1H). 13 C NMR(101MHz,CDCl3) δ 166.2, 162.4, 150.1, 145.1, 131.6, 130.8, 129.9, 127.7, 125.0, 124.3, 121.2, 116.2, 115.6, 60.8, 44.2, 34.6, 26.9, 26.1, 14.4.

[0324] XPA-1290: 4-(4-cyclohexyl-2-(oxiran-2-yl)phenoxy) ethyl benzoate

[0325] [ka]

[0326] Ethyl 4-(4-cyclohexyl-2-vinylphenoxy)benzoate (40 mg, 0.11 mmol, 1 equiv) in DCM (0.57 ml, 0.2 M) at 0°C was mixed with NaHCO3 (24 mg, 0.23 mmol, 2 equiv) and mCPBA (33 mg, 0.14 mmol, 1.2 equiv) in DCM (0.14 ml, 1 M). The reaction mixture was then slowly allowed to return to room temperature over 16 hours. The mixture was then partitioned between AcOEt and aq.sat.NaHCO3, the aqueous layer was extracted twice more, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Next, the residue was purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 22 mg (52%) of ethyl 4-(4-cyclohexyl-2-(oxiran-2-yl)phenoxy)benzoate.

[0327] 1 H NMR(400MHz,CDCl3) δ 8.03-7.97(m,2H), 7.14(dd,J=8.3,2.3Hz,1H), 7.10(d,J=2.2Hz,1H), 6.96-6.88(m,3H), 4.36(qd,J=7.1,0.7Hz,2H), 4.02(dd,J=4.1,2 .6Hz,1H), 3.02(ddd,J=5.7,4.1,0.7Hz,1H), 2.69(ddd,J=5.7,2.6,0.7Hz,1H), 2.56-2.43(m,1H), 1.94-1.69(m,5H), 1.47-1.18(m,8H). 13C NMR(101MHz,CDCl3) δ 166.1, 162.1, 151.6, 145.4, 131.7, 129.5, 127.6, 124.7, 123.9, 120.3, 116.4, 60.8, 50.7, 48.1, 44.1, 34.6, 34.5, 26.8, 26.1, 14.4.

[0328] XPA-1295: 4-(4-cyclohexyl-2-cyclopropylphenoxy)benzoate

[0329] [ka]

[0330] ZnEt2 (0.15 ml, 0.23 mmol, 2 equiv, 1.5 M in toluene) was added dropwise to DCM (0.57 ml, 0.2 M) at 0°C. The reaction mixture was then stirred for 30 minutes. Next, CH2I2 (122 mg, 0.46 mmol, 4 equiv) was added dropwise, and the resulting mixture was stirred for a further 30 minutes. Then, a solution of TFA (1.8 μl, 23 μm, 0.2 equiv) and 1,4-dioxane (10 μl, 0.11 mmol, 1 equiv) in DCM (0.11 ml, 1 M) was added dropwise, and the resulting mixture was stirred for a further 30 minutes. Next, ethyl 4-(4-cyclohexyl-2-vinylphenoxy)benzoate (40 mg, 0.11 mmol, 1 equiv) in DCM (0.11 ml, 1 M) was added, and the resulting mixture was stirred at room temperature for 16 hours. Next, the reactants are DCM and aq.HC. The mixture was partitioned between 1 M and 1 M, the aqueous layer was extracted twice more, and the combined organic phase was then washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to obtain 33.7 mg (81%) of ethyl 4-(4-cyclohexyl-2-cyclopropylphenoxy)benzoate.

[0331] 11H NMR (400 MHz, CDCl3) δ 8.00 - 7.94 (m, 2H), 7.01 (dd, J = 8.3, 2.2 Hz, 1H), 6.93 - 6.86 (m, 3H), 6.77 (d, J = 2.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.46 (s, 1H), 1.96 - 1.69 (m, 6H), 1.46 - 1.17 (m, 8H), 0.86 - 0.74 (m, 2H), 0.69 - 0.59 (m, 2H). 13 13C NMR (101 MHz, CDCl3) δ 166.3, 162.8, 151.5, 145.2, 135.4, 131.5, 124.9, 124.1, 123.9, 120.9, 115.9, 60.7, 44.2, 34.6, 26.9, 26.1, 14.4, 9.8, 8.0.

