Phenoxy(hetero)aryl ethers with antiproliferative activity

Abstract

The present invention includes novel aromatic molecules which can be used for treating pathological conditions in human and veterinary medicine, such as cancer, skin diseases, muscle disorders, and immune system-related disorders, such as disorders of the hematopoietic system including the blood system.

Description

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

[0002] Description of the Invention

[0003] The present invention encompasses novel molecules that exhibit significant biological activity against cells of human and animal origin. It has been found that the corresponding compounds affect the growth and survival of cancer cells and primary non-cancerous cells. In particular, molecules capable of completely or partially inhibiting cell growth or causing cell death have been identified.

[0004] Accordingly, the present invention relates to compounds having anti-proliferative activity as defined herein, which can be used to treat benign and malignant hyperproliferative disorders in human and veterinary medicine. Specifically, the present invention relates to compounds as defined herein for treating the following disorders in human and veterinary medicine: compounds for hematopoietic system disorders (including blood system and immune system related disorders), related to myeloid and lymphoid malignancies, malignant and non-malignant diseases of the skin and mucosa (such as keratosis), malignant and non-malignant diseases of the muscle (including muscle hyperplastic diseases, such as muscle hyperplasia and muscle hypertrophy), neuroendocrine system disorders, hyperproliferative disorders, cancers and precancerous lesions of the skin and mucosa, such as non-melanoma skin cancer (including squamous cell carcinoma and basal cell carcinoma), actinic keratosis, hyperproliferative diseases and cancers of the oral cavity and tongue, hyperproliferative disorders and cancers of the neuroendocrine system (such as medullary thyroid carcinoma), hyperproliferative diseases and cancers of the hematopoietic system (including blood system) (such as leukemia and lymphoma), hyperproliferative disorders and cancers of the lung, breast, stomach, urogenital tract, such as cervical cancer, including ovarian cancer.

[0005] The compounds of the present invention relate to a biaryl ether structure composed of two six-membered aromatic rings, wherein one of the aromatic rings is an unsubstituted or substituted benzyl ring, and the other aromatic ring is an unsubstituted or substituted aryl ring, which optionally contains an N atom and is thus optionally a six-membered heteroaromatic ring. All such biaryl ether structures share the common feature of having substituents at both para positions relative to the ether bond, wherein such substituents that cannot be heteroaromatic rings on the benzyl ring are preferably selected from non-polar residues and / or sterically demanding residues; and wherein such substituents that are optionally heteroaromatic rings on the aryl ring are selected from structural units preferably containing a large number of heteroatoms.

[0006] A first aspect of the present invention relates to compounds of formula (I) and their salts and solvates:

[0007]

[0008] R 1= C1–C 12 alkyl, preferably C4–C 12 alkyl, C2–C 12 alkenyl, preferably C4–C 12 alkenyl, C2–C 12 alkynyl, preferably C4–C 12 alkynyl, C3–C8 cycloalkyl, C5–C8 cycloalkenyl, C5–C 12 bicycloalkyl, C7–C 12 bicycloalkenyl, C8–C 14 tricycloalkyl, -OC1–C 12 alkyl, preferably -OC3–C 12 alkyl, -OC2–C 12 alkenyl, preferably -OC3–C 12 alkenyl, -OC2–C 12 alkynyl, preferably -OC3–C 12 alkynyl, -OC3–C8 cycloalkyl, -OC5–C8 cycloalkenyl, -OC5–C 12 bicycloalkyl, -OC7–C 12 bicycloalkenyl, -OC8–C 14 tricycloalkyl, -SC1–C 12 alkyl, preferably -SC3–C 12 alkyl, -SC2–C 12 alkenyl, preferably -SC3–C 12 alkenyl, -SC2–C 12 alkynyl, preferably -SC3–C 12 alkynyl, -SC3–C8 cycloalkyl, -SC5–C8 cycloalkenyl, -SC5–C 12 bicycloalkyl, -SC7–C 12 bicycloalkenyl, -SC8–C 14 tricycloalkyl, -NHR 9 or -NR 9 R 10 wherein R 9 and R 10 are each independently selected from: C1–C 12 alkyl, preferably C3–C 12 alkyl, C2–C 12 alkenyl, preferably C3–C 12 alkenyl, C2–C 12 alkynyl, preferably C3–C 12 alkynyl, C3–C8 cycloalkyl, C5–C8 cycloalkenyl, C5–C 12 bicycloalkyl, C7–C 12 bicycloalkenyl, C8–C 14 tricycloalkyl, or wherein R 9 may be combined with R10 Together form a ring structure, wherein the ring structure containing N atoms is selected from 3- to 8-membered cyclic structures or 5- to 12-membered bicyclic structures, and wherein all of said ring structures may additionally contain one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in the ring structure, in particular wherein such replacement results in a residue containing at least twice as many C atoms as the number of heteroatoms independently selected from O, S, and N;

[0009] Wherein contained in R 1 、R 9 and R 10 All alkyl, alkenyl, and alkynyl residues in the definitions of are straight-chain or branched-chain and are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, C3–C8 cycloalkyl, C5–C8 cycloalkenyl, C5–C 12 bicycloalkyl, C7–C 12 bicycloalkenyl, C8–C 14 tricycloalkyl, straight-chain or branched-chain -OC1–C5 alkyl such as -OCH3, -OC3–C5 cycloalkyl such as –O(cyclopropyl), straight-chain or branched-chain -NH(C1–C5 alkyl), straight-chain or branched-chain -N(C1–C5 alkyl)(C1–C5 alkyl), -NH(C3–C5 cycloalkyl) such as -NH(cyclopropyl), -N(C3–C5 cycloalkyl)(C3–C5 cycloalkyl), straight-chain or branched-chain -N(C1–C5 alkyl)(C3–C5 cycloalkyl);

[0010] Wherein when the alkyl, alkenyl, and alkynyl residues in the definitions of contained in R 1 、R 9 and R 10 are substituted by one or more substituents that are =O, such substitution with =O cannot result in one of the groups selected from C=O, S=O, and N=O being directly bonded to the aromatic ring;

[0011] Wherein contained in R 1 、R 9 and R 10All cyclic, bicyclic, and tricyclic structures in the definition, including cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues, are unsubstituted or substituted with one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, =O, straight-chain or branched C1–C5 alkyl such as -CH3, straight-chain or branched -OC1–C5 alkyl such as -OCH3, straight-chain or branched -NH(C1–C5 alkyl), straight-chain or branched -N(C1–C5 alkyl)(C1–C5 alkyl), -NH(C3–C5 cycloalkyl) such as -NH(cyclopropyl), -N(C3–C5 cycloalkyl)(C3–C5 cycloalkyl), straight-chain or branched -N(C1–C5 alkyl)(C3–C5 cycloalkyl);

[0012] wherein all alkyl, alkenyl, and alkynyl residues included in the definition of R 1 , R 9 , and R 10 may contain one or more heteroatoms independently selected from O, S, and N in place of carbon atoms, and wherein such substitution results in the residue containing at least twice the number of C atoms as the number of heteroatoms independently selected from O, S, and N, and wherein such substitution additionally does not result in one of the groups selected from C=O, S=O, and N=O being directly bonded to an aromatic ring;

[0013] wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition of R 1 , R 9 , and R 10 may contain one or more heteroatoms independently selected from O, S, and N in place of carbon atoms, and wherein such substitution results in the residue containing at least the same number of carbon atoms as the number of heteroatoms independently selected from O, S, and N;

[0014] wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues included in the definition of R 1 , R 9 , and R 10 may be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;

[0015] wherein bicyclic and tricyclic residues include fused, bridged, and spiro ring systems;

[0016] and wherein R 1Preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, sec-butyl, tert-butyl, tert-pentyl, tert-octyl, 3-pentyl, -CF3, -CF2CF3, -(CF2)2CF3, -CH(CF3)2, -CH2SCH3, -CH2CH2SCH3, -CH2SCH2CH3, -CH2CH2SCH2CH3, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, dimethyl-aminomethyl, dimethyl-aminoethyl, diethyl-aminomethyl, ethyl-methyl-aminomethyl, cyclopropyl, methyl-cyclopropyl, ethyl-cyclopropyl, trifluoromethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, dicyclopentyl, dicyclohexyl, bicycloheptyl (preferably norbornyl), bicyclooctyl, bicyclooctenyl, bicyclononyl, methylbicyclononyl, adamantyl, tricyclodecyl, oxiranyl, oxetanyl, tetrahydrofuryl, methyltetrahydrofuryl, trimethyltetrahydrofuryl, tetrahydropyranyl, aziridinyl, N-methylaziridine, azetidinyl, N-methylazetidinyl, difluoroazetidinyl, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thiiranyl, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethylpiperazinyl, dithianly, morpholinyl, N-methylmorpholinyl, thiomorpholinyl, N-methylthiomorpholinyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methylazaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecanyl, N-methyloxa-azaspirodecanyl, azaspirodecanyl, N-methylazaspirodecanyl, dihydro-oxazinyl, N-methyldihydro-oxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxolanyl, imidazolidinyl, N-methylimidazolidinyl, N,N-dimethylimidazolidinyl, azepanyl, N-methylazepanyl, azaspirohexyl, N-methylazaspirohexyl, oxa-azaspirododecyl, N-methyloxa-azaspirododecyl, azaspirododecyl, N-methylazaspirododecyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N-methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N-methylazabicyclononyl, azadamantyl, -O(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]hept-1-yl;,

[0017] and wherein R 1 is even more preferably selected from C4–C 12 alkyl, C4–C 12 alkenyl, C4–C 12 alkynyl, cyclic, bicyclic and tricyclic residues, wherein the alkyl, alkenyl and alkynyl residues are preferably branched, including:

[0018]

[0019] R 2 –R 5 are each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C4 alkyl, straight-chain or branched C2–C4 alkenyl, straight-chain or branched C2–C4 alkynyl, C3–C6 cycloalkyl, -CH2(C3–C6 cycloalkyl), straight-chain or branched -OC1–C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl);

[0020] wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues included in the definition of R 2 –R 5 are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2;

[0021] wherein included in R2 –R 5 All alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of may include one or more heteroatoms independently selected from O, S and N in the substitution of carbon atoms, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring;

[0022] wherein R 2 –R 3 are each preferably -H, R 4 is preferably -H or -F, R 5 is preferably -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;

[0023] wherein the substituents R 1 to R 5 bonded to the six-membered aromatic ring are preferably selected from:

[0024]

[0025] X 1 –X 4 are each independently selected from N, CR 11 , CR 12 , CR 13 , CR 14 ;

[0026] R 11 –R 14 are each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C4 alkyl, straight-chain or branched C2–C4 alkenyl, straight-chain or branched C2–C4 alkynyl, C3–C6 cycloalkyl, -CH2(C3–C6 cycloalkyl), straight-chain or branched -OC1–C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl);

[0027] wherein included in R 11 –R 14All alkyl, alkenyl, alkynyl, and cycloalkyl residues in the definition are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2;

[0028] wherein all alkyl, alkenyl, alkynyl, and cycloalkyl residues included in R 11 –R 14 may include one or more heteroatoms independently selected from O, S, and N in the replacement of carbon atoms, and wherein such replacement cannot result in one of the groups selected from C═O and S═O being directly bonded to the aromatic ring;

[0029] wherein R 11 –R 14 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;

[0030] and wherein the six-membered aromatic ring containing X 1 –X 4 in the general formula (I) is preferably selected from:

[0031]

[0032] R 6 and R 7 are independently selected from -H, -F, -CH3; or R 6 and R 7 together form a cyclic residue containing the carbon atom to which they are attached, and wherein the cyclic residue is C3 cycloalkyl;

[0033] R 8 is selected from -H, C1–C3 alkyl (preferably -CH3), C2–C3 alkenyl, C2–C3 alkynyl, -F, -CF3, and aromatic and heteroaromatic residues (preferably six-membered aromatic rings and five- to six-membered heteroaromatic rings);

[0034] wherein the aromatic and heteroaromatic residues included in the definition of R 8 may optionally be connected to the carbon atom to which R 8 is attached via a C1 alkylene or C2 alkylene linker;

[0035] wherein included in R 8All aromatic and heteroaromatic residues in the definition of are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C3 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, cyclopropyl, straight-chain or branched -OC1–C3 alkyl such as -OCH3, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl);

[0036] Wherein all heteroaromatic residues contained in R 8 may contain one or more heteroatoms independently selected from O, S, and N, substituting for C atoms;

[0037] Wherein all alkyl, alkenyl, and alkynyl residues contained in R 8 are straight-chain or branched and are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, and -NH2;

[0038] Wherein R 8 is preferably -H, -F, -CH3, -CH2CH3 -CF3, -C6H5;

[0039] Wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic, and heteroaromatic residues contained in R 2 –R 8 and R 11 –R 14 may be partially or fully halogenated, particularly fluorinated, and more particularly perfluorinated;

[0040] Z 1 and Z 2 are selected from the following group:

[0041]

[0042] Wherein Z 1 is selected from -H, straight-chain or branched C1–C3 alkyl (preferably -CH3), cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -N3, -CF3, -CF2CF3, and wherein Z 2 is independently selected from straight-chain or branched C1–C3 alkyl, preferably -CH3, -CF3, -CF2CF3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3, -CN, and -OR15 (General formula Ia), where R 15 is selected from -H, C1–C8 alkyl, preferably C1–C4 alkyl, C2–C8 alkenyl, preferably C2–C4 alkenyl, C2–C8 alkynyl, preferably C2–C4 alkynyl, C3–C6 cycloalkyl, C5–C6 cycloalkenyl, C5–C 12 bicycloalkyl, C7–C 12 bicycloalkenyl, C8–C 14 tricycloalkyl, and aromatic and heteroaromatic residues, preferably five- to six-membered aromatic rings and five- to six-membered heteroaromatic rings;

[0043] and wherein the bicyclic and tricyclic residues include fused, bridged and spiro systems;

[0044] wherein the cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues included in the definition of R 15 may optionally be linked via a C1 alkylene or C2 alkylene or C3 alkylene linker to the O to which R 15 is attached;

[0045] wherein all aromatic and heteroaromatic residues included in the definition of R 15 are unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C3 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, cyclopropyl, straight-chain or branched -OC1–C3 alkyl such as -OCH3, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl);

[0046] wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues and alkylene linkers included in the definition of R 15 are straight-chain or branched and are unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, =O, straight-chain or branched C1–C3 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, cyclopropyl, straight-chain or branched -OC1–C3 alkyl such as -OCH3, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl);

[0047] All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaromatic residues and alkylene linkers included in the definition of R 15 may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms;

[0048] All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaromatic residues and alkylene linkers included in the definition of R 15 may be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated

[0049] wherein R 15 is preferably -H, -CH3, -CH2CH3, n-propyl, isopropyl, cyclopropyl, benzyl;

[0050] wherein Z 1 is preferably -H, -CH3, -CF3 and cyclopropyl; and / or wherein Z 2 is preferably -OH, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2-C6H4-Me and -CN; for example:

[0051]

[0052] or wherein Z 1 and Z 2 together are =O, =S, =NR 16 , or the zwitterion =N [+] R 17 O [–] (general formula Ib); wherein R 16 is selected from -H, -OH, -OCH3, -CN, -S(O)CH3, -S(O)CF3, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, linear or branched C1–C3 alkyl (preferably -CH3), cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5 and -CH2C6H5; wherein R 17 is selected from linear or branched C1-C3 alkyl (preferably -CH3), cyclopropyl, -C6H5 and -CH2C6H5;

[0053] wherein Z 1 and Z 2 together are preferably =O, =NR 16 or the zwitterion =N [+] R 17 O [–] ; wherein R 16 is preferably selected from -H, -OH, -OCH3, -CH3, cyclopropyl and -CH2C6H5; wherein R17 Preferably -CH3, -C(CH3)3 and -CH2C6H5:

[0054]

[0055] or wherein Z 1 and Z 2 together form a cyclic residue (general formula Ic) containing the carbon atoms to which they are attached; wherein said cyclic residue is selected from three-membered, four-membered, five-membered and six-membered rings, wherein all rings may optionally contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms; wherein all rings are unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3;

[0056] wherein Z 1 and Z 2 together preferably form a three-membered or four-membered or five-membered cyclic residue, said cyclic residue containing the carbon atoms to which they are attached; wherein said cyclic residue is preferably selected from cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl, thietanyl, thiazolyl, methylthiazolyl, thiazolidine-dionyl, methylthiazolidine-dionyl and oxazolyl, methyloxazolyl, oxazolidine-dionyl and methyloxazolidine-dionyl; and wherein said cyclic residue is optionally preferably substituted by -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3;

[0057]

[0058] wherein all alkyl and cyclic residues included in the definition of Z 1 and Z 2 may be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated.

[0059] R 1 –R 17 、X 1 –X 4 、Z 1 and Z 2 The following preferred definitions of

[0060] 1) R 1Preferably contain four or more, preferably six or more, even more preferably seven or more carbon atoms;

[0061] 2) R 1 Preferably selected from branched alkyl, alkenyl and alkynyl residues;

[0062] 3) R 1 Preferably selected from cyclic, bicyclic and tricyclic structures, wherein the bicyclic and tricyclic residues include fused, bridged and spiro ring systems;

[0063] 4) R 1 Preferably free of heteroatoms;

[0064] 5) R 1 Preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methyldicyclononyl, tricyclodecyl, most preferably adamantyl, such as 1 - adamantyl and 2 - adamantyl;

[0065] 6) R 1 Preferably contains one or more heteroatoms, preferably one, two or three heteroatoms independently selected from O, S and N to replace the carbon atoms contained in R 1 ;

[0066] 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, azadamantyl and - O(adamantyl);

[0067] 8) Preferably two, or more preferably three substituents independently selected from R 2 –R 5 are - H, that is, preferably two substituents independently selected from R 2 –R 5 are, more preferably one of the substituents is different from - H;

[0068] 9) When two substituents independently selected from R 2 –R 5 are different from - H and are in the ortho position relative to the ether bond, these two substituents are preferably different from - F, - Cl, - Br, - I and - NO2, more preferably different from each other;

[0069] 10) The composition of the ring atoms defined by X 1 –X 4 is preferably selected from the following cases: all X 1 –X 4 are independently selected from CR 11 、CR12 , CR 13 , CR 14 , or X 1 –X 4 One of them is N, and the other three are independently selected from CR 11 , CR 12 , CR 13 , CR 14 , or X 1 –X 4 Two of them are N, and the other two are independently selected from CR 11 , CR 12 , CR 13 , CR 14 ; that is, the aromatic or heteroaromatic ring is selected from benzene, pyridine, pyrimidine, pyridazine, and pyrazine;

[0070] 11) Preferably two, or more preferably three substituents independently selected from R 11 –R 14 are -H, that is, preferably two substituents independently selected from R 11 –R 14 , and more preferably one of the substituents is different from -H;

[0071] 12) When two substituents independently selected from R 11 –R 14 are different from -H and are in the ortho position relative to the ether bond, these two substituents are preferably different from -F, -Cl, -Br, -I, and -NO2, and more preferably different from each other;

[0072] 13) R 6 , R 7 , and R 8 are preferably each -F;

[0073] 14) R 6 and R 7 preferably together form a cyclic residue containing the carbon atom to which they are attached, and wherein the cyclic residue is cyclopropyl.

