Novel compounds

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 in the treatment of pathological conditions including cancer, skin disorders, muscle disorders, disorders of the lung, disorders of the haematopoietic system including the haematologic system and immune system-related disorders.

Description of the Invention

The present invention covers novel molecules that show remarkable biological activity on human and animal derived cells. According compounds were found to influence the growth and survival of cancer cells and primary non-cancer cells. In particular, molecules were identified that are able to completely or partially inhibit cell growth or result in cell death. Moreover, some of the compounds were found to impact cellular signaling pathways, in particular the Notch signaling pathway. According molecules were found to enhance the Notch signaling pathway.

Thus, the present invention relates to compounds as defined herein that feature antiproliferative activity, which can be used in the treatment of benign and malignant hyperproliferative disorders in human and veterinary medicine. In particular, the present invention relates to compounds as defined herein for the treatment of disorders of the haematopoietic system including the haematologic system and immune system-related disorders, concerning malignancies of both the myeloid lineage and the lymphoid lineage, malignant and non-malignant disorders of the skin and mucosa, e.g. cornification disorders, malignant and non-malignant disorders of the muscle, including hyperproliferative disorders of the muscle, such as muscle hyperplasia and muscle hypertrophy, disorders of the neuroendocrine system, hyperproliferative disorders, cancer and pre-cancerous lesions of the skin and mucosa, such as non-melanoma skin cancer including squamous and basal cell carcinoma, actinic keratosis, hyperproliferative disorders and cancer of the oral cavity and tongue, hyperproliferative disorders and cancer of the neuroendocrine system such as medullary thyroid cancer, hyperproliferative disorders and cancer of the haematopoietic system including the haematologic system such as leukemia and lymphoma, hyperproliferative disorders and cancer of the lung, breast, stomach, genitourinary tract, e.g. cervical cancer and including cancer of the ovaries, in human and veterinary medicine.

The biological activity, e.g. the antiproliferative activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. Thus, the present invention also relates to compounds as defined herein that feature Notch enhancing activity, which can be used in the treatment of pathological conditions that are responsive for Notch- regulation, such as cancer, skin diseases, muscle disorders, disorders of the haematopoietic system including the haematologic system and immune system-related disorders, in human and veterinary medicine.

The compounds of the present invention relate to bisarylether structures composed of two six- membered aromatic cycles, wherein one of the aromatic cycles is an unsubstituted or substituted benzyl ring and the other aromatic cycle is an unsubstituted or substituted aryl ring, which optionally contains N-atoms, thus optionally being a six-membered heteroaromatic cycle. All such bisarylether structures share the common feature of containing a substituent in both para-positions relative to the ether bond, wherein such substituent on the benzyl ring, which cannot be a heteroaromatic cycle, is preferably selected from apolar residues and/or from sterically demanding residues; and wherein such substituent on the aryl ring which can optionally be a heteroaromatic cycle, is selected from structural units preferably containing a high amount of heteroatoms.

A first aspect of the present invention relates to compounds of general formula (I] and salts and solvates thereof:

Cl)

R ¹ = C ₁ -C ₁₂ preferably C ₄ -C ₁₂ alkyl, C ₂ -C ₁₂ preferably C ₄ -C ₁₂ alkenyl, C ₂ -C ₁₂ preferably C ₄ -C ₁₂ alkynyl, C ₃ -C ₈ cycloalkyl, Cs-Ce cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, CB-CM tricycloalkyl, -OC ₁ -C ₁₂ preferably -OC3-C ₁₂ alkyl, -OC ₂ -C ₁₂ preferably -OC3-C ₁₂ alkenyl, -OC ₂ -C ₁₂ preferably -OC ₃ -C ₁₂ alkynyl, -OC ₃ -C ₈ cycloalkyl, -OC _S -C _B cycloalkenyl, -OC ₅ -C ₁₂ bicycloalkyl, -OC ₇ -C ₁₂ bicycloalkenyl, -OC ₈ -C ₁₄ tricycloalkyl, -SC ₁ -C ₁₂ preferably -SC ₃ -C ₁₂ alkyl, -SC ₂ -C ₁₂ preferably -SC ₃ -C ₁₂ alkenyl, -SC ₂ -C ₁₂ preferably -SC ₃ -C ₁₂ alkynyl, -SC ₃ -C ₈ cycloalkyl, -SC _S -C _B cycloalkenyl, -SC ₅ -C ₁₂ bicycloalkyl, -SC ₇ -C ₁₂ bicycloalkenyl, -SCe-Ci ₄ tricycloalkyl, -NHR ⁷ or -NR ⁷ R ⁸ wherein R ⁷ and R ⁸ are independently from each other selected from: C ₁ -C ₁₂ preferably C ₃ -C ₁₂ alkyl, C ₂ -C ₁₂ preferably C ₃ -C ₁₂ alkenyl, C ₂ -C ₁₂ preferably C ₃ -C ₁₂ alkynyl, C ₃ -Ca cycloalkyl, C _S -C _B cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, C _B -C _M tricycloalkyl, or wherein R ⁷ can form a ring structure together with R ⁸ wherein the said ring structure including the N-atom is selected from three to eight membered cyclic structures or five to twelve membered bicyclic structures and wherein all said ring structures can additionally contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in the ring structure, and particularly wherein such a replacement results in residues that contain at least twice the number of C atoms than heteroatoms independently selected from 0, S and N;

wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R ¹ , R ⁷ and R ⁸ are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , =0, C ₃ -C ₈ cycloalkyl, Cs-Ce cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, C _S -CM tricycloalkyl, linear or branched -OC ₁ -C ₅ alkyl such as -OCH ₃ , -OC ₃ -C ₅ cycloalkyl such as -0 [cyclopropyl], linear or branched -NH[Ci-Cs alkyl], linear or branched -N[Ci-Cs alkyl] (C ₁ -C ₅ alkyl], -NH(C ₃ -Cs cycloalkyl] such as -NH (cyclopropyl], -N(C ₃ -Cs cycloalkyl] (C ₃ -C ₅ cycloalkyl], linear or branched - N (C ₁ -C ₅ alkyl] (C ₃ -C ₅ cycloalkyl];

wherein when an alkyl, alkenyl and alkynyl residue contained in the definitions of R ¹ , R ⁷ and R ⁸ is substituted with one or more substituents being =0, such substitution with =0 cannot result in one of the groups selected from C=0, S=0 and N=0 directly bound to an aromatic ring; wherein all cyclic structures, bicyclic structures and tricyclic structures including cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R ¹ , R ⁷ and R ⁸ are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , =0, linear or branched C ₁ -C ₅ alkyl such as -CH ₃ , linear or branched -OC ₁ -C ₅ alkyl such as -0CH ₃ , linear or branched -NH(Ci-Cs alkyl], linear or branched -NfCi-Cs alkyl] (C ₁ -C ₅ alkyl], -NH(C ₃ -Cs cycloalkyl] such as - NH (cyclopropyl], -N(C ₃ -Cs cycloalkyl] (C ₃ -C ₅ cycloalkyl], linear or branched -N(Ci-Cs alkyl] (C ₃ - C ₅ cycloalkyl]; wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R ¹ , R ⁷ and R ^B can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom, and wherein such a replacement results in residues that contain at least twice the number of C atoms than heteroatoms independently selected from 0, S and N, and wherein such replacement additionally cannot result in one of the groups selected from C=0, S=0 and N=0 directly bound to an aromatic ring;

wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R ¹ , R ⁷ and R ⁸ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom, and wherein such a replacement results in residues that contain at least the same number of C atoms than heteroatoms independently selected from 0, S and N;

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R ¹ , R ⁷ and R ⁸ can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;

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

and wherein R ¹ is preferably selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, sec-butyl, tert-butyl, tert-pentyl, tert-octyl, 3-pentyl, -CF ₃ , -CF ₂ CF ₃ , -[CF ₂ ]zCF ₃ , - CH(CF ₃ ) 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, bicyclopentyl, bicyclohexyl, bicycloheptyl preferably norbornyl, bicyclooctyl, bicyclooctenyl, bicyclononyl, methylbicyclononyl, adamantyl, tricyclodecyl, oxiranyl, oxetanyl, tetrahydrofuranyl, methyltetrahydrofuranyl, trimethyltetrahydrofuranyl, tetrahydropyranyl, aziridinyl, N- methylaziridinyl, azetidinyl, N-methylazetidinyl, difluoroazetidinyl, pyrrolidinyl, N- methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, difluoropiperidinyl, thiiranyl, thietanyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, dioxanyl, piperazinyl, dimethylpiperazinyl, dithianly, morpholinyl, N-methylmorpholinyl, thiomorpholinyl, N-methylthiomorpholinyl, oxa- azaspiroheptyl, N-methyloxa-azaspiroheptyl, azaspiroheptyl, N-methylazaspiroheptyl, thia- azaspiroheptyl, N-methylthia-azaspiroheptyl, difluorothia-azaspiroheptyl, azaspirooctyl, N- methylazaspirooctyl, oxa-azaspirooctyl, N-methyloxa-azaspirooctyl, oxa-azaspirononyl, N- methyloxa-azaspirononyl, azaspirononyl, N-methylazaspirononyl, oxa-azaspirodecyl, N- methyloxa-azaspirodecyl, azaspirodecyl, N-methylazaspirodecyl, dihydro-oxazinyl, N- methyldihydro-oxazinyl, oxazolidinyl, N-methyloxazolidinyl, dioxolanyl, imidazolidinyl, N- methylimidazolidinyl, N,N-dimethylimidazolidinyl, azepanyl, N-methylazepanyl, azaspirohexyl, N-methylazaspirohexyl, oxa-azadispirodecyl, N-methyloxa-azadispirodecyl, azadispirodecyl, N- methylazadispirodecyl, oxa-azabicyclooctyl, N-methyloxa-azabicyclooctyl, azabicyclooctyl, N- methylazabicyclooctyl, azabicycloheptyl, N-methylazabicycloheptyl, azabicyclononyl, N- methylazabicyclononyl, azaadamantyl, -0 [adamantyl], oxa-azabicyclononyl, N-methyloxa- azabicyclononyl, oxa-azabicycloheptyl, N-methyloxa-azabicycloheptyl, diazabicyclooctyl, N- methyldiazabicyclooctyl, N,N-dimethyldiazabicyclooctyl, diazabicycloheptyl, N- methyldiazabicycloheptyl, N,N-dimethyldiazabicycloheptyl; 4-oxocyclohexyl; 3-oxocyclopentyl; 2-oxocyclobutyl, 4-oxobicyclo[4.1.0]heptan-l-yl;