[0332] XPA - 1317: 3 - (Benzyloxy) - 3 - (4 - (4 - cyclohexylphenoxy)phenyl)azetidine

[0333]

Chemical Structure

[0334] 3 - (Benzyloxy) - 3 - (4 - (4 - cyclohexylphenoxy)phenyl)azetidine - 1 - carboxylic acid tert - butyl (60 mg, 0.12 mmol, 1 equiv) was dissolved in a mixture of 1,4 - dioxane and aq 1M HCl (0.6 ml, 0.2 M, 4:1 mixture). Then the reaction mixture was stirred at 80 °C until the reaction was complete. Then it was partitioned between AcOEt and aq. sat. NaHCO3, the aqueous layer was extracted twice more, then the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give 40 mg (82%) of 3 - (benzyloxy) - 3 - (4 - (4 - cyclohexylphenoxy)phenyl)azetidine.

[0335] MS: m / z [M + H] + , calc for [C 28 H 31 NO2]+ = 414.24; found 414.72 1 H NMR(400MHz,CDCl3) δ 7.51-7.42(m,2H), 7.39-7.23(m,5H), 7.21-7.14(m,2H), 7.07-7.01(m,2H), 6.99-6.94(m,2H), 4.18(s,2H), 4.05(d,J=8.7Hz,2 H), 3.90(d,J=8.6Hz,2H), 2.50(tt,J=8.4,3.6Hz,1H), 1.95-1.80(m,4H), 1.76(dtt,J=12.7,3.2,1.6Hz,1H), 1.49-1.20(m,5H). 13 C NMR(101MHz,CDCl3) δ 157.5, 154.6, 143.5, 138.1, 135.2, 131.9, 128.4, 128.0, 127.7, 127.6, 119.1, 118.4, 67.1, 65.9, 57.5, 43.9, 34.7, 26.9, 26.2.

[0336] XPA-0238: 3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-3-methoxy-1-methylazetidine

[0337] [ka]

[0338] 3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-3-methoxyazetidine (20 mg, 0.05 mmol, 1 equiv) in acetonitrile (0.26 ml, 0.2 M) was mixed with formaldehyde (0.03 ml, 0.31 mmol, 6 equiv, 37% w / w in water), followed by NaBH3CN (6.45 mg, 0.10 mmol, 2 equiv). The reaction mixture was stirred until the reaction was complete, then partitioned between AcOEt and aq.sat.NaHCO3. The aqueous layer was extracted twice more, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Next, the residue was purified by flash chromatography (SiO2, gradient DCM / MeOH / NEt3) to obtain 15 mg (72%) of 3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)-3-methoxy-1-methylazetidine.

[0339] MS: m / z[M+H] + , calc for [C 26 H 32 NO2] + = 404.57; found 404.72 1 H NMR(400MHz,CDCl3) δ 7.43-7.37(m,2H), 7.34-7.29(m,2H), 7.04-6.98(m,2H), 6.98-6.93(m,2H), 3.67-3.57(m,2H), 3.42-3 .33(m,2H), 3.03(s,3H), 2.44(s,3H), 2.09(q,J=3.2Hz,3H), 1.91(d,J=2.9Hz,6H), 1.84-1.69(m,6H). 13 C NMR(101MHz,CDCl3) δ 157.0, 154.6, 146.6, 135.4, 127.7, 126.1, 118.5, 118.5, 76.3, 66.2, 51.3, 46.2, 43.3, 36.8, 35.8, 29.0.