[0074] A preferred aspect of the present invention relates to compounds of formula (I) and their salts and solvates, wherein R 6 , R 7 , and R 8 are each -F,

[0075] and R 1 –R 5 , R 9 –R 17 , X 1 –X 4 , Z 1 and Z 2As defined in general formula (I), including substituted and preferred definitions.

[0076] A further preferred aspect of the present invention relates to compounds of general formula (Ia) and their salts and solvates, wherein R 6 , R 7 and R 8 are each -F or each -H, and wherein Z 2 is -OH or -OS(O)2CH3,

[0077] and R 1 –R 5 , R 9 –R 14 , X 1 –X 4 and Z 1 are as defined in general formula (I), including substituted and preferred definitions.

[0078] A further preferred aspect of the present invention relates to compounds of general formula (Ia) and their salts and solvates, wherein R 6 and R 7 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein said cyclic residue is cyclopropyl, and wherein R 8 is -H,

[0079] and wherein Z 1 is selected from -H, -CH3 and -CF3, and wherein Z 2 is -OH or -OS(O)2CH3,

[0080] and R 1 –R 5 , R 9 –R 14 and X 1 –X 4 are as defined in general formula (I), including substituted and preferred definitions.

[0081] A further preferred aspect of the present invention relates to compounds of general formula (I) and their salts and solvates, wherein R 1 is selected from the residues included in the general definition of R 1 which contains four or more, preferably six or more, even more preferably seven or more carbon atoms,

[0082] and wherein R 1 contains no heteroatoms,

[0083] and wherein R 1 is more preferably selected from cyclic, bicyclic and tricyclic structures,

[0084] and wherein R 1Even more preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl, and adamantyl,

[0085] and wherein R 1 is most preferably adamantyl,

[0086] and R 2 –R 8 、R 11 –R 17 、X 1 –X 4 、Z 1 and Z 2 are as defined in general formula (I), including the substituted and preferred definitions.

[0087] Another preferred aspect of the present invention relates to compounds of general formula (I) and their salts and solvates, wherein R 1 is selected from residues included in the general definition of R 1 which contains four or more, preferably six or more, even more preferably seven or more carbon atoms,

[0088] and wherein R 1 contains one or more (preferably 1 to 2) heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in R 1 ,

[0089] and wherein R 1 is even more preferably selected from cyclic, bicyclic, and tricyclic structures, or wherein R 1 is selected from residues containing cyclic, bicyclic, and tricyclic structures,

[0090] and wherein R 1 is even more preferably 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),

[0091] and wherein R 1 is most preferably tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicyclooctyl, aza-adamantyl, and -O(adamantyl),

[0092] and R 2 –R 17 、X 1 –X 4 、Z 1 and Z 2As defined in general formula (I), including substituted and preferred definitions.

[0093] In certain embodiments, the present invention relates to compounds of general formula (I) and their salts and solvates, wherein R 1 is adamantyl,

[0094] and wherein Z 1 and Z 2 As defined in general formula (I) (including general formula (Ia), general formula (Ib) and general formula (Ic)), including substituted and preferred definitions,

[0095] and wherein R 15 As defined in general formula (Ia), including substituted and preferred definitions, and wherein R 16 and R 17 As defined in general formula (Ib), including substituted and preferred definitions,

[0096] and wherein R 2 –R 8 、R 11 –R 14 and X 1 –X 4 As defined in general formula (I), including substituted and preferred definitions,

[0097] and wherein the compounds share the following structure (I-1):

[0098]

[0099] and wherein the compounds of structure (I-1) are preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancers.

[0100] Examples are the compounds XPF-0014, XPF-0042, XPF-0070, XPF-0182, XPF-0210, XPF-0266, XPF-0434, XPF-0476, XPF-0504, XPF-0518, XPF-0630, XPF-1162, XPF-1190, XPF-1330, XPF-1554, XPF-1596, XPF-1624, XPF-2242, XPF-2244, XPF-2245, XPF-2247, XPF-2251, XPF-2252, XPF-2253 and XPF-2254.

[0101] In yet another specific embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, wherein R 1 As defined in general formula (I), including substituted and preferred definitions, wherein R 1 Is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 Contains six or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I),

[0102] Wherein R 6 As defined in general formula (I), including substituted and preferred definitions, wherein R 6 Is different from -H, with the optional condition that R 6 Is different from -CH3,

[0103] And wherein Z 1 And Z 2 As defined in general formula (I) (including general formula (Ia), general formula (Ib) and general formula (Ic)), including substituted and preferred definitions,

[0104] And wherein R 15 As defined in general formula (Ia), including substituted and preferred definitions, and wherein R 16 And R 17 As defined in general formula (Ib), including substituted and preferred definitions,

[0105] And wherein R 2 –R 5 、R 7 –R 14 And X 1 –X 4 As defined in general formula (I), including substituted and preferred definitions,

[0106] And wherein the compounds share the following structure (I-2):

[0107]

[0108] And the compounds of structure (I-2) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and cancers of the neuroendocrine system.

[0109] Examples are the compounds XPF-0042, XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0426, XPF-0429, XPF-0434, XPF-0454, XPF-0469, XPF-0476, XPF-0496, XPF-0504, XPF-0518, XPF-0630, XPF-1162, XPF-1182, XPF-1185, XPF-1190, XPF-1196, XPF-1322, XPF-1325, XPF-1330, XPF-1546, XPF-1549, XPF-1554, XPF-1588, XPF-1596, XPF-1602, XPF-1616, XPF-1624, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2245, XPF-2246, XPF-2247, XPF-2248, XPF-2249, XPF-2250, XPF-2251, XPF-2252, XPF-2253 and XPF-2254.

[0110] In another specific embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, and wherein R 1 As defined in general formula (I), including substituted and preferred definitions, wherein R 1 Is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 Contains six or more carbon atoms, which are optionally independently substituted by heteroatoms selected from O, S and N as defined in general formula (I),

[0111] Wherein R 8 As defined in general formula (I), including substituted and preferred definitions, wherein R 8 Is different from -H, optionally with the additional condition that R 8Unlike -CH3,

[0112] and wherein Z 1 and Z 2 as defined in general formula (I) (including general formulas (Ia), (Ib) and (Ic)), including substituted and preferred definitions,

[0113] and wherein R 15 as defined in general formula (Ia), including substituted and preferred definitions, and wherein R 16 and R 17 as defined in general formula (Ib), including substituted and preferred definitions,

[0114] and wherein R 2 –R 7 、R 9 –R 14 and X 1 –X 4 as defined in general formula (I), including substituted and preferred definitions,

[0115] and wherein the compound has the following structure (I-3):

[0116]

[0117] and wherein the compound of structure (I-3) - especially in the absence of additional conditions - is preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancers.

[0118] Examples are compounds XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0426, XPF-0429, XPF-0434, XPF-0454, XPF-0469, XPF-0476, XPF-0496, XPF-0504, XPF-0518, XPF-0630, XPF-1182, XPF-1185, XPF-1190, XPF-1196, XPF-1322, XPF-1325, XPF-1330, XPF-1546, XPF-1549, XPF-1554, XPF-1588, XPF-1596, XPF-1602, XPF-1616, XPF-1624, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2245, XPF-2246, XPF-2247, XPF-2248, XPF-2249, XPF-2250, XPF-2251, XPF-2252, XPF-2253 and XPF-2254.

[0119] In another specific embodiment, the present invention relates to compounds of general formula (I) and their salts and solvates, wherein R 6 , R 7 and R 8 are each -H, and wherein X 1 is CR 11 , X 2 is CR 12 , X 3 is CR 13 and X 4 is CR 14 ,

[0120] and wherein R 1 is as defined in general formula (I), including substituted and preferred definitions, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally independently replaced by heteroatoms selected from O, S and N as defined in general formula (I), provided that R 1 including any substituents does not contain heteroatoms selected from O, S, N, or contains one such heteroatom,

[0121] and wherein Z 1 and Z 2 are as defined in general formula (I) (including general formula (Ia), general formula (Ib) and general formula (Ic)), including substituted and preferred definitions,

[0122] and wherein R 15 as defined in general formula (Ia), including substituted and preferred definitions, and wherein R 16 and R 17 as defined in general formula (Ib), including substituted and preferred definitions,

[0123] and wherein R 2 –R 5 and R 9 –R 14 as defined in general formula (I), including substituted and preferred definitions,

[0124] and wherein the compound has the following structure (I-4):

[0125]

[0126] and wherein the compound of structure (I-4) is preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including hematopoietic and blood system cancers (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer and neuroendocrine system cancers.

[0127] Examples are the compounds XPF-0006, XPF-0014, XPF-0174 and XPF-0182, XPF-0258, XPF-0266.

[0128] In another specific embodiment, the present invention relates to compounds of general formula (Ia) and their salts and solvates, wherein Z 2 is -OR 15 and R 15 is -H, and wherein R 6 、R 7 and R 8 are each -F,

[0129] and wherein Z 1 as defined in general formula (Ia), including substituted and preferred definitions, optionally with the proviso that Z 1 is different from -CF3,

[0130] and wherein R 1 –R 5 、R 9 –R 14 and X 1 –X 4As defined in general formula (I), including substituted and preferred definitions,

[0131] and wherein said compounds share the following structure (Ia-1):

[0132]

[0133] and wherein the compounds of structure (Ia-1) - especially in the absence of additional conditions - are preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and cancers of the neuroendocrine system.

[0134] Examples are the compounds XPF-0057, XPF-0058, XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0169, XPF-0170, XPF-0174, XPF-0182, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0630, XPF-1178, XPF-1182, XPF-1185, XPF-1190, XPF-1322, XPF-1325, XPF-1330, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2248, XPF-2251 and XPF-2252.

[0135] In yet another specific embodiment, the present invention relates to compounds of general formula (Ia) and their salts and solvates, wherein Z 1 is cyclopropyl,

[0136] and wherein R 1 is as defined in general formula (I), including substituted and preferred definitions, optionally with the additional condition that R 1 is different from -CF3 and -CHF2,

[0137] and wherein Z 2 and R 15 are as defined in general formula (Ia), including substituted and preferred definitions,

[0138] and wherein R 2 –R 14 and X 1 –X 4As defined in general formula (I), including the substituted and preferred definitions,

[0139] and wherein said compounds share the following structure (Ia-2):

[0140]

[0141] and wherein the compounds of structure (Ia-2) - especially in the absence of additional conditions - are preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer and cancers of the neuroendocrine system.

[0142] Examples are the compounds XPF-0202, XPF-0205, XPF-0210, XPF-1322, XPF-1325 and XPF-1330.

[0143] In yet another specific embodiment, the present invention relates to compounds of general formula (Ia) and their salts and solvates, wherein R 6 and R 7 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein said cyclic residue is C3 cycloalkyl, i.e., cyclopropyl,

[0144] and wherein Z 1 、Z 2 and R 15 as defined in general formula (Ia), including the substituted and preferred definitions,

[0145] and wherein R 1 –R 5 、R 8 –R 14 and X 1 –X 4 as defined in general formula (I), including the substituted and preferred definitions,

[0146] and wherein said compounds share the following structure (Ia-3):

[0147]

[0148] And the compounds of structure (Ia-3) are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, ovarian cancer and cancers of the neuroendocrine system.

[0149] Examples are the compounds XPF-0042, XPF-0202, XPF-0205, XPF-0210, XPF-1162, XPF-1322, XPF-1325 and XPF-1330.

[0150] In another specific embodiment, the present invention relates to compounds of general formula (Ia) and their salts and solvates, wherein R 6 、R 7 and R 8 are each -F,

[0151] and wherein Z 1 is as defined in general formula (Ia), including substituted and preferred definitions, optionally with the additional condition that Z 1 is different from -CF3,

[0152] and wherein Z 2 and R 15 are as defined in general formula (Ia), including substituted and preferred definitions,

[0153] and wherein R 1 –R 5 、R 9 –R 14 and X 1 –X 4 are as defined in general formula (I), including substituted and preferred definitions,

[0154] and wherein the compounds share the following structure (Ia-4):

[0155]

[0156] And the compounds of structure (Ia-4) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and cancers of the neuroendocrine system.

[0157] Examples are the compounds XPF-0057, XPF-0058, XPF-0062, XPF-0063, XPF-0064, XPF-0065, XPF-0070, XPF-0169, XPF-0170, XPF-0174, XPF-0182, XPF-0202, XPF-0205, XPF-0210, XPF-0230, XPF-0630, XPF-1178, XPF-1182, XPF-1185, XPF-1190, XPF-1196, XPF-1322, XPF-1325, XPF-1330, XPF-2241, XPF-2242, XPF-2243, XPF-2244, XPF-2248, XPF-2251 and XPF-2252.

[0158] In yet another specific embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, wherein Z 1 and Z 2 together are =NR 16 and wherein R 6 , R 7 and R 8 are each -F,

[0159] and wherein R 1 is as defined in general formula (I), including the substituted and preferred definitions, optionally with the additional condition that R 1 is different from -CF3,

[0160] and wherein R 16 is as defined in general formula (Ib), including the substituted and preferred definitions,

[0161] and wherein R 2 –R 5 , R 9 –R 14 and X 1 –X 4 are as defined in general formula (I), including the substituted and preferred definitions,

[0162] and wherein said compounds share the following structure (Ib-1):

[0163]

[0164] and wherein the compounds of structure (Ib-1) - especially without additional conditions - are preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and cancers of the neuroendocrine system.

[0165] Examples are the compounds XPF-0454, XPF-0469, XPF-0476, XPF-1588, XPF-1596, XPF-1602 and XPF-2249.

[0166] In yet another specific embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, wherein Z 1 and Z 2 together are an zwitterionic =N [+] R 17 O [–] ,

[0167] and wherein R 17 is as defined in general formula (Ib), including the substituted and preferred definitions,

[0168] and wherein R 1 –R 14 and X 1 –X 4 are as defined in general formula (I), including the substituted and preferred definitions,

[0169] and wherein said compounds share the following structure (Ib-2):

[0170]

[0171] and wherein the compounds of structure (Ib-2) are preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer and cancers of the neuroendocrine system.

[0172] The examples are the compounds XPF-0496, XPF-0504, XPF-1616 and XPF-1624.

[0173] In yet another specific embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, wherein Z 1 and Z 2 together are an zwitterionic =N [+] R 17 O [–] ,

[0174] wherein R 6 , R 7 and R 8 are each -F,

[0175] and wherein R 17 is as defined in general formula (Ib), including the substituted and preferred definitions,

[0176] and wherein R 1 –R 5 , R 9 –R 14 and X 1 –X 4 are as defined in general formula (I), including the substituted and preferred definitions,

[0177] and wherein the compounds share the following structure (Ib-3):

[0178]

[0179] and wherein the compounds of structure (Ib-3) are preferably for human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer and neuroendocrine system cancers.

[0180] The examples are the compounds XPF-0496, XPF-0504, XPF-1616 and XPF-1624.

[0181] In yet another specific embodiment, the present invention relates to compounds of general formula (Ib) and their salts and solvates, wherein Z 1 and Z 2 together are =O, and wherein R 6 , R 7 and R 8 are each -F,

[0182] and wherein R 1 as defined in general formula (I), including substituted and preferred definitions, optionally with the additional condition that R 1 is different from -CH3 and -OCH3,

[0183] and wherein R 2 –R 5 、R 9 –R 14 and X 1 –X 4 as defined in general formula (I), including substituted and preferred definitions,

[0184] and wherein the compounds share the following structure (Ib-4):

[0185]

[0186] and wherein the compounds of structure (Ib-4) - especially in the absence of additional conditions - are preferably used in human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer and neuroendocrine system cancers.

[0187] Examples are the compounds XPF-0421, XPF-0422, XPF-0426, XPF-0429, XPF-0434, XPF-1541, XPF-1542, XPF-1546, XPF-1549, XPF-1554, XPF-2245, XPF-2246, XPF-2247, XPF-2250, XPF-2253 and XPF-2254.

[0188] In yet another specific embodiment, the present invention relates to compounds of general formula (Ic) and their salts and solvates, wherein Z 1 and Z 2 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein Z 1 and Z 2 as defined in general formula (Ic), including substituted and preferred definitions,

[0189] and wherein R 6 、R 7 and R 8 are each -F,

[0190] and wherein R 1–R 5 、R 9 –R 14 and X 1 –X 4 as defined in general formula (I), including substituted and preferred definitions,

[0191] and wherein said compounds share the following structure (Ic-1):

[0192]

[0193] and wherein the compounds of structure (Ic-1) are preferably for human and veterinary medicine, particularly for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods defined in the present invention, and for treating 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), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancers.

[0194] An example is the compound XPF-0518.

[0195] In yet another specific embodiment, the present invention relates to compounds of general formula (Ic) and their salts and solvates, wherein Z 1 and Z 2 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein Z 1 and Z 2 are as defined in general formula (Ic), including substituted and preferred definitions, and wherein said cyclic residue is selected from a three-membered ring and a four-membered ring,

[0196] and wherein R 8 is as defined in general formula (I), including substituted and preferred definitions, optionally with the additional condition that R 8 is different from -H,

[0197] and wherein R 1 –R 7 、R 9 –R 14 and X 1 –X 4 are as defined in general formula (I), including substituted and preferred definitions,

[0198] and wherein said compounds share the following structure (Ic-2):

[0199]

[0200] And the compounds of structure (Ic-2) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancers.