and wherein R ¹ is even more preferably selected from C4-C12 alkyl, C4-C12 alkenyl, C4-C12 alkynyl, cyclic, bicyclic and tricyclic residues, wherein the alkyl, alkenyl and alkynyl residues are preferably branched, including: R ² -R ⁵ are independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, - NH ₂ , -N0 ₂ , linear or branched C1-C4 alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C2-C4 alkynyl, C ₃ -C ₆ cycloalkyl, -CH ₂ (C ₃ -C ₆ cycloalkyl], linear or branched -OCi-C ₃ alkyl, - 0 (cyclopropyl], linear or branched -NH(Ci-C ₃ alkyl], linear or branched -N(Ci-C ₃ alkyl] (Ci-C ₃ alkyl], -NH(cyclopropyl], -N(cyclopropyl] ₂ , linear or branched -N(Ci-C ₃ alkyl] (cyclopropyl]; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R ² -R ⁵ are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -OCH ₃ , -OCF ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ] ₂ ;

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R ² -R ⁵ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom, and wherein such a replacement cannot result in one of the groups selected from C=0 and S=0 directly bound to an aromatic ring;

wherein R ² -R ³ each are preferably -H, R ⁴ is preferably -H or -F, and R ⁵ is preferably -H, -F, -Cl, - Br, -CH ₃ , -CF _3I -CH=CH ₂ , -CºCH, -CH ₂ OH, -CH ₂ NHCH ₃ , -OH, -OCH ₃ , -OCF ₃ , cyclopropyl, oxiranyl, - CH ₂ -JV-morpholinyl, -C(CH ₃ ] ₃ , -CH ₂ OCH ₃ , -N0 ₂ , -CN, -NH ₂ , -N(CH ₃ ] ₂ , -OCH(CH ₃ ] ₂ , -CH ₂ NH ₂ , - CH ₂ N(CH ₃ ] ₂ ;

wherein the six-membered aromatic ring, to which substituents R ¹ to R ⁵ are bound as defined in general formula [I], is preferably selected from:

X ⁱ -X ⁴ are independently from each other selected from N, CR ⁹ , CR ¹⁰ , CR ¹¹ , CR ¹² ;

R ⁹ -R ¹² are independently from each other 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, -CH ₂ (C3-C6 cycloalkyl], linear or branched -OC1-C3 alkyl, - 0 (cyclopropyl], linear or branched -NH(C _I -C3 alkyl], linear or branched -N(C _I -C3 alkyl] (C1-C3 alkyl], -NH(cyclopropyl], -N(cyclopropyl]2, linear or branched -N(C _I -C3 alkyl] (cyclopropyl]; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R ⁹ -R ¹² are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -OCH ₃ , -OCF ₃ , -NH ₂ , -NHCH3, -N(CH ₃ ] ₂ ;

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R ⁹ -R ¹² can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom, and wherein such a replacement cannot result in one of the groups selected from C=0 and S=0 directly bound to an aromatic ring;

wherein R ⁹ -R ¹² are preferably selected from -H, -F, -Cl, -Br, -CH ₃ , -CF ₃ , -OH, -OCH ₃ , -OCF ₃ , cyclopropyl, oxiranyl, -C(CH ₃ ]3, -N(CH ₃ ] ₂ , -NH ₂ , -CN, -CH ₂ OCH3, -OCH(CH ₃ ] ₂ , -CH ₂ NH ₂ , - CH ₂ N(CH ₃ ] ₂ , -CH ₂ OH, -NO ₂ , -CHz-iV-morpholinyl;

and wherein the six-membered aromatic ring containing X ^! -X ⁴ as defined in general formula [I) is preferably selected from:

R ⁶ = -H, Ci-Ca preferably C ₁ -C ₄ alkyl, C ₂ -C ₈ preferably C ₂ -C ₄ alkenyl, C ₂ -C ₈ preferably C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, C _B -C _M tricycloalkyl, and aromatic and heteroaromatic residues preferably six-membered aromatic cycles and five to six membered heteroaromatic cycles;

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

wherein said cycloalkyl, cycloalkenyl bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues contained in the definition of R ⁶ can optionally be linked through a Ci alkylene or a C ₂ alkylene or a C ₃ alkylene linker to the N to which R ⁶ is bound;

wherein all aromatic and heteroaromatic residues contained in the definition of R ⁶ are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , linear or branched C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, linear or branched -OC ₁ -C ₃ alkyl such as -OCH ₃ , -O(cyclopropyl), linear or branched -NH(C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) (C ₁ -C ₃ alkyl), -NH[cyclopropyl), - N(cyclopropyl) ₂ , linear or branched -N(C _I -C ₃ alkyl) [cyclopropyl);

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues, and alkylene linkers contained in the definition of R ⁶ are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , =0, linear or branched C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, linear or branched -OC ₁ -C ₃ alkyl such as -OCH ₃ , - 0 (cyclopropyl), linear or branched -NH(C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) (C ₁ -C ₃ alkyl), -NH(cyclopropyl), -N(cyclopropyl) ₂ , linear or branched -N(C _I -C ₃ alkyl) (cyclopropyl); wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl and heteroaromatic residues, and alkylene linkers contained in the definition of R ⁶ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

wherein R ⁶ is preferably -H, -CH3, -CH2CH3, n-propyl, isopropyl, cyclopropyl, -CF3 and -CF2CF3, benzyl, tert-butyl, phenyl, cyclohexyl, 1 -phenyl ethyl, 2,2-dimethyl-l-phenylpropyl, (1-naphtyl)- methyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, tetrahydropyranyl;

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl, tricycloalkyl, aromatic and heteroaromatic residues contained in the definitions of R ² -R ⁶ and R ⁹ -R ¹² can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;

Y = -H, linear or branched C ₁ -C ₆ alkyl, linear or branched C ₂ -C ₆ alkenyl, linear or branched C ₂ -C ₆ alkynyl, C _3- C ₆ cycloalkyl, C _5- C ₆ cycloalkenyl, -OH, linear or branched -OC _1- C ₆ alkyl, linear or branched -OC ₂ -C ₆ alkenyl, linear or branched -OC ₂ -C ₆ alkynyl, -OC ₃ -C ₆ cycloalkyl, -OC ₅ -C ₆ cycloalkenyl, -CN, aromatic and heteroaromatic residues preferably six-membered aromatic cycles and five- to six- membered heteroaromatic cycles, -S(0)R ¹³ and -S(0) ₂ R ¹³ wherein R ¹³ is selected from linear or branched Ci-Ce alkyl, linear or branched C ₂ -C ₆ alkenyl, linear or branched C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, Cs-Ce cycloalkenyl, -CF ₃ , and -C ₆ H ₄ CH ₃ ;

wherein all cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues contained in the definition of Y can optionally be linked through a Ci alkylene, or a C ₂ alkylene, or a C ₃ alkylene, or an -0-, or an -O-CH ₂ -, or an -O-CH ₂ -CH ₂ - linker to the N to which Y is bound; wherein all aromatic and heteroaromatic residues contained in the definition of Y are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH2, -NO2, linear or branched C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, linear or branched -OC1-C3 alkyl such as -OCH3, -O(cyclopropyl), linear or branched -NH(C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) [C1-C3 alkyl), -NH[cyclopropyl), - N(cyclopropyl) ₂ , linear or branched -N(C _I -C3 alkyl) [cyclopropyl);

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues, and alkylene linkers contained in the definition of Y are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , =0, linear or branched C ₁ -C ₃ alkyl, C ₂ -C ₃ alkenyl, C ₂ -C ₃ alkynyl, cyclopropyl, linear or branched -OC ₁ -C ₃ alkyl such as -OCH ₃ , -O(cyclopropyl), linear or branched -NH(C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) (C ₁ -C ₃ alkyl), -NH(cyclopropyl), -N[cyclopropyl) ₂ , linear or branched -N(C _I -C ₃ alkyl) [cyclopropyl);

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and heteroaromatic residues, and alkylene linkers contained in the definition of Y can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic and heteroaromatic residues and alkylene linkers contained in the definition of Y can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;

wherein Y is preferably -H, -CH ₃ , -CH ₂ CH ₃ , n-propyl, isopropyl, cyclopropyl, cyclohexyl, tetrahydropyranyl, -CF ₃ , -CF ₂ CF ₃ , -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ (cyclopropyl), -CN, -S[0)C(CH ₃ ) ₃ , -S(0) ₂ CH ₃ , -S[0) _Z CF ₃ , -S[0) ₂ CeH ₄ CH ₃ , -OCH ₂ C ₆ H ₅ and -OC ₆ H ₅ ; and for R ⁶ = -H or -CH ₃ or benzyl, then Y is preferably -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ [cyclopropyl);

wherein Y can form a ring structure together with R ⁶ , wherein the said ring structure including the N-atom of formula I is selected from three-membered rings, four-membered rings, five- membered rings, six-membered rings, from five- to twelve-membered bicyclic residues, from eight- to fourteen-membered tricyclic residues, and from heteroaromatic residues, wherein all rings, bicyclic, tricyclic and heteroaromatic residues can additionally contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in the ring structure, and wherein all rings, bicyclic, tricyclic and heteroaromatic residues are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -0CH ₃ , -NH ₂ , -NHCH ₃ , -N[CH ₃ ) ₂ , =0, -CH ₃ , -CF ₃ , morpholinyl;