Claims

1. A compound or salt or solvate thereof that conforms to the general formula (I) defined herein. 【Chemistry 1】 (wherein, R １ is C １ -C １２ preferably C ４ -C １２ alkyl, C ２ -C １２ preferably C ４ -C １２ alkenyl, C ２ -C １２ preferably C ４ -C １２ alkynyl, C ３ -C ８ cycloalkyl, C ５ -C ８ cycloalkenyl, C ５ -C １２ bicycloalkyl, C ７ 0-C １２ bicycloalkenyl, C ８ -C １４ tricycloalkyl, -OC １ -C １２ preferably -OC ３ -C １２ alkyl, -OC ２ -C １２ preferably -OC ３ -C １２ alkenyl, -OC ２ -C １２ preferably -OC ３ -C １２ alkynyl, -OC ３ -C ８ cycloalkyl, -OC ５ -C ８ cycloalkenyl, -OC ５ -C １２ bicycloalkyl, -OC3 ７ -C １２ bicycloalkenyl, -OC ８ -C １４ tricycloalkyl, -SC １ -C １２ preferably -SC ３ -C １２ alkyl, -SC ２ -C １２ preferably -SC ３ -C １２ alkenyl, -SC ２ -C １２ Preferably -SC ３ -C １２ Alkynyl, -SC ３ -C ８ Cycloalkyl, -SC ５ -C ８ Cycloalkenyl, -SC ５ -C １２ Bicycloalkyl, -SC ７ -C １２ Bicycloalkenyl, -SC<000--066>-C １４ Tricycloalkyl, -NHR ６ Or -NR ６ R ７ (Wherein, R ６ And R ７ Are, independently of each other, C １ -C １２ Preferably C ３ -C １２ Alkyl, C ２ -C １２ Preferably C ３ -C １２ Alkenyl, C ２ -C １２ Preferably C ３ -C １２ Alkynyl, C ３ -C ８ Cycloalkyl, C ５ -C ８ Cycloalkenyl, C ５ -C １２ Bicycloalkyl, C ７ -C １２ Bicycloalkenyl, C ８ -C １４ Selected from tricycloalkyl, or R ６ Is R ７ Can form a ring structure together with; wherein, the ring structure containing an N atom is selected from a 3- to 8-membered cyclic structure or a 5- to 12-membered bicyclic structure, and wherein, all of the said ring structures can further contain one or more heteroatoms independently selected from O, S and N in place of the carbon atoms contained in the ring structure, particularly here, such substitution results in a residue containing at least twice the number of C atoms as the heteroatom independently selected from O, S and N); Here, R １ 、R ６ and R ７ All alkyl, alkenyl, and alkynyl residues included in the definitions of are linear or branched and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ２ , -NO ２ , =O, C ３ -C ８ cycloalkyl, C ５ -C ８ cycloalkenyl, C ５ -C １２ bicycloalkyl, C ７ -C １２ bicycloalkenyl, C ８ -C １４ tricycloalkyl, linear or branched -OCH ３ such as -OC １ -C ５ alkyl, -O(cyclopropyl) such as -OC ３ -C ５ cycloalkyl, linear or branched -NH(C １ -C ５ alkyl), linear or branched -N(C １ -C ５ alkyl)(C １ -C ５ alkyl), -NH(cyclopropyl) such as -NH(C ３ -C ５ cycloalkyl), -N(C ３ -C ５ cycloalkyl)(C ３ -C ５ cycloalkyl), linear or branched -N(C １ -C ５ alkyl)(C ３ -C ５ cycloalkyl); Here, R １ , R ６ and R ７ If an alkyl, alkenyl, or alkynyl residue included in the definition is substituted with one or more substituents that are =O, such =O substitution cannot be one of the groups selected from C=O, S=O, and N=O directly bonded to the aromatic ring; Here, R １ , R ６ and R ７ All cyclic, bicyclic, and tricyclic structures containing cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition are unsubstituted or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -NH ２ , -NO ２ ,=O, linear or branched -CH ３ C such as １ -C ５ Alkyl, linear, or branched -OCH ３ -OC １ -C ５ Alkyl, linear or branched -NH(C) １ -C ５ Alkyl), linear or branched -N(C) １ -C ５ (Alkyl) (C １ -C ５ Alkyl), -NH (cyclopropyl), etc. -NH (C ３ -C ５ Cycloalkyl), -N(C ３ -C ５ Cycloalkyl) (C ３ -C ５ Cycloalkyl), linear or branched -N(C) １ -C ５ (Alkyl) (C ３ -C ５ It is substituted with one or more substituents independently selected from cycloalkyl; Here, R １ , R ６ and R ７ All alkyl, alkenyl, and alkynyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, wherein such substitution results in a residue containing at least twice as many carbon atoms as heteroatoms independently selected from O, S, and N, wherein such substitution cannot be one of the groups selected from C=O, S=O, and N=O directly bonded to the aromatic ring; Here, R １ , R ６ and R ７ All cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, where such substitution results in a residue containing at least the same number of carbon atoms as heteroatoms independently selected from O, S, and N; Here, R １ , R ６ and R ７ All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition may be partially or completely halogenated, in particular fluorinated, and more particularly perfluorinated; Here, bicyclic and tricyclic residues include condensation, crosslinking, and spirosystems; R ２ -R ５ These are -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ２ , -NO ２ , linear or branched C １ -C ４ Alkyl, linear, or branched C ２ -C ４ Alkenyl, linear or branched C ２ -C ４ Alkinyl, C ３ -C ６ Cycloalkyl, -CH ２ (C ３ -C ６ Cycloalkyl, linear or branched -OC １ -C ３ Alkyl, -O (cyclopropyl), linear or branched -NH(C) １ -C ３ Alkyl), linear or branched -N(C) １ -C ３ (Alkyl) (C １ -C ３ Alkyl), -NH(cyclopropyl), -N(cyclopropyl) ２ , linear or branched -N(C) １ -C ３ Selected from alkyl (cyclopropyl); Here, R ２ -R ５ All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or -F, -Cl, -Br, -I, -CH ３ , -CF ３ , -OH and -OCH ３ , -OCF ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ It is substituted with one or more substituents independently selected from; Here, R ２ -R ５ All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, where such substitutions cannot be one of the groups selected from C=O and S=O directly bonded to the aromatic ring; X １ -X ４ N and CR are independent of