[0201] One example is the compound XPF-0518.

[0202] In another specific embodiment, the present invention relates to compounds of general formula (Ic) and their salts and solvates, wherein Z 1 and Z 2 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein Z 1 and Z 2 are as defined in general formula (Ic), including the substituted and preferred definitions, and wherein said cyclic residue is selected from three-membered and four-membered rings, optionally provided that said cyclic residue is different from an oxiranyl group,

[0203] and wherein R 1 –R 14 and X 1 –X 4 are as defined in general formula (I), including the substituted and preferred definitions,

[0204] and wherein the compounds share the following structure (Ic-3):

[0205]

[0206] And the compounds of structure (Ic-3) - especially without additional conditions - are preferably used in human and veterinary medicine, in particular for the medical uses described in the present invention, preferably for immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and for the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancers, including cancers of the hematopoietic and blood systems (such as leukemia and lymphoma), skin cancer, oral mucosal cancer, tongue cancer, lung cancer, gastric cancer, breast cancer, cervical cancer, ovarian cancer and neuroendocrine system cancers.

[0207] One example is the compound XPF-0518.

[0208] In some embodiments, the following compounds shown in Tables 1 to 3 are expressly excluded from the scope of the present invention:

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237] Other definitions:

[0238] The term "C1–C 12 alkyl" includes all isomers of the corresponding saturated aliphatic hydrocarbon groups containing from 1 to 12 carbon atoms; this includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, 3-pentyl, 2-methylbutyl, isopentyl, 2-methylbut-2-yl, 3-methylbut-2-yl, all hexyl isomers, all heptyl isomers, all octyl isomers, all nonyl isomers, all decyl isomers, all undecyl isomers, and all dodecyl isomers.

[0239] The term "C2–C 12 alkenyl" includes all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing from 2 to 12 carbon atoms connected by (i.e., containing) one or more double bonds; this includes vinyl, all propenyl isomers, all butenyl isomers, all pentenyl isomers, all hexenyl isomers, all heptenyl isomers, all octenyl isomers, all nonenyl isomers, all decenyl isomers, all undecenyl isomers, and all dodecenyl isomers.

[0240] The term "C2–C 12 alkynyl" includes all isomers of the corresponding unsaturated acetylenic hydrocarbon groups containing from 2 to 12 carbon atoms connected by (i.e., containing) one or more triple bonds; this includes ethynyl, all propynyl isomers, all butynyl isomers, all pentynyl isomers, all hexynyl isomers, all heptynyl isomers, all octynyl isomers, all nonynyl isomers, all decynyl isomers, all undecynyl isomers, and all dodecynyl isomers. The term "alkynyl" also includes compounds having one or more triple bonds and one or more double bonds.

[0241] The term "C3–C8 cycloalkyl" includes the corresponding saturated hydrocarbon groups containing from 3 to 8 carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0242] The term "C5–C8 cycloalkenyl" includes the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing from 5 to 8 carbon atoms, where at least one is sp 3Hybridized and they are arranged in a monocyclic structure and connected by (i.e., containing) one or more double bonds; this includes all cyclopentenyl isomers, all cyclohexenyl isomers, all cycloheptenyl isomers, all cyclooctenyl isomers.

[0243] The term "C5–C 12 bicycloalkyl" includes the corresponding saturated hydrocarbon groups containing 5 to 12 carbon atoms arranged in a bicyclic structure; where these bicyclic structures include fused, bridged and spiro ring systems;

[0244] The term "C7–C 12 bicycloalkenyl" includes the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing 7 to 12 carbon atoms arranged in a bicyclic structure and connected by (i.e., containing) one or more double bonds; where these bicyclic structures include fused, bridged and spiro ring systems;

[0245] The term "C8–C 14 tricycloalkyl" includes the corresponding saturated hydrocarbon groups containing 8 to 14 carbon atoms arranged in a tricyclic structure; where these tricyclic structures include fused, bridged and spiro ring systems;

[0246] For R 1 the terms "cyclic", "bicyclic", "tricyclic", "cycloalkyl", "cycloalkenyl", "bicycloalkyl", "bicycloalkenyl" and "tricycloalkyl" mean that such cyclic, bicyclic or tricyclic residues are directly connected by a chemical bond to the aromatic ring to which R 1 is attached; and where the terms "cyclic", "bicyclic", "tricyclic", "cycloalkyl", "cycloalkenyl", "bicycloalkyl", "bicycloalkenyl" and "tricycloalkyl" of the substituents of R 1 mean that such cyclic, bicyclic or tricyclic residues are directly connected by a chemical bond to one of the C atoms or N atoms or O atoms or S atoms contained in R 1 ; for example, "R 1 is cyclohexyl" means that the cyclohexyl residue is connected to the aromatic ring to which R 1 is attached; "R 1 is methyl and R 1 is substituted by cyclohexyl" means that the resulting -CH2(cyclohexyl) residue is connected to the aromatic ring to which R 1 is attached.

[0247] If a carbon atom is substituted by a heteroatom selected from O, N or S, the number of substituents on the corresponding heteroatom is adjusted according to its valence, for example, the –CR2– group can be replaced by –NR–, –NR2 + –, –O– or –S– groups.

[0248] The term "perhalogenated" relates to the complete halogenation of a carbon backbone; the corresponding residues include the corresponding perfluorinated, perchlorinated, perbrominated, and perchlorinated groups. Preferably, the term "perhalogenated" relates to perfluorinated or perchlorinated groups, more preferably perfluorinated groups.

[0249] The following includes definitions of terms used in this specification. Unless otherwise stated, the initial definitions provided herein for a group or term apply, either individually or as part of another group, to the group or term throughout the specification.

[0250] The compounds of the present invention may form salts, which are also within the scope of the present invention. Unless otherwise stated, references herein to the compounds of the present invention are to be understood as including references to their salts. As used herein, the term "one or more salts" refers to acidic and / or basic salts formed from inorganic and / or organic acids and bases. Zwitterions (internal salts or inner salts) are included within the term "one or more salts" as used herein (and may be formed, for example, when a substituent contains an acid moiety such as a carboxyl group and an amino group). Quaternary ammonium salts, such as alkylammonium salts, are also included herein. The salts of the compounds may be formed, for example, by reacting the compound with an amount of an acid or base, such as an equivalent amount of an acid or base, in a medium such as a medium in which the salt precipitates or in an aqueous medium, and then lyophilizing.

[0251] Exemplary salts obtained by adding an acid include acetates (such as those formed from acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, chlorates, bromates, iodates, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, and the like.

[0252] Exemplary salts formed by the addition of a base (e.g., formed in cases where the substituent includes an acidic moiety such as a carboxyl group) include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as benzathine penicillin, dicyclohexylamine, hydrabamine, N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl, and octadecyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), etc.

[0253] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; base salts or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present invention include conventional non-toxic salts of the parent compound, e.g., salts formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from the parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of both; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science 1977, 66(2), each of which is incorporated herein by reference in its entirety.

[0254] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0255] In addition, in the case where the compounds of the present invention contain asymmetric carbon atoms or atropoisomeric bonds, the present invention relates to D-form, L-form, and D, L mixtures, and when there is more than one asymmetric carbon atom or atropoisomeric bond, it also relates to diastereomeric forms. Those compounds of the present invention that contain asymmetric carbon atoms or atropoisomeric bonds and are generally obtained in the form of racemates can be separated into optically active isomers in a known manner, for example, using optically active acids. However, it is also possible to use optically active starting materials from the beginning and then obtain the corresponding optically active or diastereomeric compounds as the final products.

[0256] The compounds of the present invention also include tautomeric forms. Tautomeric forms are produced by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which the proton can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. The tautomeric forms can be in equilibrium or can be sterically locked into one form by appropriate substitution.

[0257] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are intended. The compounds of the present invention containing atoms with asymmetrically substituted carbons can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically active starting materials are known in the art, such as by resolution of a racemic mixture or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are contemplated within the scope of the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0258] The compounds of the present invention can also include all atomic isotopes that occur in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0259] Also included are solvates and hydrates of the compounds of the present invention and solvates and hydrates of their pharmaceutically acceptable salts.

[0260] Unless otherwise indicated, the term "compound" as used herein means all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the described structure.

[0261] 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, is chemically transformed by a metabolic or chemical process to produce a compound of the invention or a salt and / or solvate thereof.

[0262] In some embodiments, the compounds of the invention and their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation may include, for example, a composition enriched in the compound of the invention. Substantial isolation may include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention or its salt.

[0263] Pharmaceutical methods

[0264] It has been found that the compounds according to the invention have pharmacologically important properties and can be used for treatment. The compounds of the invention can be used alone, in combination with each other, or in combination with other active compounds.

[0265] In certain embodiments, the compounds of the invention may exhibit growth inhibitory properties during hyperproliferative processes.

[0266] The anti-proliferative activities of the compounds of formula (Ia), (Ib) and (Ic) were studied on cells or cell lines derived from the hematopoietic system (including the myeloid and lymphoid cell compartments (T and B cells)), the neuroendocrine system, the cervix, breast, ovary, lung, gastrointestinal tract and mucosal epithelium, as well as from skin epithelium and from muscle. To this end, HL-60 cells, NB-4 cells, HH cells, RPMI-8402 cells, TANOUE cells, TT cells, HeLa cells, MDA-MB-231 cells, FU-OV-1 cells, LOU-NH91 cells, 23132 / 87 cells, CAL-27 cells, BHY cells, SCC-25 cells, A-431 cells, human primary epidermal keratinocytes (HPEK) and C2C12 cells were seeded into 96-well plates (CORNING #3598) suitable for fluorescence assays at the following initial cell numbers: 1000 cells per well for HL-60; 1000 cells per well for NB-4; 5000 cells per well for HH; 5000 cells per well for RPMI-8402; 1500 cells per well for TANOUE; 9000 cells per well for TT; 2000 cells per well for HeLa; 3000 cells per well for MDA-MB-231; 3000 cells per well for FU-OV-1; 4000 cells per well for LOU-NH91; 2000 cells per well for 23132 / 87; 2000 cells per well for CAL-27; 1500 cells per well for BHY; 1500 cells per well for SCC-25; 700 cells per well for A-431; 1000 cells per well for HPEK; 500 cells per well for C2C12. The cells were treated for 5 days with the compounds at the specified final concentrations (diluted from a 1000-fold stock solution in DMSO to a final DMSO concentration of 0.1% v / v in H2O (Water for Injection, WFI, Fisherscientific #10378939)), or with 0.1% v / v of vehicle DMSO as a control for 5 days. On day 5 after the start of treatment, the cells were subjected to a proliferation assay (Bio-Rad Serotec GmbH, BUF012B). Readouts were performed in fluorescence mode using a microplate reader with filters (excitation at 560 nm (bandwidth 10 nm), emission at 590 nm (bandwidth 10 nm)). Each plate included control treatments with commercially available compounds such as methotrexate (MTREX) and resveratrol (RES) to inhibit growth.

[0267] The determination is performed in two or more independent, individual experiments repeated in duplicate, with each experiment repeated six times for each condition. For each individual plate, the measured fluorescence intensity values under the conditions treated with the compound are normalized relative to the corresponding equally weighted arithmetic mean of the fluorescence intensity values of six DMSO-treated control wells to obtain relative values for a baseline level of 1.0.

[0268] Two independent outlier analyses were performed according to the methods of Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1–12). Outliers confirmed by at least one method were excluded from the calculations, but in an individual experiment, no more than 1 value out of 6 values for each compound. The weighted arithmetic mean (abbreviated herein as AVE w ) of each compound was calculated from the normalized values of all independent replicates of each individual experiment repeated six times. The corresponding standard deviation of the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Mühlig, Taschenbuch der Mathematik, 5th Edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun), and the standard deviation was combined with the Gauβ’ error propagation associated with the normalization calculations performed. The resulting standard deviation is referred to herein as the “combined standard deviation”.

[0269] In cases where there is a substantial variation in the normalized equally weighted arithmetic means obtained from two independent replicates, the number of independent replicates is increased to three or more. In cases of four or more independent replicates, a two-line outlier analysis is performed on all normalized equally weighted arithmetic means according to the above methods of Peirce and Chauvenet.

[0270] In certain embodiments, the compounds of the present invention can be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes.

[0271] In one embodiment, several compounds of the invention were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 3. The HL-60 cells were cultured in RPMI 1640 medium (Fisher scientific, #11554526) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0272] If, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values, after addition of the corresponding combined standard deviation, is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of HL-60 cells. Similar to the calculation performed for the test compound, the overall baseline level is calculated as the weighted arithmetic mean of all normalized values from DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0273] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia), (Ib) and (Ic) herein have been identified as growth inhibitors of HL-60 cells. The HL-60 growth inhibitors identified so far relate to the compounds listed in Table 29. The entries in Table 29 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity range.

[0274] Table 29: Proliferation assay using HL-60 cells at 20 μM

[0275]

[0276]

[0277]

[0278] In one embodiment, several compounds of the present invention were found to inhibit the growth of NB-4 cells (human acute promyelocytic leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 207. The NB-4 cells were cultured in RPMI 1640 medium (Fisher scientific, #11554526) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0279] If, at a reference concentration of 20 μm, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered an inhibitor of NB-4 cell growth. Similar to the calculations performed on the test compounds, the total baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0280] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia) and (Ib) herein have been identified as inhibitors of NB-4 cell growth. The NB-4 growth inhibitors identified so far relate to the compounds listed in Table 30. The entries in Table 30 are classified according to the corresponding weighted arithmetic mean of the compounds, regardless of their respective standard deviations, and thus fall within the indicated activity range.

[0281] Table 30: Proliferation assay using NB-4 cells at 20 μM

[0282]

[0283]

[0284] In one embodiment, several compounds of the present invention were found to inhibit the growth of HH cells (human cutaneous T-cell lymphoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 707. The HH cells were cultured in RPMI 1640 medium (Fisher scientific, #11554526) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0285] If, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, when the corresponding combined standard deviations of the respective combinations are added, the compound is considered a growth inhibitor of HH cells. Similar to the calculation performed for the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0286] According to the above method, several molecules falling within the scope of the compounds defined in formulas (Ia) and (Ib) herein have been identified as growth inhibitors of HH cells. The HH growth inhibitors identified so far relate to the compounds listed in Table 31. The entries in Table 31 are classified according to the corresponding weighted arithmetic mean of the compounds, regardless of their respective standard deviations, and thus fall within the indicated activity range.

[0287] Table 31: Proliferation assay using HH cells at 20 μM

[0288]

[0289]

[0290] In one embodiment, several compounds of the present invention were found to inhibit the growth of RPMI-8402 cells (human T-cell acute lymphoblastic leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 290. The RPMI-8402 cells were cultured in RPMI 1640 medium (Fisher scientific, #11554526) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0291] If, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, when the corresponding combined standard deviations of the respective combinations are added, the compound is considered an inhibitor of the growth of RPMI-8402 cells. Similar to the calculation performed for the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0292] According to the above method, several molecules falling within the scope of the compounds defined in formulas (Ia), (Ib) and (Ic) herein have been identified as inhibitors of the growth of RPMI-8402 cells. The RPMI-8402 growth inhibitors identified so far relate to the compounds listed in Table 32. The entries in Table 32 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity range.

[0293] Table 32: Proliferation assay using RPMI-8402 cells at 20 μM

[0294]

[0295]

[0296]

[0297] In one embodiment, several compounds of the present invention were found to inhibit the growth of TANOUE cells (human B cell leukemia cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 399. TANOUE cells were cultured in RPMI 1640 medium (Fisher scientific, #11554526) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0298] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered an inhibitor of the growth of TANOUE cells. Similar to the calculations performed on the test compounds, the overall baseline level was calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0299] According to the above method, several molecules falling within the scope of the compounds defined in formulas (Ia), (Ib), and (Ic) herein have been identified as inhibitors of the growth of TANOUE cells. The TANOUE growth inhibitors identified so far relate to the compounds listed in Table 33. The entries in Table 33 are classified according to the corresponding weighted arithmetic mean of the compounds, regardless of their respective standard deviations, and thus fall within the indicated activity range.

[0300] Table 33: Proliferation assay using TANOUE cells at 20 μM

[0301]

[0302]

[0303]

[0304] In one embodiment, several compounds of the present invention were found to inhibit the growth of TT cells (human medullary thyroid carcinoma cells), which are available from the American Type Culture Collection (ATCC) under accession number ATCC-CRL-1803. The TT cells were cultured in F-12K medium (Fisherscientific, #11580556, or ATCC, #ATCC-30-2004) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37 °C and 5% CO2.

[0305] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of TT cells. Similar to the calculations performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0306] According to the above method, several molecules falling within the scope of the compounds defined in formulas (Ia) and (Ib) herein have been identified as growth inhibitors of TT cells. The TT growth inhibitors identified so far relate to the compounds listed in Table 34. The entries in Table 34 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity range.

[0307] Table 34: Proliferation assay using TT cells at 20 μM

[0308]

[0309]

[0310]

[0311] In one embodiment, several compounds of the present invention were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells), which are available from the American Type Culture Collection (ATCC) under 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.

[0312] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of HeLa cells. Similar to the calculation performed on the test compound, the overall baseline level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0313] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia) and (Ib) herein have been identified as growth inhibitors of HeLa cells. The HeLa growth inhibitors identified so far relate to the compounds listed in Table 35. The entries in Table 35 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity range.

[0314] Table 35: Proliferation assay using HeLa cells at 20 μM

[0315]

[0316]

[0317] In one embodiment, several compounds of the present invention were found to inhibit the growth of MDA-MB-231 cells (human breast cancer cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), accession number ACC 732. The MDA-MB-231 cells were cultured in Leibovitz’s L-15 (phenol red-free) medium (Fisher scientific, #11540556) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 0% CO2.

[0318] If, at a reference concentration of 20 μM, the corresponding combined standard deviations are added and the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of MDA-MB-231 cells. Similar to the calculations performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 .