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

wherein the ring structure of Y together with R ⁶ including the N-atom of formula I is preferably selected from aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, difluoropiperidinyl, morpholinyl, morpholinylazetidinyl, hydroxyazetidinyl, azetidinonyl, azetidinyl, difluoroazetidinyl, azaspirohexyl, azaspiroheptyl, difluoroazaspiroheptyl, hydroxyazaspiroheptyl, methylhydroxyazaspiroheptyl, trifluoromethylhydroxyazaspiroheptyl, azaspirooctyl, azaspirononyl, oxa-azaspiroheptyl, oxa-azaspirooctyl, oxa-azaspirononyl, thia-azaspiroheptyl, oxazolidinyl, tetrahydro-oxazinyl, isoxazolidinyl, oxazinane, isoxazolidine, piperazine;

and wherein the ring structure of Y together with R ⁶ including the N-atom of formula I is even more preferably selected from:

Z ¹ and Z ² are selected from the following groups:

la) (lb) [Ic) wherein Z ¹ is selected from linear or branched C ₁ -C ₃ alkyl preferably -CH ₃ , cyclopropyl, oxiranyl, N-methyl-aziridinyl, thiiranyl, -CN, -N ₃ , -CF ₃ , -CF ₂ CF ₃ , and wherein Z ² is independently selected from -H and linear or branched C ₁ -C ₃ alkyl preferably -CH ₃ , -CF ₃ , -CF ₂ CF ₃ [general formula la);

wherein Z ¹ is preferably -CH ₃ , -CF ₃ , -CN, cyclopropyl; and/or wherein Z ² is preferably -H, -CH ₃ and -CF ₃ ; e.g.:

or wherein Z ¹ and Z ² are together =0, =S, =NR ¹⁴ [general formula lb); wherein R ¹⁴ is selected from -H, -OH, -OCH ₃ , -CN, -S(0)C(CH ₃ ) ₃ , -S(0) ₂ CH ₃ , -S[0) ₂ CF ₃ , linear or branched C1-C3 alkyl preferably -CH ₃ , cyclopropyl, -CF ₃ , -CF ₂ CF ₃ , -CH2CF3, -C ₆ H ₅ , -CH ₂ C6H ₅ ; wherein Z ¹ and Z ² are together preferably =0, =NR ¹⁴ ; wherein R ¹⁴ is preferably selected from -H, -CH ₃ , cyclopropyl, -OH, -OCH ₃ , -CN: or wherein Z ¹ and Z ² form together a cyclic residue including the carbon atom to which they are bound [general formula Ic]; wherein the cyclic residue is selected from three-membered rings, four-membered rings five-membered rings and six-membered rings, wherein all rings optionally can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in the ring structure; wherein all rings are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -OCH ₃ , -NH ₂ , -NHCH ₃ , -N[CH ₃ ] ₂ , =0, -CH ₃ and -CF ₃ ;

wherein Z ¹ and Z ² form together preferably a three membered or four membered cyclic residue including the carbon atom to which they are bound; wherein this cyclic residue is preferably selected from cyclopropyl, cyclobutyl, oxiranyl, oxetanyl, aziridinyl, azetidinyl and thietanyl; and wherein this cyclic residue is optionally substituted preferably with -F, -OH, -OCH ₃ , -NH ₂ , - NHCH ₃ , -N(CH _{3 2} , =0, -CH ₃ and -CF ₃ ;

and wherein this cyclic residue is even more preferably selected from:

wherein all alkyl and cyclic residues contained in the definitions of Z ¹ and Z ² can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated.

Following preferred definitions of R ^: -R ¹⁴ , X ⁴ -X ⁴ , Z ¹ , Z ² and Y may be optionally independently and/or in combination applied on all aspects including preferred and certain aspects, on all embodiments including preferred and certain embodiments, and on all subgenera as defined in the present invention:

1) R ¹ preferably contains four or more preferably six or more and even more preferably seven or more carbon atoms;

2] R ¹ is preferably selected from branched alkyl, alkenyl and alkynyl residues;

3] R ¹ is preferably selected from cyclic, bicyclic and tricyclic structures, wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;

4] R ¹ preferably contains no heteroatom; 5] R ¹ is preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and most preferably adamantyl, e.g. 1-adamantyl and 2-adamantyl;

6] R ¹ preferably contains one or more heteroatoms, preferably one, two or three heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in R ¹ ;

7] R ¹ is preferably selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4- oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N- methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azaadamantyl and -Ofadamantyl];

8] preferably two, or more preferably three of the substituents independently selected from R ² -R ⁵ are -H, i.e. preferably two and more preferably one of the substituents independently selected from R ² -R ⁵ are different from -H;

9] in the case that two of the substituents independently selected from R ² -R ⁵ are different from -H and are in 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;

10] the composition of ring atoms as defined by X ⁴ -X ⁴ is preferably selected from the cases that all of X ⁴ -X ⁴ are independently selected from CR ⁹ , CR ¹⁰ , CR ¹¹ , CR ¹² , or that one of X ¹ - X ⁴ is N and the other three are independently selected from CR ⁹ , CR ¹⁰ , CR ¹¹ , CR ¹² , or that two of X ⁴ -X ⁴ are N and the other two are independently selected from CR ⁹ , CR ¹⁰ , CR ¹¹ , CR ¹² ; i.e. the aromatic or heteroaromatic ring is selected from benzene, pyridine, pyrimidine, pyridazine and pyrazine;

11] preferably two, or more preferably three of the substituents independently selected from R ⁹ -R ¹² are -H, i.e. preferably two and more preferably one of the substituents independently selected from R ⁹ -R ¹² are different from -H;

12] in the case that two of the substituents independently selected from R ⁹ -R ¹² are different from -H and are in 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;

13] Y is preferably selected from residues as contained in the general definition of Y which are bound with an oxygen atom to the N to which Y is bound.

A preferred aspect of the present invention relates to compounds of general formula (lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0 and wherein at least one of R ⁶ and Y is different from H,

and R ^! -R ⁵ , R ⁷ -R ¹³ and X ⁴ -X ⁴ are defined as in general formula [I) including their substitutions and preferred definitions.

A further preferred aspect of the present invention relates to compounds of general formula [I] and salts and solvates thereof, wherein Y is selected from residues as contained in the general definition of Y, which are bound with an oxygen atom to the N to which Y is bound, and wherein Y is even more preferably -OH, -OCH3, -OCH2CH3, -OCH2 [cyclopropyl], -OC6H5 and - OCH ₂ C ₆ H ₅ ,

and R ^! -R ¹² , R ¹⁴ , C ⁴ -C ⁴ , Z ¹ and Z ^z are defined as in general formula (I] including the substitutions and preferred definitions.

A further preferred aspect of the present invention relates to compounds of general formula [I] and salts and solvates thereof, wherein R ¹ is selected from residues as contained in the general definition of R ¹ , which contain four or more preferably six or more and even more preferably seven or more carbon atoms,

and wherein R ¹ contains no heteroatom,

and wherein R ¹ is even more preferably selected from cyclic, bicyclic and tricyclic structures, and wherein R ¹ is even more preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and adamantyl,

and wherein R ¹ is most preferably adamantyl,

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

A further preferred aspect of the present invention relates to compounds of general formula [I) and salts and solvates thereof, wherein R ¹ is selected from residues as contained in the general definition of R ¹ , which contain four or more, preferably six or more and even more preferably seven or more carbon atoms,

and wherein R ¹ contains one or more preferably one to two heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in R ¹ ,

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, 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 0 (adamantyl],

and wherein R ¹ is most preferably tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4- oxocyclohexyl, azabicyclooctyl, aza-adamantyl and -0 (adamantyl],

and R ² -R ¹⁴ , X ⁴ -X ⁴ , Z ¹ , Z ^z and Y are defined as in general formula [I] including the substitutions and preferred definitions.

A further preferred aspect of the present invention relates to compounds of general formula (I] and salts and solvates thereof, which fall under the scope of the herein defined subgenera: S.l If Z ¹ and Z ² are defined as in general formula (I] including their substitutions and preferred definitions, with the proviso that Z ¹ and Z ² are different from being together =0 or =S,

then R ^! -R ¹³ , X ⁴ -X ⁴ , and Y are defined as in general formula [I) including their substitutions and preferred definitions.

S.2 If R ⁶ is defined as in general formula [I] including the substitutions and preferred definitions, with the proviso that R ⁶ is different from -H, or linear unsubstituted or branched unsubstituted C1-C6 alkyl,

then R ^: -R ⁵ , R ⁷ -R ¹⁴ , C ⁴ -C ⁴ , Y, Z ¹ and Z ² are defined as in general formula (I) including their substitutions and preferred definitions.

S.3 If Y is defined as in general formula [I) including the substitutions and preferred definitions, with the proviso that Y is different from -H, linear unsubstituted or branched unsubstituted Ci-Ce alkyl, or -OH,

then R ¹ -R ¹⁴ , X ⁴ -X ⁴ , Z ¹ and Z ² are defined as in general formula (I] including their substitutions and preferred definitions.

S.4 If Z ¹ and Z ² are together =0 or =S, and Y is -OH,

then R ⁶ is defined as in general formula (I] including the substitutions and preferred definitions, with the proviso that R ⁶ is different from -H,

and then R ⁴ -R ⁵ , R ⁷ -R ¹² and X ⁴ -X ⁴ are defined as in general formula [I] including their substitutions and preferred definitions.