each other. ８ CR ９ CR １０ CR １１ Selected from; R ８ -R １１ These are -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ２ , -NO ２ , linear or branched C １ -C ４ Alkyl, linear, or branched C ２ -C ４ Alkenyl, linear or branched C ２ -C ４ Alkinyl, C ３ -C ６ Cycloalkyl, -CH ２ (C ３ -C ６ Cycloalkyl, linear or branched -OC １ -C ３ Alkyl, -O (cyclopropyl), linear or branched -NH(C) １ -C ３ Alkyl), linear or branched -N(C) １ -C ３ (Alkyl) (C １ -C ３ Alkyl), -NH(cyclopropyl), -N(cyclopropyl) ２ , linear or branched -N(C) １ -C ３ Selected from alkyl (cyclopropyl); Here, R ８ -R １１ All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition are either unsubstituted or -F, -Cl, -Br, -I, -CH ３ , -CF ３ , -OH and -OCH ３ , -OCF ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ It is substituted with one or more substituents independently selected from; Here, R ８ -R １１ All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms, where such substitutions cannot be one of the groups selected from C=O and S=O directly bonded to the aromatic ring; Here, R ８ -R １１ Preferably, -H, -F, -Cl, -Br, -CH ３ , -CF ３ -OH, -OCH ３ , -OCF ３ Cyclopropyl, oxyranyl, -C (CH ３ ) ３ , -N(CH ３ ) ２ , -NH ２ -CN, -CH ２ OCH ３ , -OCH(CH ３ ) ２ ien-CH ２ NH ２ ien-CH ２ N(CH ３ ) ２ ien-CH ２ OH, -NO ２ or -CH ２ Selected from -N-morpholinyl; Here, R ２ -R ５ and R ８ -R １１ All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition may be partially or completely halogenated, especially fluorinated, and more especially perfluorinated; Y is -OH, linear or branched -OC １ -C ６ Alkyl, linear, or branched -OC ２ -C ６ Alkenyl, linear or branched -OC ２ -C ６ Alkinyl, -OC ３ -C ６ Cycloalkyl, -SH, linear or branched -SC １ -C ６ Alkyl, linear, or branched -SC ２ -C ６ Alkenyl, linear or branched -SC ２ -C ６ Alkinyl, -SC ３ -C ６ Cycloalkyl, aromatic, and heteroaromatic residues, preferably 6-membered aromatic rings and 5- to 6-membered heteroaromatic rings; Here, all aromatic and heteroaromatic residues included in the definition of Y are -O-, -S-, or -O-CH ２ - or -O-CH ２ -CH ２ - or - S-CH ２ - or - S-CH ２ -CH ２ - or -O-CH ２ -O- or -S-CH ２ -O- or -O-CH ２ -NH- or -S-CH ２ Y is bonded to the carbon atom to which it is bonded via an NH-linker; where the linker is bonded to the carbon atom to which Y is bonded via its heteroatoms; Here, the linker included in the definition of Y is unsubstituted or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ２ , -NO ２ , linear or branched C １ -C ３ Alkyl, C ２ -C ３ Alkenil, C ２ -C ３ Alkynyl, cyclopropyl, linear or branched -OCH ３ -OC １ -C ３ Alkyl, -O (cyclopropyl), linear or branched -NH(C) １ -C ３ Alkyl), linear or branched -N(C) １ -C ３ (Alkyl) (C １ -C ３ Alkyl), -NH(cyclopropyl), -N(cyclopropyl) ２ , linear or branched -N(C) １ -C ３ Substituted with one or more substituents independently selected from alkyl(cyclopropyl); Here, all aromatic and heteroaromatic residues included in the definition of Y are either unsubstituted or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ２ , -NO ２ , linear or branched C １ -C ３ Alkyl, C ２ -C ３ Alkenil, C ２ -C ３ Alkynyl, cyclopropyl, linear or branched -OCH ３ -OC １ -C ３ Alkyl, -O (cyclopropyl), linear or branched -NH(C) １ -C ３ Alkyl), linear or branched -N(C) １ -C ３ (Alkyl) (C １ -C ３ Alkyl), -NH(cyclopropyl), -N(cyclopropyl) ２ , linear or branched -N(C) １ -C ３ Substituted with one or more substituents independently selected from alkyl(cyclopropyl); Here, all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues included in the definition of Y are linear or branched and unsubstituted or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ２ ,=O, linear or branched C １ -C ３ Alkyl, C ２ -C ３ Alkenil, C ２ -C ３ Alkynyl, cyclopropyl, linear or branched -OCH ３ -OC １ -C ３ Alkyl, -O (cyclopropyl), linear or branched -NH(C) １ -C ３ Alkyl), linear or branched -N(C) １ -C ３ (Alkyl) (C １ -C ３ Alkyl), -NH(cyclopropyl), -N(cyclopropyl) ２ , linear or branched -N(C) １ -C ３ Substituted with one or more substituents independently selected from alkyl(cyclopropyl); Here, all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and heteroaromatic residues included in the definition of Y may contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; Here, all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues included in the definition of Y, as well as the linker, may be partially or completely halogenated, in particular fluorinated, and more particularly perfluorinated; Here, the compound is defined according to formula (Ic): 【Chemistry 2】 Here, Z １ and Z ２ These combine to form a cyclic residue containing the carbon atoms to which they are bonded (general formula Ic); where the cyclic residue is selected from a 3-membered ring, a 4-membered ring, a 5-membered ring, and a 6-membered ring, where all rings may optionally contain one or more heteroatoms independently selected from O, S, and N instead of carbon atoms; where all rings are unsubstituted or -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , = O, -CH ３ and -CF ３ tert-butyloxycarbonyl, and -CH ２ C ６ H ５ It is substituted with one or more substituents independently selected from; Here, Z １ and Z ２ All cyclic residues included in the definition may be partially or completely halogenated, especially fluorinated, and more particularly perfluorinated.