[0319] According to the above method, several molecules falling within the ranges of the compounds defined in formulas (Ia), (Ib) and (Ic) herein have been identified as growth inhibitors of MDA-MB-231 cells. The MDA-MB-231 growth inhibitors identified so far relate to the compounds listed in Table 36. The entries in Table 36 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity ranges.

[0320] Table 36: Proliferation assay using MDA-MB-231 cells at 20 μM

[0321]

[0322]

[0323]

[0324] In one embodiment, several compounds of the present invention were found to inhibit the growth of FU-OV-1 cells (human ovarian cancer cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), accession number ACC 444. The FU-OV-1 cells were cultured in Ham’s F-12 / DMEM (1:1) medium (Fisher scientific, #11514436) containing 10% fetal bovine serum (Fisher scientific, #15517589) and 1 mM sodium pyruvate (Fisher scientific, #11501871) at 37 °C and 5% CO2.

[0325] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of FU-OV-1 cells. Similar to the calculation performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0326] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia) herein have been identified as growth inhibitors of FU-OV-1 cells. The FU-OV-1 growth inhibitors identified to date relate to the compounds listed in Table 37. The entries in Table 37 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity range.

[0327] Table 37: Proliferation assay using FU-OV-1 cells at 20 μM

[0328]

[0329] In one embodiment, several compounds of the present invention were found to inhibit the growth of LOU-NH91 cells (human lung squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), accession number ACC 393. The LOU-NH91 cells were cultured in RPMI 1640 medium (Fisher scientific, #11554526) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0330] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of LOU-NH91 cells. Similar to the calculation performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0331] According to the above method, several molecules falling within the scope of the compounds defined in Formula (Ia) and (Ib) herein have been identified as growth inhibitors of LOU-NH91 cells. The LOU-NH91 growth inhibitors identified so far involve the compounds listed in Table 38. The entries in Table 38 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering their respective standard deviations, and thus fall within the indicated activity range.

[0332] Table 38: Proliferation assay using LOU-NH91 cells at 20 μM

[0333]

[0334]

[0335] In one embodiment, several compounds of the present invention were found to inhibit the growth of 23132 / 87 cells (human gastric adenocarcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 201. The 23132 / 87 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37 °C and 5% CO2.

[0336] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of 23132 / 87 cells. Similar to the calculations performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0337] According to the above method, several molecules falling within the scope of the compounds defined in Formula (Ia) and (Ib) herein have been identified as growth inhibitors of 23132 / 87 cells. The 23132 / 87 growth inhibitors identified so far involve the compounds listed in Table 39. The entries in Table 39 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering their respective standard deviations, and thus fall within the indicated activity range.

[0338] Table 39: Proliferation assay using 23132 / 87 cells at 20 μM

[0339]

[0340]

[0341]

[0342] In one embodiment, several compounds of the present invention were found to inhibit the growth of CAL-27 cells (human tongue squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 446. The CAL-27 cells were cultured in DMEM medium (Fisher scientific, #11584456) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0343] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of CAL-27 cells. Similar to the calculations performed on the test compounds, the total baseline level is calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0344] According to the above method, several molecules falling within the scope of the compounds defined in formulas (Ia), (Ib), and (Ic) herein have been identified as growth inhibitors of CAL-27 cells. The CAL-27 growth inhibitors identified so far relate to the compounds listed in Table 40. The entries in Table 40 are classified according to the corresponding weighted arithmetic mean of the compounds, regardless of their respective standard deviations, and thus fall within the indicated activity range.

[0345] Table 40: Proliferation assay using CAL-27 cells at 20 μM

[0346]

[0347]

[0348]

[0349] In one embodiment, several compounds of the present invention were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under accession number ACC 404. The BHY cells were cultured in DMEM medium (Fisher scientific, #11584456) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0350] If, at a reference concentration of 20 μM, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, when the corresponding combined standard deviations are added for the respective combinations, the compound is considered an inhibitor of the growth of BHY cells. Similar to the calculations performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0351] According to the above method, several molecules falling within the ranges of the compounds defined in formula (Ia) and (Ib) herein have been identified as inhibitors of the growth of BHY cells. The BHY growth inhibitors identified so far relate to the compounds listed in Table 41. The entries in Table 41 are classified according to the respective weighted arithmetic means of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity ranges.

[0352] Table 41: Proliferation assay using BHY cells at 20 μM

[0353]

[0354]

[0355] In one embodiment, several compounds of the present invention were found to inhibit the growth of SCC-25 cells (human tongue squamous cell carcinoma cells), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), accession number ACC 617. SCC-25 cells were cultured in Ham's F-12 / DMEM (1:1) medium (Fisher scientific, #11514436) containing 10% fetal bovine serum (Fisher scientific, #15517589) and 1 mM sodium pyruvate (Fisher scientific, #11501871) at 37 °C and 5% CO2.

[0356] If, at a reference concentration of 20 μM, when the corresponding combined standard deviations are added, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of SCC-25 cells. Similar to the calculation for the test compound, the total baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0357] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia) and (Ib) herein have been identified as growth inhibitors of SCC-25 cells. The SCC-25 growth inhibitors identified so far relate to the compounds listed in Table 42. The entries in Table 42 are classified according to the corresponding weighted arithmetic mean of the compounds, regardless of their respective standard deviations, and thus fall within the indicated activity range.

[0358] Table 42: Proliferation assay using SCC-25 cells at 20 μM

[0359]

[0360]

[0361] In one embodiment, several compounds of the present invention were found to inhibit the growth of A-431 cells (human epidermoid squamous carcinoma cells), which are available from Cell Lines Service GmbH (CLS) under accession number 300112. A-431 cells were cultured in DMEM medium (Fisher scientific, #11584456) containing 10% fetal bovine serum (Fisher scientific, #15517589) at 37 °C and 5% CO2.

[0362] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of A-431 cells. Similar to the calculation performed on the test compound, the overall baseline level is calculated as the weighted arithmetic mean of all normalized values from DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0363] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia) and (Ib) herein have been identified as growth inhibitors of A-431 cells. The A-431 growth inhibitors identified so far relate to the compounds listed in Table 43. The entries in Table 43 are classified according to the corresponding weighted arithmetic mean of the compounds, regardless of their respective standard deviations, and thus fall within the indicated activity range.

[0364] Table 43: Proliferation assay using A-431 cells at 20 μM

[0365]

[0366]

[0367]

[0368] In one embodiment, several compounds of the present invention were found to inhibit the growth of human epidermal keratinocyte progenitor cells (HPEKp, pooled), which are available from CELLnTEC Advanced Cell Systems AG under accession number HPEKp. HPEKp cells were cultured in CnT-Prime epithelial medium (CELLnTEC, #CnT-PR, a completely defined low-calcium formulation that is completely free of components of animal or human origin) without the addition of additional components at 37 °C and 5% CO2.

[0369] If, at a reference concentration of 10 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of HPEKp cells. Similar to the calculations performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 。

[0370] According to the above method, several molecules falling within the scope of the compounds defined in formulas (Ia), (Ib), and (Ic) herein have been identified as growth inhibitors of HPEKp cells. The HPEKp growth inhibitors identified to date relate to the compounds listed in Table 44. The entries in Table 44 are classified according to the corresponding weighted arithmetic mean of the compounds, regardless of their respective standard deviations, and thus fall within the indicated activity range.

[0371] Table 44: Proliferation assay using HPEKp cells at 10 μM

[0372]

[0373]

[0374]

[0375] In one embodiment, several compounds of the present invention were found to inhibit the growth of C2C12 cells (mouse myoblasts), which are available from Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ), accession number ACC 565. The C2C12 cells were cultured in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37 °C and 5% CO2.

[0376] If, at a reference concentration of 20 μM, after adding the corresponding combined standard deviations, the weighted arithmetic mean of the normalized fluorescence intensity values is equal to or lower than 0.9, particularly equal to or lower than 0.8, equal to or lower than 0.7, equal to or lower than 0.6, equal to or lower than 0.4, equal to or lower than 0.2, relative to an overall baseline level of 1.0, the compound is considered a growth inhibitor of C2C12 cells. Similar to the calculations performed on the test compounds, the overall baseline level is calculated as the weighted arithmetic mean of all the normalized values from the DMSO control measurements. The corresponding combined standard deviation of the DMSO values is less than 1·10 –2 .

[0377] According to the above method, several molecules falling within the scope of the compounds defined in formula (Ia) and (Ib) herein have been identified as growth inhibitors of C2C12 cells. The C2C12 growth inhibitors identified so far relate to the compounds listed in Table 45. The entries in Table 45 are classified according to the corresponding weighted arithmetic mean of the compounds, without considering the respective standard deviations, and thus fall within the indicated activity range.

[0378] Table 45: Proliferation assay using C2C12 cells at 20 μM

[0379]

[0380]

[0381]

[0382] On the one hand, the present invention relates to the treatment of the skin, skin appendages, mucous membranes, mucous membrane appendages, cornea and all kinds of epithelial tissues. The term "skin" relates to the tissue including the epidermis and the dermis. The term "mucous membrane" relates to the mucous membrane and the submucous tissue, including the oral mucosa, nasal mucosa, ocular mucosa, ear mucosa, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa. The term "appendage" relates to the tissue including hair follicles, hair, fingernails, toenails and glands, and the glands include sebaceous glands, sweat glands, such as apocrine or eccrine sweat glands and mammary glands.

[0383] In one embodiment, the present invention relates to the treatment of the following diseases: non-melanoma skin cancer and precancerous lesions, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), sebaceous gland carcinoma, Merkel cell carcinoma, angiosarcoma, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatofibrosarcoma, actinic keratosis (AK) or Bowen's disease (BD), and other cancers and precancerous lesions of the squamous epithelium, such as cutaneous SCC, lung SCC, head and neck SCC, oral SCC, tongue SCC, esophageal SCC, cervical SCC, periorbital SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate and SCC of the bladder.

[0384] In yet another embodiment, the present invention relates to the treatment of the following diseases: skin and mucosal disorders with keratinization defects (keratosis) and / or abnormal keratinocyte proliferation, such as psoriasis, Darier's disease, lichen planus, lupus erythematosus, ichthyosis or verruca vulgaris (senile).

[0385] In another embodiment, the present invention relates to the treatment of the following diseases: skin and mucosal diseases and skin and mucosal cancers that are respectively associated with and / or caused by viral infections, such as warts, and warts associated with HPV (human papillomavirus), papillomas, HPV-associated papillomas, papillomatosis and HPV-associated papillomatosis, such as warts (plantar warts), flat warts (flat wart / plane wart), filiform warts (filiform wart), mosaic warts, periungual warts, subungual warts, oral warts, genital warts, fibroepithelial papillomas, intraductal papillomas, ductal papillomas, inverted papillomas, basal cell papillomas, squamous papillomas, cutaneous papillomas, fibrovascular papillomas, plexiform papillomas, nasal papillomas, pharyngeal papillomas, papillomatosis cutis carcinoides, Papillomatosis cutis lymphostatica, Papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis), herpes-related diseases, such as herpes labialis, genital herpes, herpes zoster, herpes keratitis or Kaposi's sarcoma, and HPV-related cancers of the cervix, vulva, penis, vagina, anus, oropharynx, tongue and oral cavity.

[0386] In yet another embodiment, the present invention relates to the treatment of atopic dermatitis.

[0387] In yet another embodiment, the present invention relates to the treatment of acne.

[0388] In yet another embodiment, the present invention relates to the treatment of skin wounds, wherein the process of wound healing is accelerated.

[0389] In yet another embodiment, the present invention relates to the treatment of cancers associated with and / or caused by viral infections, i.e., oncoviral infections, such as cancers associated with HBV- and HCV (hepatitis B and C viruses), such as liver cancer, cancers associated with EBV (Epstein-Barr virus), such as Burkitt lymphoma, Hodgkin lymphoma and non-Hodgkin lymphoma, and gastric cancer, cancers associated with HPV (human papillomavirus), such as cervical cancer, cancers associated with HHV (human herpesvirus), such as Kaposi sarcoma, and cancers associated with HTLV (human T-cell lymphotropic virus), such as T-cell leukemia and T-cell lymphoma.

[0390] Yet another aspect of the present invention relates to the treatment of immune system-related disorders. As used herein, the term "immune system-related disorders" applies to pathological conditions of the hematopoietic system, including the blood system, in particular pathological conditions of immune cells belonging to the innate or adaptive immune system.

[0391] Examples are hematopoietic system diseases, including the blood system, such as myeloid malignancies, including acute and chronic leukemias, such as chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL); or malignancies of lymphoid lineage, including acute and chronic forms of leukemia and lymphoma, such as T-cell acute lymphoblastic leukemia (T-ALL), pre-T-cell acute lymphoblastic leukemia (pre-T-ALL), cutaneous T-cell lymphoma, chronic lymphocytic leukemia (CLL), including T-cell CLL (T-CLL) and B-cell CLL (B-CLL), prolymphocytic leukemia (PLL), including T-cell PLL (T-PLL) and B-cell PLL (B-PLL), B-cell acute lymphoblastic leukemia (B-ALL), pre-B-cell acute lymphoblastic leukemia (pre-B-ALL), cutaneous B-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, myeloma or multiple myeloma; or acute lymphoblastic and acute myeloid mixed lineage leukemia with MLL gene translocation.

[0392] Another aspect of the present invention relates to therapeutic uses 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 cell lineages of the hematopoietic system, including the blood system, to regulate the immune response (immunomodulation). As used herein, the term "immune system-related application" also applies to interventions on the cellular and acellular microenvironment at the site of action of immune cells to support and / or enable immune cells to exert their performance. In particular, the interventions defined herein by the term "immune system-related application" relate to immune cells belonging to the innate or adaptive immune system.

[0393] Thus, the compounds of the present invention can be used alone or in combination with other immunotherapeutic methods or compounds (as immunoadjuvants, such as vaccine adjuvants, or as adjuvants for immunotherapy) in immunotherapy. As used herein, the term "immunotherapy" applies to active immunotherapy in patients without immunodeficiency or with acquired or congenital immunodeficiency, as well as immune restoration to enhance the functionality of the immune system in its response to pathogens or endogenous cells undergoing pathological transformation, such as cancer cells.

[0394] As used herein, the term "other immunotherapeutic methods" applies to vaccination, antibody therapy, cytokine therapy, the use of immune checkpoint inhibitors and immune response-stimulating drugs, as well as autologous transplantation of genetically modified or unmodified immune cells, which can be stimulated by intercellular signals, signaling molecules, antigens, or antibodies, i.e., adoptive immune cell transfer.

[0395] The methods of use of the present invention in immune system-related applications and other immunotherapeutic methods relate to in vivo, in vitro, and ex vivo use, respectively.

[0396] Specific examples are the activation and / or enhanced activation of peripheral T lymphocytes (including T helper cells and cytotoxic T cells) to enhance the immune response, particularly to stimulate proliferation and / or the production and / or secretion of cytokines and / or cytotoxic agents upon antigen recognition to amplify the immune response; and the activation of B lymphocytes and / or enhanced activation of B lymphocytes to amplify the immune response, particularly to stimulate proliferation and / or antibody production and / or secretion; and enhancing the immune response by increasing the number of specific immune cell subtypes by regulating differentiation and / or cell fate determination during immune cell development (e.g., regulating, particularly increasing the number of immune cells belonging to the T cell and B cell lineages, including marginal zone B cells, cytotoxic T cells, or T helper (Th) subsets (particularly Th1, Th2, Th17) and regulatory T cells); or used as an immunoadjuvant such as a vaccine adjuvant.

[0397] Yet another aspect of the present invention relates to the treatment of muscle diseases (including diseases of skeletal muscle, cardiac muscle, and smooth muscle).

[0398] In one embodiment, the present invention relates to the treatment of muscular dystrophy (MD).

[0399] Specific examples are Duchenne MD, Becker MD, congenital MD, Limb-Girdle MD, facioscapulohumeral MD, Emery-Dreifuss MD, distal MD, myotonic MD or oculopharyngeal MD.

[0400] In another embodiment, the present invention relates to the treatment of muscle hyperproliferative disorders, including myoblastoma, rhabdomyoma and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy.

[0401] In another embodiment, the compounds of the present invention can be used in muscle regeneration after pathological muscle degeneration or atrophy caused, for example, by trauma, muscle ischemia or inflammation, in muscle atrophy associated with aging or in muscle atrophy associated with diseases such as myositis and fibromyositis or poliomyelitis.

[0402] On the other hand, it relates to the treatment of the following diseases: disorders of the neuroendocrine system, such as cancers of the neuroendocrine system, including neuroendocrine small cell carcinoma, neuroendocrine large cell carcinoma and carcinoid tumors, for example tumors of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus and lung, such as neuroendocrine tumors of the pituitary gland, neuroendocrine tumors of the adrenal gland, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroid nodules, insular carcinoma, clear trabecular tumor, paraganglioma, pulmonary carcinoid tumor, neuroblastoma, gastrointestinal carcinoid, goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagonoma, somatostatinoma, VIPoma, insulinoma, non-functional islet cell tumor, multiple endocrine neoplasia type 1 or pulmonary carcinoid.

[0403] On the other hand, it relates to the treatment of pulmonary disorders such as lung cancer, which includes small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), including squamous cell carcinoma of the lung, adenocarcinoma of the lung and large cell carcinoma of the lung.

[0404] On the other hand, it relates to the treatment of the following diseases: hyperproliferative diseases, cancers or pre-cancerous lesions of the brain, pancreas, breast, ovary, liver, thyroid, urogenital tract, gastrointestinal tract and endothelial tissues, including glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brainstem glioma, optic glioma and forebrain tumors, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic solid pseudopapillary tumor, intraductal papillary-mucinous neoplasm of the pancreas, mucinous cystadenocarcinoma of the pancreas, pancreatoblastoma and pancreatic intraepithelial neoplasia, hepatocellular carcinoma, fibrolamellar 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.

[0405] The methods of use of the present invention relate to in vivo, in vitro and ex vivo use, respectively.