S.5 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C1-C6 alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C1-C6 alkyl, and Y is -H, linear unsubstituted or branched unsubstituted C1-C6 alkyl,

then R ¹ = C ₁ -C ₁₂ preferably C ₁ -C ₆ alkyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkenyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, Ce-Ci ₄ tricycloalkyl, -OC ₁ -C ₁₂ preferably -OC ₁ -C ₆ alkyl, -OC ₂ -C ₁₂ preferably -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₁₂ preferably -OC ₂ -C ₆ alkynyl, -OC ₃ -C ₈ cycloalkyl, - OC ₅ -C ₈ cycloalkenyl, -OC ₅ -C ₁₂ bicycloalkyl, -OC ₇ -C ₁₂ bicycloalkenyl, -0Cs-Ci ₄ tricycloalkyl, -SC ₁ -C ₁₂ preferably -SC ₁ -C ₆ alkyl, -SC ₂ -C ₁₂ preferably -SC ₂ -C ₆ alkenyl, -SC ₂ - C ₁₂ preferably -SC ₂ -C ₆ alkynyl, -SC ₃ -C ₈ cycloalkyl, -SCs-Cs cycloalkenyl, -SC ₅ -C ₁₂ bicycloalkyl, -SC ₇ -C ₁₂ bicycloalkenyl, -SCe-Ci ₄ tricycloalkyl, -NHR ⁷ or -NR ⁷ R ⁸ wherein R ⁷ and R ^B are independently from each other selected from: C ₁ -C ₁₂ preferably C ₁ -C ₆ alkyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkenyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, Cs-Ce cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, Ce-Ci ₄ tricycloalkyl, or wherein R ⁷ can form a ring structure together with R ⁸ wherein the said ring structure including the N-atom is selected from three to eight membered cyclic structures or five to twelve membered bicyclic structures and wherein all said ring structures can additionally contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in the ring structure;

wherein all C ₁ -C ₁₂ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, norbornyl and adamantyl residues are linear or branched, and are substituted with one or more substituents, here referred to as side-substituents, independently selected from: -OH, -NH ₂ , -NO ₂ , =0, C _3- C ₈ cycloalkyl, Cs-Cs cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl including norbornyl, C ₇ -C ₁₂ bicycloalkenyl, C _S -C _M tricycloalkyl including adamantyl, linear or branched -OC ₁ -C ₅ alkyl such as -0CH ₃ , -OC ₃ -C _S cycloalkyl such as -O(cyclopropyl], linear or branched -NH(Ci-Cs alkyl], linear or branched -N(Ci- C ₅ alkyl](Ci-C ₅ alkyl], -NH(C ₃ -Cs cycloalkyl] such as -NH (cyclopropyl], -N(C ₃ -Cs cycloalkyl] (C ₃ -C ₅ cycloalkyl], linear or branched -N(Ci-Cs alkyl] (C ₃ -C ₅ cycloalkyl]; and wherein all said C ₁ -C ₁₂ alkyl, C ₂ -C _B alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, C _S -C _B cycloalkenyl, adamantyl or norbornyl residues can optionally contain in addition one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS;

and all C ₉ -C ₁₂ alkenyl, C ₉ -C ₁₂ alkynyl, -OC ₁ -C ₁₂ alkyl, -OC ₂ -C ₁₂ alkenyl, -OC ₂ -C ₁₂ alkynyl, - SC ₁ -C ₁₂ alkyl, -SC ₂ -C ₁₂ alkenyl, -SC ₂ C ₁₂ alkynyl, and all alkyl, alkenyl and alkynyl residues contained in the definition of R ⁷ and R ⁸ are linear or branched, and are unsubstituted or substituted with one or more substituents, here referred to as side- substituents, independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , - NO ₂ , =0, C ₃ -C ₈ cycloalkyl, Cs-Cs cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, C _B -C _M tricycloalkyl, linear or branched -OC ₁ -C ₅ alkyl such as -OCH ₃ , -OC ₃ -C ₅ cycloalkyl such as -O(cyclopropyl], linear or branched -NH(Ci-Cs alkyl], linear or branched -N(Ci- C ₅ alkyl)(Ci-Cs alkyl], -NH(C ₃ -Cs cycloalkyl] such as -NH (cyclopropyl], -N(C ₃ -Cs cycloalkyl] (C ₃ -C ₅ cycloalkyl], linear or branched -N(Ci-Cs alkyl] (C ₃ -C ₅ cycloalkyl];

wherein all -OC ₃ -C ₈ cycloalkyl, -OCs-Cs cycloalkenyl, -SC ₃ -C ₈ cycloalkyl, -SC _S -C _B cycloalkenyl residues, and all cycloalkyl and cycloalkenyl residues contained in the definition of R ⁷ and R ⁸ and contained in the selection of the named side-substituents, and all bicyclic and tricyclic structures including bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R ¹ , R ⁷ and R ⁸ , with the proviso that they are different from adamantyl and norbornyl, are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, - OH, -NH ₂ , -NO ₂ , =0, linear or branched C1-C5 alkyl such as -CH ₃ , linear or branched -OCi- C5 alkyl such as -0CH ₃ , linear or branched -NH(Ci-Cs alkyl], linear or branched -N(Ci-Cs alkyl](Ci-Cs alkyl], -NH(C ₃ -Cs cycloalkyl] such as -NH(cyclopropyf), -N(C ₃ -Cs cycloalkyl] (C _3- C ₅ cycloalkyl], linear or branched -N(Ci-Cs alkyl] (C _3- C ₅ cycloalkyl];

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions R ⁷ and R ⁸ can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom; and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definition of R ¹ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom, with the optional proviso that the combination of the said heteroatoms in a terminal position is different from the residues -CN, -NCO, -NCS and -N3 if not explicitly contained in the definition of R ¹ ;

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R ¹ , R ⁷ and R ⁸ can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated; wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;

and then R ² -R ⁵ , R ⁹ -R ¹² and X ⁴ -X ⁴ are defined as in general formula (I] including their substitutions and preferred definitions.

S.6 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, and Y is -H, linear unsubstituted or branched unsubstituted Ci-Ce alkyl,

then R ² is selected from -CN, -NCO, -NCS, -OH, -NH ₂ , -N0 ₂ , linear or branched Ci-C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, - CH ₂ [C ₃ -Ce cycloalkyl), linear or branched -OC ₁ -C ₃ alkyl, -O(cyclopropyl), linear or branched -NH[C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) [C ₁ -C ₃ alkyl), - NH(cyclopropyl), -N(cyclopropyl) ₂ , linear or branched -N(C _I -C ₃ alkyl) [cyclopropyl); wherein all C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, and C ₃ -C ₄ cycloalkyl residues are substituted with one or more substituents independently selected from -OH, - OCH ₃ , -OCF ₃ , -NHz, -NHCH ₃ and -N(CH ₃ ) ₂ ;

wherein the Cs-Ce cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, - NHz, -NHCH3 and -N(CH ₃ ) ₂ ;

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ² can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and R ³ -R ⁵ are independently from each other selected from -H, -F, -Cl, -Br, -I, -CN, -NCO, - NCS, -OH, -NH ₂ , -NO ₂ , linear or branched C1-C4 alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -CH ₂ [C ₃ -C ₆ cycloalkyl), linear or branched -OC ₁ -C ₃ alkyl, -0 [cyclopropyl), linear or branched -NH(Ci-C ₃ alkyl), linear or branched -N[C _I -C ₃ alkyl)[Ci-C ₃ alkyl), -NH [cyclopropyl), -N[cyclopropyl) ₂ , linear or branched -N[C _I -C ₃ alkyl) [cyclopropyl);

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R ³ -R ⁵ are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -0CH ₃ , -0CF ₃ , -NH ₂ , -NHCH ₃ , -N[CH ₃ ) ₂ ; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R ³ -R ⁵ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and then R ¹ , R ⁷ -R ¹² and X ⁴ -X ⁴ are defined as in general formula (I) including their substitutions and preferred definitions.

S.7 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted Ci-Cg alkyl, or -OH, or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted Ci-Ce alkyl, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl,

then X ¹ is CR ⁹

and R ⁹ is selected from -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , linear or branched Ci-C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, - CH ₂ [C ₃ -C ₆ cycloalkyl), linear or branched -OC ₁ -C ₃ alkyl, -O(cyclopropyl), linear or branched -NH[C _I -C ₃ alkyl), linear or branched -N[Ci-C ₃ alkyl) [C ₁ -C ₃ alkyl), - NH(cyclopropyl), -N(cyclopropyl) ₂ , linear or branched -N(Ci-C ₃ alkyl) [cyclopropyl); wherein all C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, and C ₃ -C ₄ cycloalkyl residues are substituted with one or more substituents independently selected from -OH, - OCH ₃ , -OCF ₃ , -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ ;

wherein the C ₅ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH, -OCH ₃ , -OCF ₃ , - NH ₂ , -NHCH3 and -N(CH ₃ )2;

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and then R ^! -R ⁵ , R ⁷ , R ^a , R ¹⁰ -R ¹² and X ² -X ⁴ are defined as in general formula [I) including their substitutions and preferred definitions.

S.8 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl,

then X ² is CR ⁹

and R ⁹ is selected from -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , linear or branched Ci-C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, - CH ₂ [C ₃ -C ₆ cycloalkyl), linear or branched -OC ₁ -C ₃ alkyl, -O(cyclopropyl), linear or branched -NH[C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) [C ₁ -C ₃ alkyl), - NH(cyclopropyl), -N(cyclopropyl) ₂ , linear or branched -N(Ci-C ₃ alkyl) [cyclopropyl); wherein all C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, and C ₃ -C ₄ cycloalkyl residues are substituted with one or more substituents independently selected from -OH, - OCH ₃ , -OCF ₃ , -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ ;

wherein the C ₅ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH, -OCH ₃ , -OCF ₃ , - NH ₂ , -NHCHS and -N(CH ₃ ) ₂ ;

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom; and then R^R ⁵ , R ⁷ , R ⁸ , R ¹⁰ -R ¹² , X ¹ , X ³ and X ⁴ are defined as in general formula (I] including their substitutions and preferred definitions.