2. (i) R １ Methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, sec-butyl, tert-butyl, tert-pentyl, tert-octyl, 3-pentyl, -CF ３ , -CF ２ CF ３ , - (CF ２ ) ２ CF ３ ,-CH(CF ３ ) ２ ien-CH ２ SCH ３ ien-CH ２ CH ２ SCH ３ ien-CH ２ SCH ２ CH ３ ien-CH ２ CH ２ SCH ２ CH ３ Methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, ethylmethylaminomethyl, cyclopropyl, methylcyclopropyl, ethylcyclopropyl, trifluoromethylcyclopropyl, perfluoroethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, preferably nor Bornyl, bicyclooctyl, bicyclooctenyl, bicyclononyl, methylbicyclononyl, adamantyl, tricyclodecyl, oxyranil, oxetanyl, tetrahydrofuranil, methyltetrahydrofuranil, trimethyltetrahydrofuranil, tetrahydropyranil, azilidinyl, N-methylazilidinyl, azetidinyl, N-methylazetidinyl, difluoroazetidinyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thyranil, thietanyl L, tetrahydrothiophenyl, tetrahydrothiopyranil, dioxanil, piperazinil, dimethylpiperazinil, dithianly, morpholinil, N-methylmorpholinil, thiomorpholinil, N-methylthiomorpholinil, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methyl Zaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecyl, N-methyloxa-azaspirodecyl, azaspirodecyl, N-methylazaspirodecyl, dihydrooxazinyl, N-methyldihydrooxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxolanil, imidazolidinyl, N-methylimidazolidinyl, N,N-dimethylimidazolidinyl, azepanil, N-methylazepanil, azaspirohexyl, N-methylazaspirohexyl, oxa-azasispirodecyl, N-methyloxa-azasispirodecyl, azadispirodecyl, N-methylazaspirodecyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N-methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N-methylazabicyclononyl, azaadamantyl, -O (adamantyl) Selected from oxa-azabicyclononyl, N-methyloxa-azabicyclononyl, oxa-azabicycloheptyl, N-methyloxa-azabicycloheptyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, N,N-dimethyldiazabicyclooctyl, diazabicycloheptyl, N-methyldiazabicycloheptyl, N,N-dimethyldiazabicycloheptyl; 4-oxocyclohexyl; 3-oxocyclopentyl; 2-oxocyclobutyl, 4-oxobicyclo[4.1.0]heptan-1-yl; or, (ii) R1 is selected from C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, cyclic, bicyclic or tricyclic residues; or (iii) R1 is selected from branched C4-C12 alkyl, branched C4-C12 alkenyl, branched C4-C12 alkynyl, cyclic, bicyclic or tricyclic residues; or (iv) R 1 is selected from the following: The compound according to claim 1. 【Transformation 3】