[0406] As used herein, the term "treating" or "treatment" refers to one or more of the following: (1) inhibiting a disease; e.g., inhibiting a disease, disorder or condition in an individual who is experiencing or manifesting the signs or symptoms of the disease, disorder or condition (i.e., preventing the further progression of the signs and / or symptoms); and (2) ameliorating a disease; e.g., ameliorating a disease, disorder or condition in an individual who is experiencing or manifesting the signs or symptoms of the disease, disorder or condition (i.e., reversing the signs and / or symptoms), such as reducing the severity of the disease; and (3) slowing the progression of a disease. The term "treatment" also includes aftercare.

[0407] In some embodiments, administering the compounds of the present invention or pharmaceutically acceptable salts thereof can be effective in preventing a disease; e.g., preventing a disease, disorder or condition in an individual who may be susceptible to the disease, disorder or condition but has not yet experienced or manifested the signs or symptoms of the disease.

[0408] The compounds of the present invention can be used in human and veterinary medicine, including the treatment of companion animals, such as horses, dogs, cats, rabbits, guinea pigs, fish (e.g., koi), birds (e.g., falcons); and livestock (e.g., cattle), poultry, pigs, sheep, goats, donkeys, yaks and camels.

[0409] Pharmaceutical composition

[0410] The present invention also provides a pharmaceutical composition for use in medicine (e.g., human or veterinary medicine), which comprises the compounds described herein or pharmaceutically acceptable salts thereof. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0411] In addition to physiologically acceptable carriers, diluents, and / or adjuvants, an effective dose of a compound or a salt, solvate, or prodrug thereof according to the invention is used to produce a pharmaceutical composition. The dose of the active compound can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated, and similar factors. The daily dose can be administered as a single dose, which can be administered once, or can be subdivided into two or more daily doses, generally being 0.001 - 2000 mg. A daily administration dose of 0.1 - 500 mg (such as 0.1 - 100 mg) is particularly preferably provided.

[0412] Suitable forms of administration are local or systemic and include enteral, oral, rectal, and parenteral, such as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardiac, epidural, intracerebral, intraventricular, intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalation, intranasal, oral, sublingual, and intralesional formulations. Particular preference is given to oral, parenteral (such as intravenous or intramuscular), and intranasal formulations (such as dry powder or sublingual) of the compounds according to the invention. Conventional galenic forms can be used, such as tablets, dragees, capsules, dispersible powders, granules, aqueous solutions, hydroalcoholic solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashes, foams, pastes, tinctures, skin patches and tapes, occlusive forms or in combination with time-release drug delivery systems, with electrophoretic skin delivery systems including implants and devices, and with jet injectors, liposomes, and transfersome vesicles, vapors, sprays, syrups, fruit juices or drops, and eye drops.

[0413] Solid pharmaceutical forms can contain inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginate, gelatin, guar gum, magnesium stearate, aluminum stearate, methylcellulose, talc, highly disperse silicic acid, silicone oil, high molecular weight fatty acids (such as stearic acid), gelatin, agar, or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); if desired, formulations suitable for oral administration can contain additional flavoring agents and / or sweetening agents.

[0414] Liquid pharmaceutical forms can be sterilized and / or, where appropriate, contain auxiliary substances such as preservatives, stabilizers, wetting agents, penetrants, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols (for adjusting the osmotic pressure or for buffering), and / or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and chelating agents such as ethylenediaminetetraacetic acid and its non-toxic salts. High molecular weight polymers such as liquid polyethylene oxide, microcrystalline cellulose, carboxymethyl cellulose, polyvinylpyrrolidone, dextran or gelatin are suitable for adjusting the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, high molecular weight fatty acids such as stearic acid, gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight polymers such as polyethylene glycol.

[0415] Oily suspensions for parenteral or topical application can be vegetable oils, synthetic oils or semi-synthetic oils such as liquid fatty acid esters having 8 to 22 carbon atoms in the fatty acid chain in each case, said fatty acid chains being, for example, palmitic acid, lauric acid, tridecylic acid, heptadecylic acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecylic acid, linoleic acid, elaidic acid, brazidic acid, erucic acid or oleic acid, which fatty acids are esterified with mono- to trihydric alcohols having 1 to 6 carbon atoms such as methanol, ethanol, propanol, butanol, pentanol or their isomers, ethylene glycol or glycerol. Examples of such fatty acid esters are, inter alia, the commercially available miglitol, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic / capric esters of saturated fatty alcohols, polyoxyethylene glyceryl trioleate, ethyl oleate, waxy fatty acid esters such as artificial duck tail gland fat, isopropyl coconut fatty acid, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters. Silicone oils or fatty alcohols of different viscosities such as isotridecanol, 2-octyldodecanol, cetearyl alcohol or oleyl alcohol, or fatty acids such as oleic acid are also suitable. Vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil can also be used.

[0416] Suitable solvents, gelling agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols such as ethanol or isopropanol, benzyl alcohol, 2-octyldodecanol, polyethylene glycol, phthalates, adipates, propylene glycol, glycerol, dipropylene glycol or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholine, dioxane, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone etc.

[0417] Cellulose ethers such as hydroxypropyl methyl cellulose, methyl cellulose or ethyl cellulose, or soluble starch, which can be dissolved or swollen in water or organic solvents, can be used as film-forming agents.

[0418] Mixtures of gelling agents and film formers are also entirely possible. In this case, ion macromolecules are particularly used, such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, amylose semi-sodium glycolate, alginic acid or propylene glycol alginate (as the sodium salt), gum arabic, xanthan gum, guar gum or carrageenan. The following substances can be used as additional formulation aids: glycerol, paraffins of different viscosities, triethanolamine, collagen, allantoin and phenylbenzimidazole sulfonic acid (novantisolic acid). The preparation also requires the use of surfactants, emulsifiers or wetting agents, such as sodium lauryl sulfate, fatty alcohol ether sulfates, disodium N-lauroyl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (such as Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono / dialkyl polyglycol ether monoethanolamine salts of orthophosphoric acid. Stabilizers for stabilizing emulsions or preventing the decomposition of active substances such as antioxidants (such as tocopherol or butylated hydroxyanisole) or preservatives (such as parabens), such as montmorillonite or colloidal silica, can also be used for preparing the required preparations.

[0419] Preparations for parenteral administration can be present in the form of individual dosage units, such as ampoules or vials. Solutions of the active compound are preferably used, preferably aqueous solutions, especially isotonic solutions and also suspensions. These injection forms can be made into ready-to-use preparations or prepared directly only before use by mixing the active compound (such as a lyophilizate, which may contain other solid carrier substances in appropriate cases) with the required solvent or suspending agent.

[0420] Intranasal preparations can be present in the form of aqueous or oily solutions or aqueous or oily suspensions. They can also be present in the form of lyophilizates, which are prepared using a suitable solvent or suspending agent before use.

[0421] Inhalable preparations can be present in the form of powders, solutions or suspensions. Preferably, the inhalable preparations are in powder form, for example, a mixture of the active ingredient and a suitable formulation aid such as lactose.

[0422] The preparations are produced, aliquoted and sealed under conventional antibacterial and aseptic conditions.

[0423] As shown above, the compounds of the present invention can be administered as combination therapy, sequential therapy or simultaneous combination therapy with other active agents (e.g., therapeutically active compounds for treating the above-mentioned diseases). These therapeutically active compounds can include, but are not limited to, chemotherapeutic agents, such as nucleoside and nucleobase analogs, e.g., cytarabine, gemcitabine, azathioprine, mercaptopurine, fluorouracil, thioguanine, azacitidine, capecitabine, doxifluridine; platinum-based drugs, such as cisplatin, oxaliplatin, carboplatin and nedaplatin; anthracyclines, such as doxorubicin, epirubicin, valrubicin, idarubicin, daunorubicin, zorubicin, pixantrone and mitoxantrone; peptide antibiotics, such as actinomycin and bleomycin; alkylating agents, such as mechlorethamine, chlorambucil, melphalan, nitrosoureas, dacarbazine, temozolomide and cyclophosphamide; anti-mitotic agents, including taxanes and vinca alkaloids, e.g., docetaxel, paclitaxel, abraxane, cabazitaxel, vinblastine, vindesine, vinorelbine and vincristine; topoisomerase inhibitors, such as irinotecan, topotecan, teniposide and etoposide; other cell growth inhibitors, such as hydroxyurea and methotrexate; proteasome inhibitors, such as bortezomib, ixazomib; and other targeted therapeutic agents, such as kinase inhibitors, cell cycle inhibitors, regulators, i.e., inhibitors and activators of signal transduction pathways (including growth factor signal transduction, cytokine signal transduction, NF-κB signal transduction, AP1 signal transduction, JAK / STAT signal transduction, EGFR signal transduction, TGF-β signal transduction, Notch signal transduction, Wnt signal transduction, Hedgehog signal transduction, hormone and nuclear receptor signal transduction), 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, aflibercept, vandetanib, vismodegib and sonidegib; retinoids, such as retinol, tretinoin, isotretinoin, alitretinoin, bexarotene, tazarotene, acitretin, adapalene and etretinate;Hormone signal transduction regulators, including estrogen receptor regulators, androgen receptor regulators, and aromatase inhibitors, such as raloxifene, tamoxifen, fulvestrant, lasofoxifene, toremifene, bicalutamide, flutamide, anastrozole, letrozole, and exemestane; histone deacetylase inhibitors, such as vorinostat, Romidepsin, panobinostat, belinostat, and chidamide; and Ingenol Mebutate; valproic acid, resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocolchicoside; N-methylhydroxyethyl chloride; and immune response regulators, including immune checkpoint inhibitors, such as imiquimod, ipilimumab, atezolizumab, ofatumumab, rituximab, nivolumab, and Pembrolizumab; and anti-inflammatory drugs, including glucocorticoids and non-steroidal anti-inflammatory drugs, such as cortisol-based preparations, dexamethasone, betamethasone, prednisone, prednisolone, methylprednisolone, triamcinolon-hexacetonid, mometasone furoat, clobetasol propionate, acetylsalicylic acid, salicylic acid, and other salicylates, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, loxoprofen, flurbiprofen, oxaprozin, indomethacin, ketorolac, tolmetin, diclofenac, etodolac, aceclofenac, nabumetone, sulindac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, parecoxib, etoricoxib, and firocoxib; and ACE inhibitors; and β-blockers; and myostatin inhibitors; and PDE-5 inhibitors; and antihistamines. For combination therapies, the active ingredients can be formulated into a composition containing several active ingredients in a single dosage form and / or a kit containing separate active ingredients in separate dosage forms. The active ingredients used in combination therapies can be administered together or separately.;

[0424] The compounds of the present invention can be administered in the form of antibody-drug conjugates.

[0425] The compounds of the present invention can be administered in combination with surgery, cryotherapy, electrocautery, 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.

[0426] Chemical synthesis

[0427] Abbreviations

[0428] Ac Acetyl

[0429] aq aqueous

[0430] BRSM Based on Recycled Stock (Yield)

[0431] Bu Butyl

[0432] DCE 1,2 - Dichloroethane

[0433] DCM Dichloromethane

[0434] DIBAL - H Diisobutylaluminum Hydride

[0435] DMF N,N - Dimethylformamide

[0436] DMSO Dimethyl Sulfoxide

[0437] equiv Equivalent

[0438] ESI Electrospray Ionization

[0439] Et Ethyl

[0440] Me Methyl

[0441] Ms Methanesulfonyl

[0442] mol% Mole Percentage

[0443] NMR Nuclear Magnetic Resonance Spectroscopy

[0444] PE Petroleum Ether

[0445] PTSA p - Toluenesulfonic Acid

[0446] sat Saturated

[0447] TBAF Tetrabutylammonium Fluoride

[0448] THF Tetrahydrofuran

[0449] TMS Trimethylsilyl

[0450] UV Ultraviolet Light

[0451] General Provisions

[0452] The compounds listed in Tables 46 and 47 have been identified by TLC using pre-coated silica TLC plates and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, toluene, triethylamine or acetic acid (as eluents, preferably as their binary or ternary solvent mixtures). Compounds were visualized using ultraviolet light at wavelengths of 254 nm or 366 nm and / or common staining solutions such as phosphomolybdic acid, potassium permanganate or ninhydrin. Completion of the reaction was also monitored in this way. Unless otherwise stated, reactions were carried out under an inert atmosphere. Anhydrous solvents were used wherever required. All reactions were stirred using a stirring plate and magnetic stir bar.

[0453] In addition, the compounds listed in Table 46 were identified by mass spectrometry (using formic acid in the mobile phase to detect positive ions and no additives to detect negative ions). If the molecule was difficult to ionize in the negative mode, ammonium carbonate was used. Representative compounds and those showing poor ionization in the mass spectrum (Table 47) were also identified by nuclear magnetic resonance spectroscopy. Chemical shifts (δ) were reported in parts per million (ppm) relative to the residual solvent peak, rounded to the nearest 0.01 ppm for protons and to the nearest 0.1 ppm for carbon (reference: CHCl3 1 H: 7.26 ppm, 13 C: 77.2 ppm], DMSO 1 H: 2.50 ppm, 13 C: 39.5 ppm]). Coupling constants (J) were reported to the nearest 0.1 Hz in Hz. Peak multiplicities were represented as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (septet), m (multiplet) and br (broad peak).

[0454] Synthesis of the Compounds

[0455] The above compounds of the invention falling within the scope 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 I) described herein, as shown in Scheme 1.

[0456]

[0457] Protocol 1: General synthesis protocol.

[0458] A) Under an argon atmosphere and with stirring, K2CO3 (1.5 equivalents) was added to the corresponding mono- or disubstituted phenol (1.0 - 1.5 equivalents) and 4-alkyl ester halo(hetero)aryl (1 equivalent) dissolved in DMSO (0.5 M), and the mixture was stirred at room temperature or heated between 40 °C and 160 °C until complete conversion. 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 phases were washed with NaOH (aqueous solution, 2 M), then with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt, DCM / MeOH or petroleum ether / AcOEt / NEt3) to give the desired bis(hetero)aryl ether ethyl ester.

[0459] B) Under an argon atmosphere and with stirring, the corresponding bis(hetero)aryl ether alkyl ester (1 equivalent) was dissolved in anhydrous THF (0.2 M), and the resulting solution was cooled to 0 °C in an ice bath. Then DIBAL-H (2.5 equivalents, 1.2 M in toluene) was added dropwise, and the mixture was stirred at this temperature until complete conversion. The reaction was terminated by the Fieser method, filtered, concentrated in vacuo, and the residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired alcohol.

[0460] C) Depending on the scale and the substrate, either of these procedures was used.

[0461] Under vigorous stirring, MnO2 (2 - 4 equivalents) was added to the corresponding alcohol (1 equivalent) dissolved in DCM (0.2 M). The resulting suspension was stirred at room temperature or 40 °C until complete conversion. The reaction mixture was then diluted with AcOEt, filtered through diatomaceous earth, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired aldehyde.

[0462] Under vigorous stirring, Dess-Martin periodinane (1.2 equivalents) was added to the corresponding alcohol (1 equivalent) dissolved in DCM or DMSO (0.2 M). The resulting suspension was stirred at room temperature until complete conversion. The solution was diluted with AcOEt and quenched with saturated aqueous NaHCO3, then phase separation was carried out. The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired aldehyde.

[0463] At -78 °C, anhydrous DMSO (4 eq) was added to a solution of oxalyl chloride (2 eq) in DCM (0.2 M), and the mixture was stirred for 30 min. Then a solution of the corresponding alcohol (1 eq) in DCM (0.2 M) was added, followed by freshly distilled NEt3 (8 eq). The resulting solution was stirred for 1 h and then slowly brought back to room temperature. The solution was diluted in AcOEt, quenched with 1 M aqueous HCl, and phase separation was carried out. The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired aldehyde.

[0464] In some cases, the desired aldehyde proved to be unstable and was used directly in the subsequent step without characterization after rapid purification by the specified method.

[0465] D) Under an argon atmosphere and with stirring, at 0 °C, TMSCF3 (2 eq) was added to the corresponding aldehyde (1 eq) dissolved in anhydrous THF (0.2 M), and then TBAF (1 mol%) was added to obtain the corresponding CF3-containing secondary alcohol, or a Grignard reagent (2 eq) was added to obtain the corresponding secondary alkyl alcohol. In both cases, the resulting solution was stirred at this temperature until complete conversion. Then aqueous HCl (2.5 M) was added and the reaction mixture was stirred for 1 h. The reaction mixture was then partitioned between AcOEt and water. The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired secondary alcohol.

[0466] E) At 0 °C, Dess-Martin periodinane (1.5 eq) was added to a stirred solution of the corresponding secondary alcohol (1 eq) in chloroform (0.2 M). After completion of the reaction, it was partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired ketone.

[0467] (F) To a stirred solution of the corresponding ketone (1 equiv) in ethanol or methanol (0.2 M) is added (hydroxy)amine (1.2 - 40 equiv), and then, either a catalytic amount of PTSA in the case of a fatty amine or a base (2.5 - 40 equiv) in the case of hydroxylamine. The reaction is then refluxed for 24 - 72 h. Thereafter, either diatomaceous earth is added and the volatiles are evaporated under vacuum, or the reaction mixture is partitioned between AcOEt and aqueous HCl (1 M), the aqueous layer is extracted twice more, and the combined organic phases are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. In both cases, the residue is then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired imine.

[0468] (G) Under an argon atmosphere and with stirring, at 0 °C, trimethylamine (2 equiv) is added to a stirred solution of the corresponding alcohol (1 equiv) in DMF (0.2 M), and then methanesulfonyl chloride (1.2 equiv) is added. The reaction mixture is then stirred for 24 h and then partitioned between AcOEt and H2O. The aqueous layer is extracted twice more, and the combined organic phases are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired mesylate.

[0469] (H) Under an argon atmosphere and with stirring, at 0 °C, TMSCF3 (1.3 equiv) is added to the corresponding ketone (1 equiv) dissolved in anhydrous THF (0.2 M), and then TBAF (1 mol%) is added to obtain the corresponding di-CF3 alcohol or a Grignard reagent (2 equiv) is added to obtain the corresponding tertiary alcohol. In both cases, the resulting solution is stirred at this temperature until complete conversion. In the first case, after completion, more TBAF (10 mol%) is added, then water (5.6 equiv) is added, and the reaction mixture is stirred for an additional 1 h. In both cases, the reaction mixture is then partitioned between AcOEt and aqueous HCl (1 M). The aqueous layer is extracted twice more, and the combined organic phases are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue is then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give the desired tertiary alcohol.