S.9 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C _1- C ₆ alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, and Y is -H, linear unsubstituted or branched unsubstituted Ci-C ₆ alkyl,

then X ³ is CR ⁹

and R ⁹ is selected from -CN, -NCO, -NCS, -OH, -NH ₂ , -N0 ₂ , linear or branched Ci-C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, - CH ₂ [C ₃ -C ₆ cycloalkyl), linear or branched -OCi-C ₃ alkyl, -O(cyclopropyl), linear or branched -NH(C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) (Ci-C ₃ alkyl), - NH(cyclopropyl), -N(cyclopropyl) ₂ , linear or branched -N(C _I -C ₃ alkyl) [cyclopropyl); wherein all C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, and C ₃ -C ₄ cycloalkyl residues are substituted with one or more substituents independently selected from -OH, - OCH ₃ , -0CF ₃ , -NH ₂ , -NHCH ₃ and -N(CH ₃ ) ₂ ;

wherein the C ₅ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF ₃ , -OH, -OCH3, -OCF3, - NH ₂ , -NHCH3 and -N(CH ₃ ) ₂ ;

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and then R ⁴ -R ⁵ , R ⁷ , R ⁸ , R ¹⁰ -R ¹² , X ¹ , X ² and X ⁴ are defined as in general formula [I) including their substitutions and preferred definitions.

S.10 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C _1- C ₆ alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl,

then X ⁴ is CR ⁹

and R ⁹ is selected from -CN, -NCO, -NCS, -OH, -NH ₂ , -N0 ₂ , linear or branched Ci-C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, - CH ₂ [C ₃ -Ce cycloalkyl), linear or branched -0Ci-C ₃ alkyl, -O(cyclopropyl), linear or branched -NH[C _I -C ₃ alkyl), linear or branched -N(C _I -C ₃ alkyl) [Ci-C ₃ alkyl), - NH(cyclopropyl), -N(cyclopropyl) ₂ , linear or branched -N(C _I -C ₃ alkyl) [cyclopropyl); wherein all C1-C4 alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, and C ₃ -C4 cycloalkyl residues are substituted with one or more substituents independently selected from -OH, - OCH ₃ , -0CF ₃ , -NH _Z , -NHCH ₃ and -N(CH ₃ ) ₂ ; wherein the Cs-Ce cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH3, -CF3, -OH, -OCH3, -OCF3, - NHz, -NHCH3 and -N(CH ₃ ) ₂ ;

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and then R^R ⁵ , R ⁷ , R ⁸ , R ¹⁰ -R ¹² and X ⁴ -X ³ are defined as in general formula [I] including their substitutions and preferred definitions.

S.ll If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, and Y is -H, linear unsubstituted or branched unsubstituted Ci-Ce alkyl,

then X ¹ , X ² and X ³ are each N

and then R^R ⁵ , R ⁷ -R ¹² , and X ⁴ are defined as in general formula (I) including their substitutions and preferred definitions.

S.12 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted Ci-Cg alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted Ci-Ce alkyl, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl,

then X ¹ , X ² and X ⁴ are each N

and then R ⁴ -R ⁵ , R ⁷ -R ¹² , and X ³ are defined as in general formula (I) including their substitutions and preferred definitions.

S.13 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, or -OH,

or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, and Y is -H, linear unsubstituted or branched unsubstituted Ci-Ce alkyl,

then X ¹ , X ³ and X ⁴ are each N

and then R^R ⁵ , R ⁷ -R ¹² , and X ² are defined as in general formula (I) including their substitutions and preferred definitions.

S.14 If Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, and Y is -H, linear unsubstituted or branched unsubstituted C ₁ -C ₆ alkyl, or -OH, or if Z ¹ and Z ² are together =0 or =S, and R ⁶ is -H, or linear unsubstituted or branched unsubstituted C1-C6 alkyl, and Y is -H, linear unsubstituted or branched unsubstituted C1-C6 alkyl,

then X ² , X ³ and X ⁴ are each N and then R ⁴ -R ⁵ , R ⁷ -R ¹² , and X ¹ are defined as in general formula (I) including their substitutions and preferred definitions.

S.15 If R ¹ is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R ¹ contains one or more heteroatoms independently selected from O, S and N, with the proviso that the combination of the said heteroatoms in a terminal position is different from the residues -CN, -NCO, -NCS,

then R ² -R ¹⁴ , X ⁴ -X ⁴ , Y, Z ¹ and Z ² are defined as in general formula [I] including their substitutions and preferred definitions.

S.16 If Z ¹ and Z ² are defined as in general formula (I] including their substitutions and preferred definitions, with the proviso that Z ¹ and Z ² are different from being together =0,

then R ¹ -R ¹⁴ , X ⁴ -X ⁴ , and Y are defined as in general formula (I] including their substitutions and preferred definitions.

S.17 If R ⁶ is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R ⁶ is different from -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, wherein all said C1-C6 alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then R ⁴ -R ⁵ , R ⁷ -R ¹⁴ , X ⁴ -X ⁴ , Y, Z ¹ and Z ² are defined as in general formula (I) including their substitutions and preferred definitions.

S.18 If Y is defined as in general formula (I] including the substitutions and preferred definitions, with the proviso that Y is different from -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH, or -OC1-C6 alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl, and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then R ^! -R ¹⁴ , X ⁴ -X ⁴ Z ¹ and Z ² are defined as in general formula (I) including their substitutions and preferred definitions.

S.19 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or Ci-Ce alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH, or -OC1-C6 alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated, then R ¹ = C ₁ -C ₁₂ preferably Ci-Ce alkyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkenyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, Cs-Ce cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, Cs-Ci ₄ tricycloalkyl, -OC ₁ -C ₁₂ preferably -OC ₁ -C ₆ alkyl, -OC ₂ -C ₁₂ preferably -OC ₂ -C ₆ alkenyl, -OC ₂ -C ₁₂ preferably -OC ₂ -C ₆ alkynyl, -OC ₃ -C ₈ cycloalkyl, - OC ₅ -C ₈ cycloalkenyl, -OC ₅ -C ₁₂ bicycloalkyl, -OC ₇ -C ₁₂ bicycloalkenyl, -0Cs-Ci ₄ tricycloalkyl, -SC ₁ -C ₁₂ preferably -SC ₁ -C ₆ alkyl, -SC ₂ -C ₁₂ preferably -SC ₂ -C ₆ alkenyl, -SC ₂ - C ₁₂ preferably -SC ₂ -C ₆ alkynyl, -SC ₃ -C ₈ cycloalkyl, -SCs-Cs cycloalkenyl, -SC ₅ -C ₁₂ bicycloalkyl, -SC ₇ -C ₁₂ bicycloalkenyl, -SC ₈ -C ₁₄ tricycloalkyl, -NHR ⁷ or -NR ⁷ R ^B wherein R ⁷ and R ⁸ are independently from each other selected from: C ₁ -C ₁₂ preferably C ₁ -C ₆ alkyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkenyl, C ₂ -C ₁₂ preferably C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, Cs-Ca cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, Ca-Ci ₄ tricycloalkyl, or wherein R ⁷ can form a ring structure together with R ⁸ wherein the said ring structure including the N-atom is selected from three to eight membered cyclic structures or five to twelve membered bicyclic structures and wherein all said ring structures can additionally contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in the ring structure;

wherein all C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₃ -C ₈ cycloalkyl, Cs-Ca cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl and Cs-Ci ₄ tricycloalkyl residues are linear or branched, and are substituted with one or more substituents, here referred to as side-substituents, independently selected from: -OH, -NH ₂ , -NO ₂ , =0, C ₃ -C ₈ cycloalkyl, Cs-Ca cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, Ca-Ci ₄ tricycloalkyl, linear or branched -OC ₄ -C ₅ alkyl, -OC ₃ -C ₅ cycloalkyl such as - O (cyclopropyl), linear or branched -NHfCi-Cs alkyl), linear or branched -NfCi-Cs alkyl)(Ci-C ₅ alkyl), -NH(C ₃ -Cs cycloalkyl) such as -NH(cyclopropyl), -N(C ₃ -Cs cycloalkyl) (C ₃ -C ₅ cycloalkyl), linear or branched -N(Ci-Cs alkyl) (C ₃ -C ₅ cycloalkyl); and wherein all said C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₃ -C ₈ cycloalkyl, Cs-Ce cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl and Ce-Ci ₄ tricycloalkyl residues can optionally contain in addition one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS;

and all -OC ₁ -C ₁₂ alkyl, -OC ₂ -C ₁₂ alkenyl, -OC ₂ -C ₁₂ alkynyl, -SC ₁ -C ₁₂ alkyl, -SC ₂ -C ₁₂ alkenyl, -SC ₂ -C ₁₂ alkynyl, and all alkyl, alkenyl and alkynyl residues contained in the definition of R ⁷ and R ^a are linear or branched, and are unsubstituted or substituted with one or more substituents, here referred to as side-substituents, independently selected from: -F, -Cl, - Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , =0, C ₃ -C ₈ cycloalkyl, Cs-Cg cycloalkenyl, C ₅ -C ₁₂ bicycloalkyl, C ₇ -C ₁₂ bicycloalkenyl, C _S -C _M tricycloalkyl, linear or branched -OC ₁ -C ₅ alkyl such as -OCH ₃ , -OC ₃ -C ₅ cycloalkyl such as -Ofcyclopropyl], linear or branched -NH(Ci-Cs alkyl], linear or branched -N(Ci-Cs alkyl] (C ₁ -C ₅ alkyl], -NH(C ₃ -Cs cycloalkyl] such as - NH(cyclopropyl], -N(C3-Cs cycloalkyl] [C3-C5 cycloalkyl], linear or branched -N(Ci-Cs alkyl] (C3-C5 cycloalkyl];

wherein all -OC ₃ -C ₈ cycloalkyl, -OCs-Ce cycloalkenyl, -OC ₅ -C ₁₂ bicycloalkyl, -OC ₇ -C ₁₂ bicycloalkenyl, -0C _B -C _I4 tricycloalkyl, -SC ₃ -C ₈ cycloalkyl, -SC _S -C _B cycloalkenyl, -SC ₅ -C ₁₂ bicycloalkyl, -SC ₇ -C ₁₂ bicycloalkenyl, -SC _S -C _M tricycloalkyl, residues, and all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definition of R ⁷ and R ⁸ and contained in the selection of the named side-substituents, are unsubstituted or substituted with one or more substituents independently selected from: -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , =0, linear or branched C ₁ -C ₅ alkyl such as -CH ₃ , linear or branched -OC ₁ -C ₅ alkyl such as -OCH ₃ , linear or branched -NH[Ci- C ₅ alkyl], linear or branched -N[Ci-Cs alkyl] (C ₁ -C ₅ alkyl], -NH[C ₃ -Cs cycloalkyl] such as - NH(cyclopropyl], -N(C ₃ -Cs cycloalkyl] [C ₃ -C ₅ cycloalkyl], linear or branched -N(Ci-Cs alkyl] (C ₃ -C ₅ cycloalkyl];

wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R ⁷ and R ⁸ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definition of R ¹ can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, with the proviso that the combination of the said heteroatoms in a terminal position is different from the residues -CN, -NCO, -NCS and -OC1-C3 alkyl if not explicitly contained in the definition of R ¹ ;