3. (i) R ２ -R ３ Each of these is -H, and / or R ４ is -H or -F, and / or R ５ -H, -F, -Cl, -Br, -CH ３ , -CF ３ ien-CH=CH ２ , -C≡CH, -CH ２ OH, -CH ２ NHCH ３ -OH, -OCH ３ , -OCF ３ Cyclopropyl, oxyranyl, -CH ２ -N-morpholinyl, -C(CH ３ ) ３ ien-CH ２ OCH ３ , -NO ２ -CN, -NH ２ , -N(CH ３ ) ２ , -OCH(CH ３ ) ２ ien-CH ２ NH ２ ien-CH ２ N(CH ３ ) ２ is, or (ii) A six-membered aromatic ring to which substituents R1 to R5 defined by general formula (I) are attached is selected from the following: A compound according to any one of claims 1 to 2. 【Chemistry 4】

4. X defined by general formula (I) １ -X ４ A compound according to any one of claims 1 to 3, wherein the six-membered aromatic ring containing the compound is selected from the following. 【Transformation 5】

5. (i) Y is -OH, -OCH ３ , -OCH ２ CH ３ -O (cyclopropyl), -OC ６ H ５ , -OCH ２ C ６ H ５ , -SH, -SCH ３ , -SCH ２ CH ３ , -S (cyclopropyl), -SCH ２ C ６ H ５ , -OS(O)C(CH ３ ) ３ , -OS(O) ２ CH ３ , -OS(O) ２ CF ３ or -OS(O) ２ C ６ H ４ CH ３ is; or (ii) Y is selected from -OH, -OCH3 and -OCH2CH3, A compound according to any one of claims 1 to 4.