[0470] I) To the corresponding 4-substituted phenol (1 - 2 equiv) and 4-substituted bromoaryl (1 - 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, stirred vigorously, and refluxed (165 °C) for 72 h. The mixture was allowed to return to room temperature and partitioned between petroleum ether and aqueous NaOH solution (2 M). The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to afford the desired diaryl ether.

[0471] Analytical data

[0472] The following compounds were synthesized according to the above protocol and characterized by mass spectrometry (Table 46) or NMR (Table 47).

[0473] Table 46:

[0474]

[0475]

[0476]

[0477] Table 47:

[0478]

[0479]

[0480]

[0481] For illustrative purposes, the synthesis and characterization of the following examples are described in detail.

[0482] XPF-0062: 1-(4-(4-Cyclohexylphenoxy)phenyl)-2,2,2-trifluoroethyl-1-ol

[0483]

[0484] At 0 °C, under an argon atmosphere and with stirring, trimethylsilyl trifluoromethanesulfonate (TMSCF3, 1.93 mL, 13.1 mmol, 2 equiv) was added to 4-(4-cyclohexylphenoxy)benzaldehyde (1.84 g, 6.55 mmol, 1 equiv) dissolved in anhydrous THF (26.2 mL, 0.2 M), and then tetrabutylammonium fluoride (TBAF, 65 μL, 66 μmol, 1 mol%) was added. The resulting solution was stirred at this temperature until complete conversion. Then aqueous HCl solution (2.5 M) was added and the reaction mixture was stirred for an additional 1 h. The reaction mixture was then partitioned between AcOEt and water. The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to afford 2.13 g of 1-(4-(4-cyclohexylphenoxy)phenyl)-2,2,2-trifluoroethanol (93%).

[0485] MS: m / z [M-OH] + , [C 20 H 20 F3O] + calcd = 333.14; found 333.19

[0486] 1 1H-NMR (300 MHz, CDCl3) δ 7.41 (dt, J = 9.0, 0.6 Hz, 2H), 7.23–7.16 (m, 2H), 7.04–6.91 (m, 4H), 5.00 (qd, J = 6.7, 4.4 Hz, 1H), 2.61–2.37 (m, 2H), 1.99–1.67 (m, 5H), 1.50–1.19 (m, 5H).

[0487] 13 13C-NMR (75 MHz, CDCl3) δ 159.1, 154.2, 143.9, 128.9, 128.1, 128.0, 124.3 (q, J = 282.0 Hz), 119.4, 118.1, 72.47 (q, J = 32.2 Hz), 43.9, 34.6, 26.9, 26.1.

[0488] XPF-0434: 1-(4-(4-(adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethanone

[0489]

[0490] At 0 °C, Dess-Martin periodinane (1.03 g, 2.42 mmol, 1.5 equiv) was added to a stirred solution of 1-(4-(4-(adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethan-1-ol (750 mg, 1.86 mmol, 1 equiv) in chloroform (9.3 mL, 0.2 M). After completion of the reaction, it was partitioned between AcOEt and saturated aqueous NaHCO3. The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give 647 mg of 1-(4-(4-(adamantan-1-yl)phenoxy)phenyl)-2,2,2-trifluoroethan-1-one (87%).

[0491] MS: m / z [M+H] + , [C 24 H 21 F3O2] + Calculated value = 399.16; found value was 399.16

[0492] 1 1H-NMR (300 MHz, CDCl3) δ 8.10–7.89 (m, 2H), 7.44–7.25 (m, 2H), 7.02–6.86 (m, 4H), 2.05 (p, J = 3.1 Hz, 3H), 1.86 (d, J = 2.9 Hz, 6H), 1.80–1.60 (m, 6H).

[0493] 13 13C-NMR (75 MHz, CDCl3) δ 179.1 (q, J = 31 Hz), 164.6, 152.0, 148.7, 132.7 (q, J = 2.3 Hz), 126.7, 123.9 (q, J = 291 Hz), 120.2, 117.1, 43.3, 36.7, 36.1, 28.9.

[0494] XPF-1330: 1-(6-(4-(adamantan-1-yl)phenoxy)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethan-1-ol

[0495]

[0496] At 0 °C, under an argon atmosphere and with stirring, cyclopropylmagnesium bromide (0.6 mL, 0.26 mmol, 2 equivalents, a THF solution of 0.4 M) was added to 1-(6-(4-(adamantan-1-yl)phenoxy)pyridin-3-yl)-2,2,2-trifluoroethan-1-one (52 mg, 0.13 mmol, 1 equivalent) dissolved in anhydrous THF (0.8 mL, 0.16 M). The resulting solution was stirred at this temperature until complete conversion. After completion, the reaction mixture was partitioned between AcOEt and aqueous HCl (1 M). The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give 43 mg of 1-(6-(4-(adamantan-1-yl)phenoxy)pyridin-3-yl)-1-cyclopropyl-2,2,2-trifluoroethan-1-ol (75%).

[0497] MS: m / z [M+H] + , [C 26 H 29 F3NO2] + Calculated value = 444.21; found value was 444.30

[0498] 1 1H-NMR (300 MHz, CDCl3) δ 8.38 (d, J = 2.5 Hz, 1H), 8.05 (dd, J = 8.7, 2.6 Hz, 1H), 7.45–7.31 (m, 2H), 7.17–6.96 (m, 3H), 6.23 (s, 1H), 2.08 (q, J = 3.1 Hz, 3H), 1.89 (d, J = 3.0 Hz, 6H), 1.79–1.62 (m, 7H), 0.87–0.72 (m, 1H), 0.64–0.48 (m, 1H), 0.40 (tdd, J = 9.1, 5.9, 4.1 Hz, 1H), 0.27 (dtd, J = 9.5, 5.9, 4.2 Hz, 1H).

[0499] 13 13C-NMR (300 MHz, CDCl3) δ 163.6, 151.7, 147.7, 146.5, 139.3, 130.4, 126.3, 121.3, 110.7, 73.68 (d, J = 27.6 Hz), 43.1, 36.5, 35.9, 28.7, 14.8, 1.6. (One remaining CF3 group was not visible due to relaxation time)

[0500] XPF-2249: 1-(4-(4-cyclohexyl-2-methylphenoxy)phenyl)-2,2,2-trifluoroethan-1-one oxime

[0501]

[0502] To a stirred solution of 1-(4-(4-cyclohexyl-2-methylphenoxy)phenyl)-2,2,2-trifluoroethan-1-one (50 mg, 0.14 mmol, 1 equiv) in methanol (0.7 mL, 0.2 M) was added hydroxylamine hydrochloride (11.5 mg, 0.17 mmol, 1.2 equiv), and then sodium acetate (34 mg, 0.41 mmol, 3 equiv). The reaction mixture was then refluxed for 24 h and then partitioned between AcOEt and aqueous HCl (1 M). The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to afford 38 mg of 1-(4-(4-cyclohexyl-2-methylphenoxy)phenyl)-2,2,2-trifluoroethan-1-one oxime (73%).

[0503] MS: m / z [M-H] - , [C 21 H 21 F3NO2] - Calcd for = 376.15; found 376.58

[0504] 1 H NMR (400 MHz, CDCl3) δ 8.56 (brs, 0.3H), 8.54 (s, 0.7H), 7.56–7.47 (m, 1.5H), 7.45–7.38 (m, 0.5H), 7.15–7.06 (m, 1H), 7.07–7.01 (m, 1H), 6.98–6.85 (m, 3H), 2.49 (tt, J = 11.5, 3.8 Hz, 1H), 2.18 (s, 2H), 2.17 (s, 1H), 1.96–1.80 (m, 4H), 1.80–1.72 (m, 1H), 1.49–1.33 (m, 4H), 1.33–1.19 (m, 1H).

[0505] 13 C NMR (101 MHz, CDCl3) δ 160.33, 160.22, 151.08, 150.93, 145.01, 144.93, 130.59, 130.07, 130.01, 125.62, 120.71, 120.58, 118.96, 116.36, 116.22, 44.02, 34.63, 26.92, 26.16, 16.22.

[0506] XPF-0518: 1-(4-(4-(1-(Trifluoromethyl)cyclopropyl)-phenoxy)phenyl)adamantane

[0507]

[0508] To 4-(Adamantan-1-yl)phenol (137 mg, 0.6 mmol, 1.5 equiv) and 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene (106 mg, 0.4 mmol, 1 equiv) dissolved in DMF (1.6 mL, 0.2 M), Cs2CO3 (260 mg, 0.8 mmol, 2 equiv), CuI (7.6 mg, 40 μmol, 10 mol%), and tBuXPos (34 mg, 80 μmol, 20 mol%) were added. The mixture was degassed using the freeze-pump-thaw method, placed under an argon atmosphere, stirred vigorously, and refluxed (165 °C) for 72 h. The mixture was allowed to return to room temperature and partitioned between petroleum ether and 2 M aqueous NaOH. The aqueous layer was extracted twice more, and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by flash chromatography (SiO2, gradient petroleum ether / AcOEt) to give 120 mg of 1-(4-(4-(1-(trifluoromethyl)cyclopropyl)-phenoxy)phenyl)adamantane (72%).

[0509] MS: [C 26 H 26 F3O] + Calculated value = 411.19; found value was 411.20

[0510] 1 1H-NMR (300 MHz, CDCl3) δ 7.43–7.36 (m, 2H), 7.36–7.30 (m, 2H), 7.03–6.91 (m, 4H), 2.18–2.04 (m, 3H), 1.95–1.88 (m, 6H), 1.86–1.68 (m, 6H), 1.38–1.30 (m, 2H), 1.05–0.97 (m, 2H).

[0511] 13 13C-NMR (300 MHz, CDCl3) δ 157.9, 154.2, 146.9, 132.6, 130.3, 126.2, 126.42 (q, J = 273.5 Hz) 118.9, 118.0, 43.3, 36.8, 35.9, 27.5 (q, J = 33.3 Hz), 9.81 (q, J = 2.3 Hz)

Claims

1. Use of a compound of general formula (I) or a salt thereof in the preparation of a medicament: R 1 = C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, -OC1-C 12 alkyl, -OC2-C 12 alkenyl, -OC2-C 12 alkynyl, -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 bicycloalkyl, -OC7-C 12 bicycloalkenyl, -OC8-C 14 tricycloalkyl, -SC1-C 12 alkyl, -SC2-C 12 alkenyl, -SC2-C 12 alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 bicycloalkyl, -SC7-C 12 bicycloalkenyl, -SC8-C 14 tricycloalkyl, -NHR 9 or -NR 9 R 10 , where R 9 and R 10 are independently selected from: C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, or where R 9 may together with R 10 form a ring structure, said ring structure including the N atom in -NR 9 R 10 , where the ring structure containing the N atom is selected from 3- to 8-membered cyclic structures or 5- to 12-membered bicyclic structures, and where all said ring structures may additionally contain one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in the ring structure; which includes all alkyl, alkenyl, and alkynyl residues in the definitions of R 1 , R 9 , and R 10 are straight-chain or branched-chain and unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, straight-chain or branched-chain -OC1-C5 alkyl, -OC3-C5 cycloalkyl, straight-chain or branched-chain -NH(C1-C5 alkyl), straight-chain or branched-chain -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), straight-chain or branched-chain -N(C1-C5 alkyl)(C3-C5 cycloalkyl); which includes all cyclic, bicyclic, and tricyclic structures in the definitions of R 1 , R 9 , and R 10 that are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C5 alkyl, straight-chain or branched -OC1-C5 alkyl, straight-chain or branched -NH(C1-C5 alkyl), straight-chain or branched -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), straight-chain or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); which includes all alkyl, alkenyl, and alkynyl residues in the definitions of R 1 , R 9 , and R 10 may contain one or more heteroatoms independently selected from O, S, and N in place of carbon atoms, and wherein such substitution results in the residue containing at least twice the number of C atoms as the number of heteroatoms independently selected from O, S, and N, and wherein such substitution additionally does not result in one of the groups selected from C=O, S=O, and N=O being directly bonded to the aromatic ring; which includes all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues in the definitions of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S, and N to replace C atoms, and wherein such replacement results in the residue containing at least the same number of C atoms as the heteroatoms independently selected from O, S, and N; which includes all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues in the definitions of R 1 , R 9 and R 10 may be partially or fully halogenated; wherein the bicyclic and tricyclic residues include fused, bridged and spiro systems; wherein R 1 is selected from residues having more than four carbon atoms; R 2 –R 5 Each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C4 alkyl, straight-chain or branched C2-C4 alkenyl, straight-chain or branched C2-C4 alkynyl, C3-C6 cycloalkyl, -CH2(C3-C6 cycloalkyl), straight-chain or branched -OC1-C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1-C3 alkyl), straight-chain or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1-C3 alkyl)(cyclopropyl); which includes all alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of R 2 –R 5 being unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; which includes all alkyl, alkenyl, alkynyl, and cycloalkyl residues in the definition of R 2 –R 5 may contain one or more heteroatoms independently selected from O, S, and N in place of carbon atoms, and wherein such substitution does not result in one of the groups selected from C═O and S═O being directly bonded to the aromatic ring; X 1 –X 4 Each independently selected from N, CR 11 , CR 12 , CR 13 , CR 14 ; R 11 –R 14 each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C4 alkyl, straight-chain or branched C2-C4 alkenyl, straight-chain or branched C2-C4 alkynyl, C3-C6 cycloalkyl, -CH2(C3-C6 cycloalkyl), straight-chain or branched -OC1-C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1-C3 alkyl), straight-chain or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1-C3 alkyl)(cyclopropyl); which includes all alkyl, alkenyl, alkynyl and cycloalkyl residues in the definition of R 11 –R 14 that are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; which includes all alkyl, alkenyl, alkynyl, and cycloalkyl residues in the definition of R 11 –R 14 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; R 6 and R 7 are independently selected from -H, -F, -CH3; or R 6 and R 7 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein said cyclic residue is C3 cycloalkyl; R 8 selected from -H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, -F, -CF3 and aromatic and heteroaromatic residues, wherein the aromatic and heteroaromatic residues are six-membered aromatic rings and five- to six-membered heteroaromatic rings, and the heteroaromatic rings contain 1-4 heteroatoms; which includes said aromatic and heteroaromatic residues in the definition of R 8 optionally being linked to the carbon atom to which R 8 is attached via a C1 alkylene or C2 alkylene linker; All aromatic and heteroaromatic residues included in the definition of R 8 are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, straight-chain or branched -OC1-C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1-C3 alkyl), straight-chain or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1-C3 alkyl)(cyclopropyl); All heteroaromatic residues included in the definition of R 8 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms; All alkyl, alkenyl, and alkynyl residues included in the definition of R 8 are straight-chain or branched and are unsubstituted or substituted with one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, and -NH2; which includes all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definitions of R 2 -R 8 and R 11 -R 14 and all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definition of -R may be partially or fully halogenated; Z 1 and Z 2 selected from the following group: Among them, In general formula Ia, Z 1 is selected from -H, linear or branched C1-C3 alkyl, cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -N3, -CF3, -CF2CF3, and wherein Z 2 is independently selected from linear or branched C1-C3 alkyl, -CF3, -CF2CF3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3 and -CN, Alternatively, in formula Ib, Z 1 and Z 2 together are =S, =NR 16 , or the zwitterion =N [+] R 17 O [-] ; where R 16 is selected from -H, -OH, -OCH3, -CN, -S(O)CH3, -S(O)CF3, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, straight-chain or branched C1–C3 alkyl, cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5 and -CH2C6H5; where R 17 is selected from straight-chain or branched C1-C3 alkyl, cyclopropyl, -C6H5 and -CH2C6H5; Alternatively, in General Formula Ic, Z 1 and Z 2 together form a cyclic residue containing the carbon atoms to which they are attached; wherein the cyclic residue is selected from three-membered, four-membered, five-membered and six-membered rings, where all rings may optionally contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms; where all rings are unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3; which includes all alkyl and cyclic residues in the definition of Z 1 and Z 2 may be partially or fully halogenated, and the medicament is for the treatment of hyperproliferative disorders, wherein the compound is subject to the condition that the following compounds are excluded, 2. The use according to claim 1, wherein the structure of the compound or its salt is according to general formula (Ia).

3. The use according to claim 1, wherein the structure of the compound or its salt is according to general formula (Ib).

4. The use according to claim 1, wherein the structure of the compound or its salt is according to general formula (Ic).

5. The use according to any one of claims 1-4, wherein R 1 is selected from n-pentyl, n-hexyl, tert-pentyl, tert-octyl, 3-pentyl, diethyl-aminomethyl, ethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, dicyclopentyl, dicyclohexyl, dicycloheptyl, norbornyl, dicyclooctyl, dicyclooctenyl, dicyclononyl, methyldicyclononyl, adamantyl, tricyclodecyl, methyltetrahydrofuranyl, trimethyltetrahydrofuranyl, tetrahydropyranyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, tetrahydrothiopyranyl, dimethylpiperazinyl, N-methylmorpholinyl, N-methylthiomorpholinyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methylazaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecanyl, N-methyloxa-azaspirodecanyl, azaspirodecanyl, N-methylazaspirodecanyl, N-methyldihydro-oxazinyl, N,N-dimethylimidazolidinyl, azacycloheptyl, N-methylazacycloheptyl, azaspirohexyl, N-methylazaspirohexyl, oxa-azadispirodecanyl, N-methyloxa-azadispirodecanyl, azadispirodecanyl, N-methylazadispirodecanyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N-methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N-methylazabicyclononyl, azadamantyl, -O(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; 4-oxodicyclo[4.1.0]hept-1-yl.

6. The use according to any one of claims 1-4, wherein R 1 is selected from:

7. The use according to any one of claims 1-4, wherein R 2 -R 3 each is -H, R 4 is -H or -F, and / or R 5 is -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.

8. The use according to any one of claims 1-4, Wherein the substituents R as defined in general formula (I) 1 to R 5 The six-membered aromatic ring to which they are attached is selected from 9. The use according to any one of claims 1-4, Among them, the six-membered aromatic ring containing X as defined in the general formula (I) 1 -X 4 is selected from the following:

10. The use according to any one of claims 1-4, wherein Z 1 is -H, -CH3, -CF3 or cyclopropyl; and / or wherein Z 2 is -OS(O)2CH3 and -CN.