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

and then R ² -R ⁵ , R ⁹ -R ^1Z and C ⁴ -C ⁴ are defined as in general formula (I] including their substitutions and preferred definitions.

S.20 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or Ci-Ce alkyl, or C ₃ -C ₆ cycloalkyl, and Y is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, or -OH, or -OC ₁ -C ₆ alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C3 alkyl and -OC1-C3 alkyl,

and wherein all said C ₃ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C1-C3 alkyl and -OC1-C3 alkyl, and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated, then R ² is selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , linear or branched C ₁ -C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -CH ₂ (C ₃ -C ₆ cycloalkyl], linear or branched -OC ₁ -C ₃ alkyl, - 0 (cyclopropyl], linear or branched -NH(C _I -C3 alkyl], linear or branched -N(C _I -C3 alkyl](Ci-C3 alkyl], -NH (cyclopropyl], -N(cyclopropyl] ₂ , linear or branched -N(C _I -C3 alkyl] (cyclopropyl];

wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ² are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -OCH ₃ , -OCF ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ] ₂ ; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ² can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and then R ¹ , R ³ -R ⁵ , R ⁷ -R ¹² and C ^c -C ⁴ are defined as in general formula [I] including their substitutions and preferred definitions.

S.21 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH, or -OC1-C6 alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ¹ is CR ⁹ and R ⁹ is selected from -Cl, -Br, -I, CN, -NCO, -NCS, -OH, -NH2, -NO ₂ , linear or branched C ₁ -C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -CH ₂ (C ₃ -C ₆ cycloalkyl], linear or branched -OC ₁ -C ₃ alkyl, -0 [cyclopropyl], linear or branched -NH(CI-C3 alkyl], linear or branched -N[CI-C3 alkyl] [C ₁ -C ₃ alkyl], - NH(cyclopropyl], -N(cyclopropyl]2, linear or branched -N(C _I -C3 alkyl] [cyclopropyl]; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -0CH ₃ , -0CF ₃ , -NH ₂ , NHCH ₃ , N[CH ₃ ] ₂ ; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom; and then R ^! -R ⁵ , R ⁷ , R ⁸ , R ¹⁰ -R ¹² and X ² -X ⁴ are defined as in general formula [I] including their substitutions and preferred definitions.

S.22 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, and Y is -H, or C _1- C ₆ alkyl, or C _3- C ₆ cycloalkyl, or -OH, or -OC _1- C ₆ alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C ₃ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ² is CR ⁹

and R ⁹ is selected from -Cl, -Br, -I, CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , linear or branched C ₁ -C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -CH ₂ (C ₃ -C ₆ cycloalkyl], linear or branched -OC ₁ -C ₃ alkyl, -O [cyclopropyl], linear or branched -NH(C _I -C ₃ alkyl], linear or branched -N[C _I -C ₃ alkyl] [C ₁ -C ₃ alkyl], - NH(cyclopropyl], -N(cyclopropyl] ₂ , linear or branched -N(C _I -C ₃ alkyl] [cyclopropyl]; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -OCH ₃ , -OCF ₃ , -NH ₂ , NHCH ₃ , N[CH ₃ ] ₂ ; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and then R ¹ -R ⁵ , R ⁷ , R ⁸ , R ¹⁰ -R ¹² , X ¹ , X ³ and X ⁴ are defined as in general formula [I] including their substitutions and preferred definitions.

S.23 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, and Y is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, or -OH, or -OC ₁ -C ₆ alkyl,

wherein all said C ₁ -C ₆ alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C ₃ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ³ is CR ⁹ and R ⁹ is selected from -F, -Cl, -Br, -I, CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , linear or branched C ₁ -C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -CH ₂ (C ₃ -C ₆ cycloalkyl], linear or branched -OC ₁ -C ₃ alkyl, -0 [cyclopropyl], linear or branched -NH[C _I -C ₃ alkyl], linear or branched -N[C _I -C ₃ alkyl] [C ₁ -C ₃ alkyl], - NH(cyclopropyl], -N(cyclopropyl] ₂ , linear or branched -N(C _I -C ₃ alkyl] [cyclopropyl]; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -0CH ₃ , -0CF ₃ , -NH ₂ , NHCH ₃ , N[CH ₃ ] ₂ ; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom;

and then R^R ⁵ , R ⁷ , R ⁸ , R ¹⁰ -R ¹² , X ¹ , X ² and X ⁴ are defined as in general formula (I] including their substitutions and preferred definitions.

S.24 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or Ci-Ce alkyl, or C ₃ -C ₆ cycloalkyl, and Y is -H, or Ci-Ce alkyl, or C ₃ -C ₆ cycloalkyl, or -OH, or -OCi-Ce alkyl,

wherein all said C ₁ -C ₆ alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C ₃ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ⁴ is CR ⁹

and R ⁹ is selected from -F, -Cl, -Br, -I, CN, -NCO, -NCS, -OH, -NH ₂ , -NO ₂ , linear or branched C ₁ -C ₄ alkyl, linear or branched C ₂ -C ₄ alkenyl, linear or branched C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, -CH ₂ (C ₃ -C ₆ cycloalkyl], linear or branched -OC ₁ -C ₃ alkyl, -0 [cyclopropyl], linear or branched -NH(C _I -C ₃ alkyl], linear or branched -N[C _I -C ₃ alkyl] [C _1- C ₃ alkyl], - NH(cyclopropyl], -N(cyclopropyl]2, linear or branched -N(C _I -C ₃ alkyl] [cyclopropyl]; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CH ₃ , -CF ₃ , -OH and -OCH ₃ , -OCF ₃ , -NH ₂ , NHCH ₃ , N[CH ₃ ] ₂ ; wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R ⁹ can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;

and then R^R ⁵ , R ⁷ , R ⁸ , R ¹⁰ -R ¹² and C ⁴ -C ³ are defined as in general formula [I] including their substitutions and preferred definitions.

S.25 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or Ci-Ce alkyl, or C ₃ -C ₆ cycloalkyl, and Y is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, or -OH, or -OC ₁ -C ₆ alkyl, wherein all said C1-C6 alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ³ is N and then R ⁴ -R ⁵ , R ⁷ -R ¹² , X ¹ , X ² and X ⁴ are defined as in general formula (I] including their substitutions and preferred definitions.

S.26 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or Ci-Ce alkyl, or C3-C6 cycloalkyl, or -OH, or -OCi-Ce alkyl,

wherein all said C1-C6 alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ⁴ is N and then R ¹ -!* ⁵ , R ⁷ -R ¹² and X ³ -X ³ are defined as in general formula (I] including their substitutions and preferred definitions.

S.27 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, and Y is -H, or C1-C6 alkyl, or C3-C6 cycloalkyl, or -OH, or -OC1-C6 alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C3-C6 cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl, and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ¹ and X ² are each N and then R ^! -R ⁵ , R ⁷ -R ¹² , X ³ and X ⁴ are defined as in general formula [I) including their substitutions and preferred definitions.

S.28 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, and Y is -H, or C _1- C ₆ alkyl, or C _3- C ₆ cycloalkyl, or -OH, or -OC _1- C ₆ alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C ₃ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ¹ and X ³ are each N

and then R^R ⁵ , R ⁷ -R ¹² , X ² and X ⁴ are defined as in general formula [I) including their substitutions and preferred definitions.

S.29 If Z ¹ and Z ² are together =0, and R ⁶ is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, and Y is -H, or C ₁ -C ₆ alkyl, or C ₃ -C ₆ cycloalkyl, or -OH, or -OC ₁ -C ₆ alkyl,

wherein all said Ci-Ce alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, Ci- C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said C ₃ -C ₆ cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl,

and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,

then X ¹ and X ⁴ are each N

and then R ^: -R ⁵ , R ⁷ -R ¹² , X ² and X ³ are defined as in general formula (I] including their substitutions and preferred definitions.

S.30 If R ¹ is defined as in general formula [I] including the substitutions and preferred definitions, with the proviso that R ¹ is different from C ₃ -C ₈ cycloalkyl,

wherein the said C ₃ -C _B cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, -NCS, C ₁ -C ₃ alkyl and -OC ₁ -C ₃ alkyl,

wherein the said C ₃ -C ₈ cycloalkyl residues can optionally be perhalogenated and wherein the said C3-C8 cycloalkyl residues are substituted at the same carbon atom, which is bound to the phenyl ring as defined in general formula (I], with a substituent selected from C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl, C3-C8 cycloalkyl or Cs-Ce cycloalkenyl,

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

wherein all said cycloalkyl and cycloalkenyl residues are unsubstituted or substituted with one or more substituents independently selected from -F, -Cl, -Br, -I, -CN, -NCO, - NCS, C1-C3 alkyl and -OC1-C3 alkyl,

and wherein all said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues can optionally be perhalogenated,

then R ² -R ¹⁴ , C ⁴ -C ⁴ , Y, Z ¹ and Z ² are defined as in general formula [I] including their substitutions and preferred definitions.