6. (i) Z １ and Z ２ They come together to form a three- or four-membered cyclic residue containing the carbon atoms to which they bond; or (ii) Z1 and Z2 together form a cyclic residue containing the carbon atom to which they are joined, where this cyclic residue is preferably selected from cyclopropyl, cyclobutyl, oxyranil, oxetanil, azilidinil, azetidinil, thietanil, thiazolidinil, methylthiazolidinil, thiazolidinyl-dionil, methylthiazolidinyl-dionil, oxazolidinil, methyloxazolidinil, oxazolidine-dionil, and where this cyclic residue is optionally preferably -F, -OH, -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , = O, -CH ３ tert-butyloxycarbonyl, -CF ３ and -CH ２ C ６ H ５ It is replaced by; or, (iii) Z1 and Z2 together form a cyclic residue containing the carbon atom to which they are bonded, and more preferably this cyclic residue 【Transformation 6】 A compound according to any one of claims 1 to 5, selected from among them.

7. R １ It does not contain heteroatoms; or R1 is selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl, and adamantyl, or R1 is adamantyl. A compound according to any one of claims 1 to 6.

8. R １ A compound according to any one of claims 1 to 7, wherein the structure is selected from cyclic, bicyclic, and tricyclic structures.

9. R １ A compound according to any one of claims 1 to 8, comprising four or more, preferably six or more, and more preferably seven or more carbon atoms.

10. R １ one or more, preferably 1 to 2, R １ A compound according to any one of claims 1 to 6 and 8 to 9, comprising a heteroatom independently selected from O, S, and N instead of a carbon atom contained in.

11. The compound's structure 【Transformation 7】 (In the formula, Z １ and Z ２ This is defined in general formula (I), including general formula (Ic), including substituents and preferred definitions, R ２ -R ５ , R ８ -R １１ , X １ -X ４ (and Y is as defined in general formula (I), including substituents and preferred definitions); or 【Transformation 8】 (wherein Z1 and Z2 are defined as in general formula (I), including the substituents and preferred definitions, R2-R5, R9-R11, X1-X4, and Y are as defined in general formula (I), including substituents and preferred definitions; or 【Chemistry 9】 (In the formula, R5 is different from -H, Z1 and Z2 are defined in general formula (I), including general formula (Ic), including substituents and preferred definitions. R2-R5, R8-R11, X1-X4, and Y are as defined in general formula (I), including their substituents and preferred definitions. A compound according to any one of claims 1 to 9, having the following characteristics:

12. The compound's structure 【Chemistry 10】 (In the formula, R １ C is an unsubstituted or substituted C as defined in general formula (I), including substituents and preferred definitions. ６ -C ８ Cycloalkyl, C ６ -C ８ Cycloalkenyl, C ６ -C １２ Bicycloalkyl, C ７ -C １２ Bicycloalkenyl, C ８ -C １４ Selected from tricycloalkyl, R １ Any carbon atom contained therein can be independently substituted with a heteroatom selected from O, S, and N as defined in general formula (I), Z １ and Z ２ This is defined in general formula (I), including general formula (Ic), including substituents and preferred definitions, Y is defined in general formula (I), including substituents and preferred definitions, R ２ -R １１ and X １ -X ４ (including substituents and preferred definitions, as defined in general formula (I); or 【Chemistry 11】 (wherein Z1 and Z2 together form a cyclic residue containing a carbon atom to which they are bonded, and Z1 and Z2 are as defined in general formula (Ic), where the cyclic residue is a four-membered ring, and the cyclic residue preferably contains one heteroatom selected from O, S and N instead of a carbon atom, and / or the cyclic residue is preferably substituted as defined in general formula (I), wherein the cyclic residue is optionally not perhalized.) And Y is defined in general formula (I), (and R1 - R11 and X1 - X4 are as defined in general formula (I); or 【Chemistry 12】 (In the formula, Z1 and Z2 together form a cyclic residue containing the carbon atom to which they are bonded, and Z1 and Z2 are as defined in general formula (Ic), And Y is as defined in general formula (I), except that Y is different from -OH and -OCH3. (and R1 - R11 and X1 - X4 are as defined in general formula (I); or 【Chemistry 13】 (In the formula, Z1 and Z2 together form a cyclic residue containing the carbon atom to which they are bonded, and Z1 and Z2 are as defined in general formula (Ic), where the cyclic residue is not perhalated.) And R1 is as defined in general formula (I), wherein R1 optionally contains two or more carbon atoms. (and R2 - R11 and X1 - X4 are as defined in general formula (I); or 【Chemistry 14】 (In the formula, Z1 and Z2 together form a cyclic residue containing the carbon atom to which they are bonded, and Z1 and Z2 are as defined in general formula (Ic), except that the cyclic residue is optionally different from oxyranyl, (And R1 - R11 and X1 - X4 are as defined in general formula (I)). A compound according to any one of claims 1 to 11, having the following characteristics:

13. The following compounds or their salts or solvates. 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】

14. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 13 or a salt or solvate thereof, and a pharmaceutically acceptable carrier.

15. A compound or salt or solvate thereof described in any one of claims 1 to 13 for treating an associated and / or caused disorder related to dysfunctional notch signaling; or A pharmaceutical composition for enhancing notch signaling.

16. A pharmaceutical composition for treating hyperproliferative disorders, comprising a compound described in any one of claims 1 to 13 or a salt or solvate thereof, including malignant and non-malignant hyperproliferative disorders.

17. A compound or a salt or solvate thereof described in any one of Claims 1 to 13, comprising: (i) cancers such as non-melanoma skin cancer including squamous cell carcinoma and basal cell carcinoma and precancerous lesions including actinic keratosis; skin and / or mucosal disorders with keratinization defects and / or abnormal keratinocyte proliferation; skin and / or mucosal diseases associated with, accompanying and / or caused by, viral infections; diseases of the skin, mucous membranes, skin and mucosal appendages, cornea and epithelial tissues, including atopic dermatitis, psoriasis and acne; and in promoting the healing of skin and mucous membrane wounds; or (ii) hyperproliferative disorders, cancers or precancerous lesions of the skin, oral mucosa, tongue, lungs, stomach, and breast; thyroid A pharmaceutical composition for treating immune system-related disorders, including leukemia and lymphoma, and hematopoietic system disorders, such as cancers of the vascular system, including adenomedullary carcinoma, cancers of the neuroendocrine system including the brain, pancreas, gastrointestinal tract, liver, esophagus, thyroid, cervical cancer and ovarian cancer; or (iii) malignant and non-malignant muscle diseases, including muscular dystrophy, or in muscle regeneration, or in hyperproliferative disorders of muscle such as muscle hyperplasia and muscle hypertrophy; or (iv) malignant tumors of the myeloid system, such as acute and chronic myeloid leukemia and acute and chronic promyelocytic leukemia, and malignant tumors of the lymphoid system, such as acute and chronic T-cell leukemia and acute and chronic B-cell leukemia and cutaneous T-cell lymphoma.

18. A pharmaceutical composition for treating cancer and precancerous lesions, comprising a compound described in any one of claims 1 to 13 or a salt or solvate thereof.

19. The pharmaceutical composition of claim 18, wherein (i) the cancer is related to and / or caused by viral infection and oncoviral infection; and / or (ii) the cancer is related to and / or caused by viral infection and oncoviral infection, such as HBV and HCV (hepatitis B and C viruses) such as liver cancer, EBV (Epstein-Barr virus) such as Burkitt lymphoma, Hodgkin lymphoma and non-Hodgkin lymphoma and gastric cancer, HPV (human papillomavirus) such as cervical cancer, HHV (human herpesvirus) such as Kaposi's sarcoma, and HTLV (human T lymphotrophic virus) such as T-cell leukemia and T-cell lymphoma.

20. A pharmaceutical composition for use in therapeutic immune system-related applications, including immunotherapy and other immunotherapies such as use as an immunological adjuvant or vaccine adjuvant, comprising a compound described in any one of claims 1 to 13 or a salt or solvate thereof.

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