11. The use according to any one of claims 1-4, In general formula Ib, Z 1 and Z 2 together are =NR 16 or zwitterionic =N [+] R 17 O [-] ; where R 16 is selected from -H, -OH, -OCH3, -CH3, cyclopropyl and -CH2C6H5; and / or where R 17 is -CH3, -C(CH3)3 and -CH2C6H5:

12. The use according to any one of claims 1-4, In general formula (Ic), Z 1 and Z 2 together form a three-membered or four-membered or five-membered ring residue, the three-membered or four-membered or five-membered ring residue including the carbon atoms to which Z 1 and Z 2 are attached; wherein the cyclic residue is selected from cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl, thienyl, thiazolyl, methylthiazolyl, thiazolidine-dione, methylthiazolidine-dione, and oxazolidinyl, methyloxazolidinyl, oxazolidine-dione, and methyloxazolidine-dione; and wherein the cyclic residue is optionally substituted with -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3, and -CF3; or wherein the cyclic residue is selected from:

13. The use according to any one of claims 1-4, wherein R 6 , R 7 and R 8 are each -F.

14. The use according to any one of claims 1-4, wherein R 6 and R 7 together form a cyclic residue, which cyclic residue contains the carbon atoms to which R 6 and R 7 are attached, and wherein said cyclic residue is cyclopropyl.

15. The use according to any one of claims 1-4, wherein R 1 contains no heteroatoms.

16. The use according to claim 15, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures.

17. The use according to claim 15, wherein R 1 is selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methyldicyclononyl, tricyclodecyl and adamantyl.

18. The use according to claim 17, wherein R 1 is adamantyl.

19. The use according to any one of claims 1-4, wherein R 1 is selected from residues having six or more, or seven or more carbon atoms.

20. The use according to any one of claims 1-4, wherein R 1 contains one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms 1 contained in R 21. The use according to claim 20, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, or wherein R 1 is selected from residues containing cyclic, bicyclic and tricyclic structures.

22. The use according to claim 20, wherein R 1 is selected from tetrahydropyranyl, N-methylpiperidinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azatricyclodecanyl and -O(tricyclodecanyl).

23. The use according to claim 22, wherein R 1 is azido - adamantyl and -O(adamantyl).

24. The use according to any one of claims 1-4, wherein the compound has structure I-1: wherein Z 1 and Z 2 as defined in general formula (I), wherein R 16 and R 17 are as defined in general formula (Ib), and wherein R 2 -R 8 、R 11 -R 14 and X 1 -X 4 are as defined in general formula (I).

25. The use according to any one of claims 1-4, wherein the compound has structure I-2: wherein R 1 as defined in general formula (I), wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally and independently replaced by heteroatoms selected from O, S and N as defined in general formula (I). wherein R 6 is as defined in general formula (I), and wherein R 6 is different from -H, optionally with the additional condition that R 6 is different from -CH3 wherein Z 1 and Z 2 as defined in general formula (I), wherein R 16 and R 17 as defined in general formula (Ib), and wherein R 2 -R 5 、R 7 -R 14 and X 1 -X 4 are as defined in general formula (I).

26. The use according to any one of claims 1-4, wherein the compound has structure I-3: wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally and independently substituted with heteroatoms selected from O, S and N as defined in formula (I). wherein R 8 as defined in general formula (I), wherein R 8 is different from -H, optionally with the additional condition that R 8 is different from -CH3 wherein Z 1 and Z 2 as defined by general formula (I), and wherein R 16 and R 17 are as defined in general formula (Ib).

27. The use according to any one of claims 1-4, wherein the compound has structure I-4: wherein R 1 is selected from cyclic, bicyclic and tricyclic structures as defined in claim 1, and wherein R 1 contains six or more carbon atoms, which are optionally independently substituted by heteroatoms selected from O, S and N as defined in formula (I), provided that R 1 does not contain heteroatoms selected from O, S, N, or contains one such heteroatom wherein R 6 , R 7 and R 8 are each -H, and wherein X 1 is CR 11 , X 2 is CR 12 , X 3 is CR 13 and X 4 is CR 14 , wherein Z 1 and Z 2 as defined in general formula (I), wherein R 16 and R 17 as defined in general formula (Ib) wherein R 2 -R 5 and R 9 -R 14 as defined in general formula (I).

28. The use according to any one of claims 1-4, wherein the compound of general formula (Ia) has structure Ia-4: wherein, R 6 、R 7 and R 8 are each -F, Z 1 、Z 2 and R 15 as defined in general formula (Ia), And, R 1 -R 5 、R 9 -R 14 and X 1 -X 4 as defined in general formula (I).

29. The use according to any one of claims 1-4, wherein the compound of general formula (Ib) has structure Ib-1: wherein, Z 1 and Z 2 together are =NR 16 where R 6 、R 7 and R 8 are each -F, R 1 As defined in general formula (I), R 16 As defined in general formula (Ib), and, R 2 -R 5 、R 9 -R 14 and X 1 -X 4 as defined in general formula (I).

30. The use according to any one of claims 1-4, wherein the compound of general formula (Ib) has structure Ib-3: wherein, Z 1 and Z 2 together form the zwitterion =N [+] R 17 O [-] , R 6 、R 7 and R 8 are each -F, R 17 As defined in general formula (Ib), And, R 1 -R 5 、R 9 -R 14 and X 1 -X 4 as defined in general formula (I).

31. The use according to any one of claims 1-4, wherein the compound of general formula (Ic) has structure Ic-3: wherein, Z 1 and Z 2 together form a cyclic residue containing the carbon atom to which they are attached, wherein Z 1 and Z 2 are as defined in general formula (Ic), and wherein said cyclic residue is selected from a three-membered ring and a four-membered ring and, R 1 -R 14 and X 1 -X 4 as defined in general formula (I).

32. The use according to any one of claims 1-4, wherein the compound is the following compound or its salt, 33. The use according to claim 1, wherein the hyperproliferative disorder is a non-malignant hyperproliferative disorder.

34. The use according to claim 1, wherein the hyperproliferative disorder is a malignant hyperproliferative disorder.

35. The use according to claim 1, wherein the hyperproliferative disorder is cancer or a pre-cancerous lesion.

36. The use according to claim 35, wherein the cancer is selected from non-melanoma skin cancer.

37. The use according to claim 35, wherein the cancer is selected from squamous cell carcinoma and basal cell carcinoma.

38. The use according to claim 35, wherein the pre-cancerous lesion is actinic keratosis.

39. The use according to claim 1, wherein the drug is used for treating hyperproliferative disorders of the skin, mucosa, skin and mucosal appendages, cornea and epithelial tissues.

40. The use according to claim 1, wherein the drug is used for treating cancer or pre-cancerous lesions of the skin, mucosa, skin and mucosal appendages, cornea and epithelial tissues.

41. The use according to claim 1, wherein the drug is used for treating hyperproliferative disorders of the skin, oral mucosa, tongue, lung, stomach, breast.

42. The use according to claim 1, wherein the drug is used for treating cancer or pre-cancerous lesions of the skin, oral mucosa, tongue, lung, stomach, breast.

43. The use according to claim 1, wherein the drug is used for treating cancer of the neuroendocrine system, cancer of the brain, pancreas, gastrointestinal tract, liver, thyroid, urogenital tract, and cancer of endothelial tissues.

44. The use according to claim 43, wherein the cancer is selected from cervical cancer, ovarian cancer, gastric cancer and medullary thyroid cancer.

45. The use according to claim 1, wherein the drug is used for treating malignant and non-malignant muscle hyperproliferative disorders.

46. The use according to claim 1, wherein the drug is used for treating hematopoietic and blood system disorders.

47. The use according to claim 46, wherein the hematopoietic and blood system cancers are selected from leukemia and lymphoma.

48. The use according to claim 47, wherein the leukemia and lymphoma are selected from myeloid malignancies and malignancies of the lymphoid lineage.

49. The use according to claim 48, wherein the myeloid malignancies are acute and chronic myeloid leukemia.

50. The use according to claim 49, wherein the acute and chronic myeloid leukemia are acute and chronic promyelocytic leukemia.

51. The use according to claim 48, wherein the malignancies of the lymphoid lineage are selected from acute and chronic T cell leukemia, acute and chronic B cell leukemia, and cutaneous T cell lymphoma.

52. The use according to claim 1, wherein the drug is used for treating hyperproliferative disorders associated with, accompanied by and / or caused by viral infections and oncoviral infections.

53. A pharmaceutical composition comprising a compound of formula (I) or a salt thereof as defined in the use according to any one of claims 1 - 32 and a pharmaceutically acceptable carrier.

54. A compound or a salt thereof according to formula (I): R 1 = C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, -OC1-C 12 alkyl, -OC2-C 12 alkenyl, -OC2-C 12 alkynyl, -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 bicycloalkyl, -OC7-C 12 bicycloalkenyl, -OC8-C 14 tricycloalkyl, -SC1-C 12 alkyl, -SC2-C 12 alkenyl, -SC2-C 12 alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 bicycloalkyl, -SC7-C 12 bicycloalkenyl, -SC8-C 14 tricycloalkyl, -NHR 9 or -NR 9 R 10 , where R 9 and R 10 are each independently selected from: C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, or where R 9 can together with R 10 form a ring structure, said ring structure including the N atom in -NR 9 R 10 , and the ring structure containing the N atom is selected from 3- to 8-membered cyclic structures or 5- to 12-membered bicyclic structures, and all said ring structures may additionally contain one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in the ring structure; which includes all alkyl, alkenyl and alkynyl residues in the definitions of R 1 , R 9 and R 10 are straight-chain or branched-chain and unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, straight-chain or branched-chain -OC1-C5 alkyl, -OC3-C5 cycloalkyl, straight-chain or branched-chain -NH(C1-C5 alkyl), straight-chain or branched-chain -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), straight-chain or branched-chain -N(C1–C5 alkyl)(C3–C5 cycloalkyl); which includes all cyclic, bicyclic, and tricyclic structures in the definitions of R 1 , R 9 , and R 10 that are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C5 alkyl, straight-chain or branched -OC1–C5 alkyl, straight-chain or branched -NH(C1–C5 alkyl), straight-chain or branched -N(C1–C5 alkyl)(C1–C5 alkyl), -NH(C3–C5 cycloalkyl), -N(C3–C5 cycloalkyl)(C3–C5 cycloalkyl), straight-chain or branched -N(C1–C5 alkyl)(C3–C5 cycloalkyl); which includes all alkyl, alkenyl, and alkynyl residues in the definitions of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms, and wherein such replacement results in the residue containing at least twice the number of C atoms as the number of heteroatoms independently selected from O, S, and N, and wherein such replacement additionally does not result in one of the groups selected from C=O, S=O, and N=O being directly bonded to the aromatic ring; which includes all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definitions of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S and N to replace C atoms, and wherein such replacement results in the residue containing at least the same number of C atoms as the heteroatoms independently selected from O, S and N; which includes all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definitions of R 1 , R 9 and R 10 may be partially or fully halogenated; wherein the bicyclic and tricyclic residues include fused, bridged and spiro systems; wherein R 1 is selected from residues having more than four carbon atoms; R 2 –R 5 Each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C4 alkyl, straight-chain or branched C2-C4 alkenyl, straight-chain or branched C2-C4 alkynyl, C3-C6 cycloalkyl, -CH2(C3-C6 cycloalkyl), straight-chain or branched -OC1-C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1-C3 alkyl), straight-chain or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1-C3 alkyl)(cyclopropyl); which includes all alkyl, alkenyl, alkynyl, and cycloalkyl residues in the definition of R 2 –R 5 are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition of R 2 –R 5 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; X 1 –X 4 Each independently selected from N, CR 11 , CR 12 , CR 13 , CR 14 ; R 11 –R 14 Each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C4 alkyl, straight-chain or branched C2-C4 alkenyl, straight-chain or branched C2-C4 alkynyl, C3-C6 cycloalkyl, -CH2(C3-C6 cycloalkyl), straight-chain or branched -OC1-C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1-C3 alkyl), straight-chain or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1-C3 alkyl)(cyclopropyl); which includes all alkyl, alkenyl, alkynyl, and cycloalkyl residues in the definition of R 11 –R 14 are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; All alkyl, alkenyl, alkynyl and cycloalkyl residues included in the definition of R 11 –R 14 may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms, and such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; R 6 and R 7 are independently selected from -H, -F, -CH3; or R 6 and R 7 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein said cyclic residue is C3 cycloalkyl; R 8 selected from -H, C1–C3 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, -F, -CF3 and aromatic and heteroaromatic residues, wherein the aromatic and heteroaromatic residues are six-membered aromatic rings and five- to six-membered heteroaromatic rings, and the heteroaromatic rings contain 1-4 heteroatoms; wherein said aromatic and heteroaromatic residues included in the definition of R 8 may optionally be linked to the carbon atom to which R 8 is attached via a C1-alkylene or C2-alkylene linker; All aromatic and heteroaromatic residues included in the definition of R 8 are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C3 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, cyclopropyl, straight-chain or branched -OC1–C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl); All heteroaromatic residues included therein in the definition of R 8 may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms; All alkyl, alkenyl, and alkynyl residues included in the definition of R 8 are straight-chain or branched and are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, and -NH2; which includes all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definitions of R 2 –R 8 and R 11 –R 14 and may be partially or fully halogenated; Z 1 and Z 2 selected from the group consisting of: Among them, In general formula Ia, Z 1 is selected from -H, straight-chain or branched C1-C3 alkyl, cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -N3, -CF3, -CF2CF3, and wherein Z 2 is independently selected from straight-chain or branched C1-C3 alkyl, -CF3, -CF2CF3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3, and -CN, Or in general formula Ib, Z 1 and Z 2 together are =S, =NR 16 , or the zwitterion =N [+] R 17 O [-] ; where R 16 is selected from -H, -OH, -OCH3, -CN, -S(O)CH3, -S(O)CF3, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, linear or branched C1-C3 alkyl, cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5 and -CH2C6H5; where R 17 is selected from linear or branched C1-C3 alkyl, cyclopropyl, -C6H5 and -CH2C6H5; Alternatively, in general formula Ic, Z 1 and Z 2 together form a cyclic residue containing the carbon atoms to which they are attached; wherein said cyclic residue is selected from four-membered rings, five-membered rings and six-membered rings, wherein all rings may optionally contain one or more heteroatoms independently selected from O, S and N in place of carbon atoms; wherein all rings are unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3; which includes all alkyl and cyclic residues in the definition of Z 1 and Z 2 may be partially or fully halogenated Among them, the conditions for the said compound are: excluding the compounds shown below, 55. The compound or its salt as described in claim 54, wherein R 1 is selected from n-pentyl, n-hexyl, tert-pentyl, tert-octyl, 3-pentyl, diethyl-aminomethyl, ethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, dicyclopentyl, dicyclohexyl, dicycloheptyl, norbornyl, dicyclooctyl, dicyclooctenyl, dicyclononyl, methyldicyclononyl, adamantyl, tricyclodecyl, methyltetrahydrofuranyl, trimethyltetrahydrofuranyl, tetrahydropyranyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, tetrahydrothiopyranyl, dimethylpiperazinyl, N-methy morpholinyl, N-methylthiomorpholinyl, oxa-azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia-azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N-methylazaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N-methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirode cyl, N-methyloxa-azaspirode cyl, azaspirode cyl, N-methylazaspirode cyl, N-methyldihydro-oxazinyl, N,N-dimethylimidazolidinyl, azacycloheptyl, N-methylazacycloheptyl, azaspirohexyl, N-methylazaspirohexyl, oxa-azadispirode cyl, N-methyloxa-azadispirode cyl, azadispirode cyl, N-methylazadispirode cyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N-methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N-methylazabicyclononyl, azadamantyl, -O(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; 4-oxodicyclo[4.1.0]hept-1-yl.

56. The compound or its salt as described in claim 54, wherein R 1 selected from:

57. The compound or its salt as described in claim 54, wherein R 2 -R 3 are each -H, R 4 is -H or -F, and / or R 5 is -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.

58. The compound or its salt as described in claim 54, Among them, the substituent R as defined in the general formula (I) 1 to R 5 The six-membered aromatic ring to which they are attached is selected from 59. The compound or its salt as described in claim 54, Wherein the six-membered aromatic ring containing X as defined in general formula (I) 1 -X 4 is selected from:

60. The compound or its salt as described in claim 54, wherein Z 1 is -H, -CH3, -CF3 or cyclopropyl; and / or wherein Z 2 is -OS(O)2CH3 and -CN.