In a certain embodiment, the present invention relates to compounds of general formula [I) and salts and solvates thereof, wherein R ¹ is adamantyl,

and wherein Z ¹ and Z ² are defined as in general formula (I), including general formula [la), general formula [lb] and general formula [Ic], including the substitutions and preferred definitions, optionally with the proviso that in the case of general formula [lb] Z ¹ and Z ² are together different from =0,

and wherein R ¹⁴ is defined as in general formula (lb) including the substitutions and preferred definitions,

and wherein Y, R ² -R ⁶ , R ⁹ -R ¹³ and X ⁴ -X ⁴ are defined as in general formula [I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (1-1):

and wherein the compounds of structure (1-1) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-0014, XPW-0028, XPW-0042, XPW-0182, XPW-0924, XPW- 3038, XPW-3052, XPW-4633, XPW-4642 and XPW-4643. In a further certain embodiment, the present invention relates to compounds of general formula [I] and salts and solvates thereof, wherein Y and R ⁶ are defined as in general formula (I) including the substitutions and preferred definitions, wherein Y forms a ring structure together with R ⁶ , and wherein such ring structure contains an O-atom in replacement of one of the ring- C-atoms that is directly linked to the N-atom to which Y and R ⁶ are bound,

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

and wherein R ¹⁴ is defined as in general formula (lb) including the substitutions and preferred definitions,

and wherein R ⁴ -R ⁵ , R ⁷ -R ¹² and X ³ -X ⁴ are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure [1-2]:

and wherein the compounds of structure (1-2] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, stomach, breast, and cancer of the neuroendocrine system.

Examples are compounds XPW-4637 and XPW-4638.

In a further certain embodiment, the present invention relates to compounds of general formula (I] and salts and solvates thereof, wherein Y is selected from -S(0]R ¹³ and -S(0] ₂ R ¹³ ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ contains four or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula (I],

and wherein Z ¹ and Z ² are defined as in general formula (I], including general formula (la], general formula (lb] and general formula (Ic], including the substitutions and preferred definitions,

and wherein R ¹⁴ is defined as in general formula (lb] including the substitutions and preferred definitions,

and wherein R ² -R ¹³ and X ³ -X ⁴ are defined as in general formula (I] including the substitutions and preferred definitions, and wherein the compounds share the following structure (1-3):

and wherein the compounds of structure (1-3) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-0547, XPW-0548, XPW-0552, XPW-0560, XPW-0566, XPW- 0574, XPW-0575, XPW-0576, XPW-0580, XPW-0588, XPW-0603, XPW-0604, XPW-0608, XPW- 0616, XPW-2675, XPW-2676, XPW-2688, XPW-2703, XPW-2704, XPW-2708, XPW-2716, XPW- 2732, XPW-2744, XPW-4633 and XPW-4642.

In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein Y is -OH,

and wherein R ⁶ is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R ⁶ is different from -H,

and wherein Z ¹ and Z ^z are defined as in general formula (I), including general formula (la), general formula (lb) and general formula (Ic), including the substitutions and preferred definitions,

and wherein R ¹⁴ is defined as in general formula (lb) including the substitutions and preferred definitions,

and wherein R ^! -R ⁵ , R ⁷ -R ¹² and C ⁴ -C ⁴ are defined as in general formula (I) including the substitutions and preferred definitions,

and wherein the compounds share the following structure (1-4):

and wherein the compounds of structure (1-4) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-0182, XPW-0674, XPW-0675, XPW-0678, XPW-0679, XPW- 0686, XPW-0700, XPW-0734, XPW-0742, XPW-1750, XPW-2805, XPW-2806, XPW-4612, XPW- 4614, XPW-4616, XPW-4617, XPW-4618, XPW-4619, XPW-4620, XPW-4621, XPW-4622, XPW- 4626, XPW-4631, XPW-4632, XPW-4640, XPW-4644, XPW-4646 and XPW-4647.

In a further certain embodiment, the present invention relates to compounds of general formula [I] and salts and solvates thereof, wherein Y is -OCH ₃ ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ including any substituent contains no heteroatom selected from 0, S, N, optionally with the proviso that R ¹ contains two or more carbon atoms,

and wherein Z ¹ and Z ² are defined as in general formula (I), including general formula (la), general formula (lb) and general formula (Ic), including the substitutions and preferred definitions,

and wherein R ¹⁴ is defined as in general formula (lb) including the substitutions and preferred definitions,

and wherein R ² -R ⁶ , R ⁹ -R ¹² and X ^! -X ⁴ are defined as in general formula (I) including the substitutions and preferred definitions,

and wherein the compounds share the following structure (1-5):

and wherein the compounds of structure (1-5) are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast.

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

In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R ⁶ is -H and Y is -OCH ₃ ,

and wherein R ¹ is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R ¹ is selected from cyclic, bicyclic and tricyclic structures, and wherein Z ¹ and Z ² are defined as in general formula (I], including general formula (la], general formula (lb] and general formula (Ic], including the substitutions and preferred definitions,

and wherein R ¹⁴ is defined as in general formula (lb] including the substitutions and preferred definitions,

and wherein R ² -R ⁵ , R ⁷ -R ¹² and X ⁴ -X ⁴ are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (1-6]:

and wherein the compounds of structure (1-6] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast.

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

In a further certain embodiment, the present invention relates to compounds of general formula [I] and salts and solvates thereof, wherein Y and R ⁶ are defined as in general formula [I] including the substitutions and preferred definitions, wherein Y forms a ring structure together with R ⁶ ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that R ¹ including any substituent contains no or one heteroatom selected from 0, S, N,

and wherein Z ¹ , Z ² and R ¹⁴ are defined as in general formula (lb], including the substitutions and preferred definitions,

and wherein R ² -R ⁵ , R ⁷ -R ¹² , and X ⁴ -X ⁴ are defined as in general formula [I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (1-7]:

and wherein the compounds of structure (1-7] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-0762, XPW-0770, XPW-0776, XPW-0784, XPW-0790, XPW- 0798, XPW-0818, XPW-2890, XPW-2898, XPW-2904, XPW-2912, XPW-2918, XPW-2926, XPW- 4576, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW-4581, XPW-4583, XPW-4586, XPW- 4589, XPW-4592 and XPW-4594.

In a further certain embodiment, the present invention relates to compounds of general formula (la] and salts and solvates thereof, wherein Z ¹ is -CF ₃ ,

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

and wherein Z ² is defined as in general formula [la] including the substitutions and preferred definitions,

and wherein R ³ -R ¹³ and C ³ -C ⁴ are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (la-1]:

and wherein the compounds of structure (la-1] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula (la] and salts and solvates thereof, wherein Z ¹ is -CF ₃ ,

and wherein R ⁶ is defined as in general formula (I] including the substitutions and preferred definitions, optionally with the proviso that R ⁶ is different from -H, and wherein Z ² is defined as in general formula [la] including the substitutions and preferred definitions,

and wherein R ^! -R ⁵ , R ⁷ -R ¹³ , X ⁴ -X ⁴ and Y are defined as in general formula [I] including the substitutions and preferred definitions,

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

and wherein the compounds of structure [la-2] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula [la] and salts and solvates thereof, wherein Z ¹ is -CF3, and wherein Y and R ⁶ are each -H, and wherein R ¹ is defined as in general formula [I] including the substitutions and preferred definitions, optionally with the proviso that R ¹ contains five or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula [I],

and wherein Z ² is defined as in general formula [la] including the substitutions and preferred definitions,

and wherein R ² -R ⁵ , R ⁷ -R ¹² and X ⁴ -X ⁴ are defined as in general formula [I] including the substitutions and preferred definitions,

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

and wherein the compounds of structure [la-3] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, ovaries, and cancer of the neuroendocrine system.

An example is compound XPW-0014.

In a further certain embodiment, the present invention relates to compounds of general formula (la] and salts and solvates thereof, wherein Z ¹ is -CN,

and wherein R ¹ is defined as in general formula [I] including the substitutions and preferred definitions, and wherein R ¹ contains three or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula [I], optionally with the proviso that R ¹ including any substituent contains no heteroatom selected from 0, S and N,

and wherein Z ² is defined as in general formula [la] including the substitutions and preferred definitions,

and wherein R ² -R ¹³ , X ^! -X ⁴ and Y are defined as in general formula (I] including the substitutions and preferred definitions,

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

and wherein the compounds of structure (la-4] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias, and cancer of the skin.

An example is compound XPW-0314.

In a further certain embodiment, the present invention relates to compounds of general formula (lb] and salts and solvates thereof, wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula [I], and wherein R ¹ is selected from cyclic, bicyclic and tricyclic structures, and wherein R ⁵ is defined as in general formula (I] including the substitutions and preferred definitions, with the proviso that R ⁵ is different from -H, and wherein Z ¹ , Z ² and R ¹⁴ are defined as in general formula [lb], including the substitutions and preferred definitions,

and wherein R ² -R ⁴ , R ⁶ -R ¹³ and X ³ -X ⁴ and Y are defined as in general formula [I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure [Ib-1]:

and wherein the compounds of structure [Ib-1] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-4575, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW- 4581, XPW-4583, XPW-4584, XPW-4585, XPW-4586, XPW-4587, XPW-4588, XPW-4589, XPW- 4590, XPW-4591, XPW-4592, XPW-4593, XPW-4594 and XPW-4595.