61. The compound or its salt as described in claim 54, In general formula (Ib), Z 1 and Z 2 together are =NR 16 or zwitterionic =N [+] R 17 O [-] ; where R 16 is selected from -H, -OH, -OCH3, -CH3, cyclopropyl and -CH2C6H5; and / or where R 17 is -CH3, -C(CH3)3 and -CH2C6H5:

62. The compound or its salt according to general formula (I): R 1 = C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, -OC1-C 12 alkyl, -OC2-C 12 alkenyl, -OC2-C 12 alkynyl, -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 bicycloalkyl, -OC7-C 12 bicycloalkenyl, -OC8-C 14 tricycloalkyl, -SC1-C 12 alkyl, -SC2-C 12 alkenyl, -SC2-C 12 alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 bicycloalkyl, -SC7-C 12 bicycloalkenyl, -SC8-C 14 tricycloalkyl, -NHR 9 or -NR 9 R 10 , where R 9 and R 10 are each independently selected from: C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, or where R 9 may together with R 10 form a ring structure, said ring structure including the N atom in -NR 9 R 10 , where the ring structure containing the N atom is selected from 3- to 8-membered cyclic structures or 5- to 12-membered bicyclic structures, and where all said ring structures may additionally contain one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in the ring structure; which includes all alkyl, alkenyl, and alkynyl residues in the definitions of R 1 , R 9 , and R 10 are straight-chain or branched-chain and unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, straight-chain or branched-chain -OC1-C5 alkyl, -OC3-C5 cycloalkyl, straight-chain or branched-chain -NH(C1-C5 alkyl), straight-chain or branched-chain -N(C1–C5 alkyl)(C1–C5 alkyl), -NH(C3–C5 cycloalkyl), -N(C3–C5 cycloalkyl)(C3–C5 cycloalkyl), straight-chain or branched-chain -N(C1–C5 alkyl)(C3–C5 cycloalkyl); All cyclic structures, bicyclic structures, and tricyclic structures in the definitions of R 1 , R 9 , and R 10 are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C5 alkyl, straight-chain or branched -OC1–C5 alkyl, straight-chain or branched -NH(C1–C5 alkyl), straight-chain or branched -N(C1–C5 alkyl)(C1–C5 alkyl), -NH(C3–C5 cycloalkyl), -N(C3–C5 cycloalkyl)(C3–C5 cycloalkyl), straight-chain or branched -N(C1–C5 alkyl)(C3–C5 cycloalkyl); which includes all alkyl, alkenyl and alkynyl residues in the definitions of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S and N in place of carbon atoms, and wherein such substitution results in the residue containing at least twice as many C atoms as the number of heteroatoms independently selected from O, S and N, and wherein such substitution additionally does not result in one of the groups selected from C═O, S═O and N═O being directly bonded to the aromatic ring; which includes all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definitions of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S and N to replace C atoms, and wherein such replacement results in the residue containing at least the same number of C atoms as the heteroatoms independently selected from O, S and N; All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R 1 , R 9 and R 10 may be partially or fully halogenated; wherein the bicyclic and tricyclic residues include fused, bridged and spiro systems; wherein R 1 is selected from residues having more than four carbon atoms; R 2 –R 5 Each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C4 alkyl, straight-chain or branched C2–C4 alkenyl, straight-chain or branched C2–C4 alkynyl, C3–C6 cycloalkyl, -CH2(C3–C6 cycloalkyl), straight-chain or branched -OC1–C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl); which includes all alkyl, alkenyl, alkynyl, and cycloalkyl residues in the definition of R 2 –R 5 being unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition of R 2 –R 5 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; X 1 –X 4 Each independently selected from N, CR 11 , CR 12 , CR 13 , CR 14 ; R 11 –R 14 Each 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); All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition of R 11 –R 14 are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; All alkyl, alkenyl, alkynyl and cycloalkyl residues included in the definition of R 11 –R 14 may contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms, and such substitution cannot result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; R 6 and R 7 are independently selected from -H, -F, -CH3; or R 6 and R 7 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein said cyclic residue is C3 cycloalkyl; R 8 selected from -H, C1–C3 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, -F, -CF3, and aromatic and heteroaromatic residues, where the aromatic and heteroaromatic residues are six-membered aromatic rings and five- to six-membered heteroaromatic rings, and the heteroaromatic rings contain 1-4 heteroatoms; which includes the aromatic and heteroaromatic residues in the definition of R 8 may optionally be linked to the carbon atom to which R 8 is attached via a C1 alkylene or C2 alkylene linker; All aromatic and heteroaromatic residues included in the definition of R 8 are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C3 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, cyclopropyl, straight-chain or branched -OC1–C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl); All heteroaromatic residues included in the definition of R 8 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms; All alkyl, alkenyl, and alkynyl residues included in the definition of R 8 are straight-chain or branched and are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, and -NH2; which includes all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definitions of R 2 –R 8 and R 11 –R 14 may be partially or fully halogenated; Z 1 and Z 2 selected from the following group: Among them, In general formula Ia, Z 1 is selected from -H, linear or branched C1-C3 alkyl, cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -N3, -CF3, -CF2CF3, and wherein Z 2 is independently selected from linear or branched C1-C3 alkyl, -CF3, -CF2CF3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3 and -CN, Or in formula Ib, Z 1 and Z 2 together are =S, =NR 16 , or the zwitterion =N [+] R 17 O [-] ; where R 16 is selected from -H, -OH, -OCH3, -CN, -S(O)CH3, -S(O)CF3, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, straight-chain or branched C1-C3 alkyl, cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5 and -CH2C6H5; where R 17 is selected from straight-chain or branched C1-C3 alkyl, cyclopropyl, -C6H5 and -CH2C6H5; Alternatively, in General Formula Ic, Z 1 and Z 2 together form a cyclic residue containing the carbon atom to which they are attached; wherein said cyclic residue is selected from three-membered, four-membered, five-membered and six-membered rings, where all rings may optionally contain one or more heteroatoms independently selected from O, S and N to replace carbon atoms; where all rings are unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3; which includes all alkyl and cyclic residues in the definitions of Z 1 and Z 2 may be partially or fully halogenated, Among them, the conditions for the said compound are: excluding the compounds shown below, wherein Z in Ic 1 and Z 2 together form a tri- or tetra- or penta-cyclic residue, the tri- or tetra- or penta-cyclic residue comprising the carbon atoms to which Z 1 and Z 2 are attached; wherein the cyclic residue is selected from cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl, thienyl, thiazolyl, methylthiazolyl, thiazolidine-dione, methylthiazolidine-dione and oxazolidinyl, methyloxazolidinyl, oxazolidine-dione and methyloxazolidine-dione; and wherein the cyclic residue is optionally substituted by -F, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3; or wherein the cyclic residue is selected from:

63. The compound or its salt as described in claim 54, wherein R 6 , R 7 and R 8 are each -F.

64. The compound or its salt as described in claim 54, wherein R 6 and R 7 together form a cyclic residue that includes the carbon atoms to which R 6 and R 7 are attached, and wherein said cyclic residue is cyclopropyl.

65. The compound or its salt as described in claim 54, wherein R 1 contains no heteroatoms.

66. The compound or its salt as described in claim 65, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures.

67. The compound or its salt as described in claim 65, wherein R 1 is selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methyldicyclononyl, tricyclodecyl and adamantyl.

68. The compound or its salt as described in claim 67, wherein R 1 is adamantyl.

69. The compound or its salt as described in claim 54, wherein R 1 is selected from residues having six or more, or seven or more carbon atoms.

70. The compound or its salt as described in claim 54, wherein R 1 contains one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms 1 contained in R 71. The compound or its salt as described in claim 70, wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, or wherein R 1 is selected from residues containing cyclic, bicyclic and tricyclic structures.

72. The compound or its salt as described in claim 70, wherein R 1 is selected from tetrahydropyranyl, N-methylpiperidinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azatricyclodecanyl and -O(tricyclodecanyl).

73. The compound or its salt as described in claim 72, wherein R 1 is azido - adamantyl and -O(adamantyl).

74. The compound or its salt as described in claim 54, wherein the said compound has structure I-1: wherein Z 1 and Z 2 as defined in general formula (I), wherein R 16 and R 17 are as defined in general formula (Ib), and wherein R 2 -R 8 、R 11 -R 14 and X 1 -X 4 are as defined in general formula (I).

75. The compound or its salt as described in claim 54, wherein the said compound has structure I-2: wherein R 1 as defined in general formula (I), wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally and independently replaced by heteroatoms selected from O, S and N as defined in general formula (I). wherein R 6 is as defined in general formula (I), and wherein R 6 is different from -H, optionally with the additional condition that R 6 is different from -CH3 wherein Z 1 and Z 2 as defined in general formula (I), wherein R 16 and R 17 as defined in general formula (Ib), and wherein R 2 -R 5 、R 7 -R 14 and X 1 -X 4 are as defined in general formula (I).

76. The compound or its salt as described in claim 54, wherein the said compound has structure I-3: wherein R 1 is selected from cyclic, bicyclic and tricyclic structures, and wherein R 1 contains six or more carbon atoms, which are optionally and independently substituted by heteroatoms selected from O, S and N as defined in general formula (I), wherein R 8 as defined in general formula (I), wherein R 8 is different from -H, optionally with the additional condition that R 8 is different from -CH3 wherein Z 1 and Z 2 as defined by general formula (I), and wherein R 16 and R 17 are as defined in general formula (Ib).

77. The compound or its salt as described in claim 54, wherein the said compound has structure I-4: wherein R 1 is selected from cyclic, bicyclic and tricyclic structures as defined in claim 1, and wherein R 1 contains six or more carbon atoms, which are optionally independently substituted by heteroatoms selected from O, S and N as defined in general formula (I), provided that R 1 does not contain heteroatoms selected from O, S, N, or contains one of said heteroatoms wherein R 6 , R 7 and R 8 are each -H, and wherein X 1 is CR 11 , X 2 is CR 12 , X 3 is CR 13 and X 4 is CR 14 , wherein Z 1 and Z 2 as defined in general formula (I), wherein R 16 and R 17 as defined in general formula (Ib) wherein R 2 -R 5 and R 9 -R 14 as defined in general formula (I).

78. The compound or its salt as described in claim 54, wherein the compound of general formula (Ia) has structure Ia-4: wherein, R 6 , R 7 and R 8 Each is -F, Z 1 as defined in general formula (Ia), and Z 1 is not -CF3, Z 2 and R 15 as defined in general formula (Ia), and, R 1 -R 5 、R 9 -R 14 and X 1 -X 4 as defined in general formula (I).

79. The compound or its salt as described in claim 54, wherein the compound of general formula (Ib) has structure Ib-1: wherein, Z 1 and Z 2 together are =NR 16 where R 6 、R 7 and R 8 are each -F, R 1 as defined in general formula (I), and R 1 is not -CF3, R 16 As defined in general formula (Ib), And, R 2 -R 5 、R 9 -R 14 and X 1 -X 4 as defined in general formula (I).

80. The compound or its salt as described in claim 54, wherein the compound of general formula (Ib) has structure Ib-3: wherein, Z 1 and Z 2 together form the zwitterion =N [+] R 17 O [-] , R 6 , R 7 and R 8 Each is -F, R 17 As defined in general formula (Ib), And, R 1 -R 5 、R 9 -R 14 and X 1 -X 4 as defined in general formula (I).

81. The compound or its salt according to general formula (I): R 1 = C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, -OC1-C 12 alkyl, -OC2-C 12 alkenyl, -OC2-C 12 alkynyl, -OC3-C8 cycloalkyl, -OC5-C8 cycloalkenyl, -OC5-C 12 bicycloalkyl, -OC7-C 12 bicycloalkenyl, -OC8-C 14 tricycloalkyl, -SC1-C 12 alkyl, -SC2-C 12 alkenyl, -SC2-C 12 alkynyl, -SC3-C8 cycloalkyl, -SC5-C8 cycloalkenyl, -SC5-C 12 bicycloalkyl, -SC7-C 12 bicycloalkenyl, -SC8-C 14 tricycloalkyl, -NHR 9 or -NR 9 R 10 , where R 9 and R 10 are each independently selected from: C1-C 12 alkyl, C2-C 12 alkenyl, C2-C 12 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, or where R 9 can together with R 10 form a ring structure, said ring structure including the N atom in -NR 9 R 10 , where the ring structure containing the N atom is selected from 3- to 8-membered cyclic structures or 5- to 12-membered bicyclic structures, and where all said ring structures may additionally contain one or more heteroatoms independently selected from O, S, and N to replace the carbon atoms contained in the ring structure; which includes all alkyl, alkenyl, and alkynyl residues in the definitions of R 1 , R 9 , and R 10 are straight-chain or branched-chain and unsubstituted or substituted by one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C5-C 12 bicycloalkyl, C7-C 12 bicycloalkenyl, C8-C 14 tricycloalkyl, straight-chain or branched-chain -OC1-C5 alkyl, -OC3-C5 cycloalkyl, straight-chain or branched-chain -NH(C1-C5 alkyl), straight-chain or branched-chain -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), straight-chain or branched-chain -N(C1-C5 alkyl)(C3-C5 cycloalkyl); which includes all cyclic, bicyclic and tricyclic structures in the definitions of R 1 , R 9 and R 10 are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C5 alkyl, straight-chain or branched -OC1-C5 alkyl, straight-chain or branched -NH(C1-C5 alkyl), straight-chain or branched -N(C1-C5 alkyl)(C1-C5 alkyl), -NH(C3-C5 cycloalkyl), -N(C3-C5 cycloalkyl)(C3-C5 cycloalkyl), straight-chain or branched -N(C1-C5 alkyl)(C3-C5 cycloalkyl); All alkyl, alkenyl, and alkynyl residues included in the definitions of R 1 , R 9 , and R 10 may contain one or more heteroatoms independently selected from O, S, and N in place of carbon atoms, and wherein such substitution results in the residue containing at least twice as many C atoms as the number of heteroatoms independently selected from O, S, and N, and wherein such substitution additionally does not result in one of the groups selected from C=O, S=O, and N=O being directly bonded to the aromatic ring; which includes all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, and tricycloalkyl residues in the definitions of R 1 , R 9 and R 10 may contain one or more heteroatoms independently selected from O, S, and N to replace C atoms, and wherein such replacement results in the residue containing at least the same number of C atoms as the heteroatoms independently selected from O, S, and N; All alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues in the definitions of R 1 , R 9 and R 10 may be partially or fully halogenated; wherein the bicyclic and tricyclic residues include fused, bridged and spiro systems; wherein R 1 is selected from residues having more than four carbon atoms; R 2 –R 5 Each independently selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1–C4 alkyl, straight-chain or branched C2–C4 alkenyl, straight-chain or branched C2–C4 alkynyl, C3–C6 cycloalkyl, -CH2(C3–C6 cycloalkyl), straight-chain or branched -OC1–C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1–C3 alkyl), straight-chain or branched -N(C1–C3 alkyl)(C1–C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1–C3 alkyl)(cyclopropyl); All alkyl, alkenyl, alkynyl and cycloalkyl residues included in the definition of R 2 –R 5 are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition of R 2 –R 5 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms, and wherein such substitution does not result in one of the groups selected from C═O and S═O being directly bonded to the aromatic ring; X 1 –X 4 each independently selected from N, CR 11 , CR 12 , CR 13 , CR 14 ; R 11 –R 14 Each 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); All alkyl, alkenyl, alkynyl and cycloalkyl residues included in the definition of R 11 –R 14 are unsubstituted or substituted by one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH and -OCH3, -OCF3, -NH2, -NHCH3, -N(CH3)2; All alkyl, alkenyl, alkynyl, and cycloalkyl residues included in the definition of R 11 –R 14 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms, and wherein such substitution does not result in one of the groups selected from C=O and S=O being directly bonded to the aromatic ring; R 6 and R 7 are independently selected from -H, -F, -CH3; or R 6 and R 7 together form a cyclic residue containing the carbon atoms to which they are attached, and wherein said cyclic residue is C3 cycloalkyl; R 8 selected from -H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, -F, -CF3, and aromatic and heteroaromatic residues, wherein the aromatic and heteroaromatic residues are six-membered aromatic rings and five- to six-membered heteroaromatic rings, and the heteroaromatic rings contain 1-4 heteroatoms; which includes the aromatic and heteroaromatic residues in the definition of R 8 may optionally be linked to the carbon atom to which R 8 is attached via a C1 or C2 alkylene linker; All aromatic and heteroaromatic residues included in the definition of R 8 are unsubstituted or substituted by one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, straight-chain or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, straight-chain or branched -OC1-C3 alkyl, -O(cyclopropyl), straight-chain or branched -NH(C1-C3 alkyl), straight-chain or branched -N(C1-C3 alkyl)(C1-C3 alkyl), -NH(cyclopropyl), -N(cyclopropyl)2, straight-chain or branched -N(C1-C3 alkyl)(cyclopropyl); All heteroaromatic residues included in the definition of R 8 may contain one or more heteroatoms independently selected from O, S, and N to replace carbon atoms; All alkyl, alkenyl, and alkynyl residues included in the definition of R 8 are straight-chain or branched and are unsubstituted or substituted with one or more substituents independently selected from the following: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, and -NH2; which includes all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues in the definitions of R 2 -R 8 and R 11 -R 14 may be partially or fully halogenated; Z 1 and Z 2 selected from the group consisting of: Among them, In general formula Ia, Z 1 is selected from -H, straight-chain or branched C1-C3 alkyl, cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -N3, -CF3, -CF2CF3, and wherein Z 2 is independently selected from straight-chain or branched C1-C3 alkyl, -CF3, -CF2CF3, -OS(O)2CH3, -OS(O)2CF3, -OS(O)2C6H4CH3 and -CN, Or in formula Ib, Z 1 and Z 2 together are =S, =NR 16 , or the zwitterion =N [+] R 17 O [-] ; where R 16 is selected from -H, -OH, -OCH3, -CN, -S(O)CH3, -S(O)CF3, -S(O)C(CH3)3, -S(O)2CH3, -S(O)2CF3, straight-chain or branched C1-C3 alkyl, cyclopropyl, -CF3, -CF2CF3, -CH2CF3, -C6H5 and -CH2C6H5; where R 17 is selected from straight-chain or branched C1-C3 alkyl, cyclopropyl, -C6H5 and -CH2C6H5; Alternatively, in General Formula Ic, Z 1 and Z 2 together form a cyclic residue containing the carbon atoms to which they are attached; wherein said cyclic residue is selected from three-membered, four-membered, five-membered and six-membered rings, wherein all rings may optionally contain one or more heteroatoms independently selected from O, S and N in place of carbon atoms; wherein all rings are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, =O, -CH3 and -CF3; which includes all alkyl and cyclic residues in the definition of Z 1 and Z 2 may be partially or fully halogenated Among them, the conditions for the said compound are: excluding the compounds shown below, wherein the compound of general formula (Ic) has structure Ic-2 or Ic-3: wherein, Z 1 and Z 2 together form a cyclic residue containing the carbon atom to which they are attached, wherein Z 1 and Z 2 are as defined in general formula (Ic), and wherein said cyclic residue is selected from three-membered and four-membered rings R 8 as defined in general formula (I), and R 8 is not -H, And, R 1 -R 7 , R 9 -R 14 and X 1 -X 4 as defined in general formula (I), or, wherein, Z 1 and Z 2 together form a cyclic residue containing the carbon atom to which they are attached, wherein Z 1 and Z 2 is as defined in general formula (Ic), and wherein said cyclic residue is selected from three-membered and four-membered rings, and said cyclic residue is not an oxiranyl group, and, R 1 -R 14 and X 1 -X 4 are as defined in general formula (I).

82. The compound or its salt, wherein the said compound is as shown below,

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