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein X ⁴ is N,

and wherein R ¹ is defined as in general formula [I] including the substitutions and preferred definitions, wherein R ¹ contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula [I], and wherein R ¹ is selected from cyclic, bicyclic and tricyclic structures,

and wherein Z ¹ , Z ² and R ¹⁴ are defined as in general formula [lb], including the substitutions and preferred definitions,

and wherein R ² -R ¹³ , X ³ -X ³ and Y are defined as in general formula [I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure [Ib-2]:

and wherein the compounds of structure (Ib-2) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula (lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein Y is -OCH3, and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ including any substituent contains no heteroatom selected from 0, S, N, optionally with the proviso that R ¹ contains two or more carbon atoms,

and wherein R ² -R ⁶ , R ⁹ -R ¹² and C ^c -C ⁴ are defined as in general formula [I] including the substitutions and preferred definitions,

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

and wherein the compounds of structure [Ib-3] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast.

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

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Y and R ⁶ are defined as in general formula (I) including the substitutions and preferred definitions, wherein Y forms a ring structure together with R ⁶ ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that R ¹ including any substituent contains no or one heteroatom selected from 0, S, N,

and wherein Z ¹ , Z ² and R ¹⁴ are defined as in general formula [lb], including the substitutions and preferred definitions,

and wherein R ² -R ⁵ , R ⁷ -R ¹² , and X ⁴ -X ⁴ are defined as in general formula [I] including the substitutions and preferred definitions,

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

and wherein the compounds of structure [Ib-4) are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-0762, XPW-0770, XPW-0776, XPW-0784, XPW-0790, XPW- 0798, XPW-0818, XPW-2890, XPW-2898, XPW-2904, XPW-2912, XPW-2918, XPW-2926, XPW- 4576, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW-4581, XPW-4583, XPW-4586, XPW- 4589, XPW-4592 and XPW-4594.

In a further certain embodiment, the present invention relates to compounds of general formula (lb) and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein R ¹ is adamantyl,

and wherein R ⁵ is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R ⁵ is different from -H,

and wherein Y, R ² -R ⁴ , R ⁶ , R ⁹ -R ¹³ and X ⁴ -X ⁴ are defined as in general formula [I) including the substitutions and preferred definitions,

and wherein the compounds share the following structure (Ib-5):

and wherein the compounds of structure [Ib-5] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein R ¹ is adamantyl, and wherein X ⁴ is N,

and wherein R ² -R ⁶ , R ⁹ -R ¹³ , X ⁴ -X ³ and Y are defined as in general formula (I) including the substitutions and preferred definitions,

and wherein the compounds share the following structure [Ib-6]:

and wherein the compounds of structure [Ib-6] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein Y is -OH, and wherein R ⁶ is -H,

and wherein R ¹ is defined as in general formula [I] including the substitutions and preferred definitions, wherein R ¹ contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula [I],

and wherein R ⁵ is defined as in general formula [I] including the substitutions and preferred definitions, with the proviso that R ⁵ is different from -H, and wherein R ² -R ⁴ , R ⁷ -R ¹² and X ⁴ -X ⁴ are defined as in general formula [I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure [Ib-7]:

and wherein the compounds of structure (Ib-7] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein Y is -OH, and wherein R ⁶ is -H, and wherein X ⁴ is N,

and wherein R ^! -R ⁵ , R ⁷ -R ¹² and X ⁴ -X ³ are defined as in general formula [I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (Ib-8]:

and wherein the compounds of structure (Ib-8] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-4623, XPW-4628, XPW-4630 and XPW-4636. In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein Y is -OH, and wherein R ⁶ is -H, and wherein X ¹ and X ² are each N,

and wherein R ^! -R ⁵ , R ⁷ -R ¹² , X ³ and X ⁴ are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure [Ib-9]:

and wherein the compounds of structure [Ib-9] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

An example is compound XPW-4625.

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein Y is -OH, and wherein R ⁶ is -H, and wherein X ¹ is N, and wherein X ⁴ is CR ¹⁰ , and wherein R ¹⁰ is defined as in general formula [I] including the substitutions and preferred definitions, with the proviso that R ¹⁰ is different from -H,

and wherein R ^! -R ⁵ , R ⁷ -R ⁹ , R ¹¹ , R ¹² , X ² and X ³ are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure [lb-10]:

and wherein the compounds of structure [lb-10] are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

An example is compound XPW-4639.

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein Y is -CH ₃ , and wherein R ⁶ is -CH ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula (I),

and wherein R ⁵ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ⁵ is different from -H, optionally with the additional proviso that R ⁵ is different from -0CH ₃ ,

and wherein R ² -R ⁴ , R ⁷ -R ¹² and X ^: -X ⁴ are are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (lb-11):

and wherein the compounds of structure (Ib-ll) are - particularly without the additional proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein R ¹ is defined as in general formula [I) including the substitutions and preferred definitions, wherein R ¹ is selected from unsubstituted and substituted cycloalkyl and cycloalkenyl, wherein such cycle contains four or more, preferably six or more ring carbon atoms that cannot be replaced by a heteroatom selected from 0, S and N,

and wherein R ⁵ is defined as in general formula (I] including the substitutions and preferred definitions, with the proviso that R ⁵ is different from -H, and wherein Z ¹ , Z ² and R ¹⁴ are defined as in general formula (lb), including the substitutions and preferred definitions,

and wherein R ² -R ⁴ , R ⁶ -R ¹³ , X ³ -X ⁴ and Y are defined as in general formula (I) including the substitutions and preferred definitions,

and wherein the compounds share the following structure (lb-12):

and wherein the compounds of structure (lb-12) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-4575, XPW-4577, XPW-4578, XPW-4579, XPW-4580, XPW- 4581, XPW-4583, XPW-4584, XPW-4588, XPW-4589, XPW-4590, XPW-4594 and XPW-4595.

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =NR ¹⁴ ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that R ¹ including any substituent contains no or one heteroatom selected from 0, S, N,

and wherein R ¹⁴ is defined as in general formula (lb) including the substitutions and preferred definitions,

and wherein R ² -R ¹³ , X ⁴ -X ⁴ and Y are defined as in general formula (I) including the substitutions and preferred definitions,

and wherein the compounds share the following structure (lb-13):

and wherein the compounds of structure (lb-13) are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue and breast.

Examples are compounds XPW-0832 and XPW-4574.

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein Y is -OH, and wherein R ⁶ is -H, and wherein X ¹ is CR ¹¹ , X ² is CR ⁸ , X ³ is CR ⁹ and X ⁴ is CR ¹⁰ ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ contains four or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula [I), with the proviso that R ¹ including any substituent contains one or two heteroatoms selected from 0, S, N,

and wherein R ² -R ⁵ and R ⁷ -R ¹² are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (lb-14):

and wherein the compounds of structure (lb-14) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula [lb] and salts and solvates thereof, wherein Z ¹ and Z ² are together =0, and wherein R ⁶ is -CH3, and wherein X ¹ is CR ¹¹ , X ² is CR ⁸ , X ³ is CR ⁹ and X ⁴ is CR ¹⁰ ,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, wherein R ¹ is selected from cyclic, bicyclic and tricyclic structures, with the proviso that R ¹ including any substituent contains one or two heteroatoms selected from 0, S, N, and wherein R ² -R ⁵ , R ⁷ -R ¹³ and Y are defined as in general formula [I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (lb-15):

and wherein the compounds of structure (lb-15) are preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, breast, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-0539, XPW-0541 and XPW-0679.

In a further certain embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z ¹ and Z ² form together a cyclic residue including the carbon atom to which they are bound, and wherein Z ¹ and Z ² are defined as in general formula [Ic) including the substitutions and preferred definitions,

and wherein R ⁶ is defined as in general formula (I) including the substitutions and preferred definitions, optionally with the proviso that R ⁶ is different from H,

and wherein R ^! -R ⁵ , R ⁷ -R ¹³ , X ³ -X ⁴ and Y are defined as in general formula (I) including the substitutions and preferred definitions,

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

and wherein the compounds of structure [Ic-1] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system. Examples are compounds XPW-0902, XPW-0916, XPW-0924, XPW-0930, XPW-3038 and XPW- 3052.

In a further certain embodiment, the present invention relates to compounds of general formula (Ic] and salts and solvates thereof, wherein Z ¹ and Z ^z form together a cyclic residue including the carbon atom to which they are bound, and wherein Z ¹ and Z ² are defined as in general formula (Ic] including the substitutions and preferred definitions, optionally with the proviso that the said cyclic residue contains one or more heteroatoms independently selected from 0, S and N in replacement of a carbon atom contained in the ring structure, and/or that the said cyclic residue is substituted with one or more substituents as defined in general formula (Ic], and wherein R ³ -R ¹³ , X ^x -X ⁴ and Y are defined as in general formula (I] including the substitutions and preferred definitions,

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

and wherein the compounds of structure (Ic-2] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula (Ic] and salts and solvates thereof, wherein Z ¹ and Z ² form together a cyclic residue including the carbon atom to which they are bound, and wherein Z ¹ and Z ² are defined as in general formula (Ic] including the substitutions and preferred definitions, optionally with the proviso that the said cyclic residue is a four-membered ring,

and wherein R ^! -R ¹³ , X ^! -X ⁴ and Y are defined as in general formula (I] including the substitutions and preferred definitions, and wherein the compounds share the following structure (Ic-3]:

and wherein the compounds of structure [Ic-3] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

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

In a further certain embodiment, the present invention relates to compounds of general formula [Ic] and salts and solvates thereof, wherein Z ¹ and Z ² form together a cyclic residue including the carbon atom to which they are bound, and wherein Z ¹ and Z ² are defined as in general formula (Ic] including the substitutions and preferred definitions,

and wherein Y and R ⁶ are each -H,

and wherein R ¹ is defined as in general formula (I] including the substitutions and preferred definitions, optionally with the proviso that R ¹ contains five or more, preferably six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from 0, S and N as defined in general formula (I],

and wherein R ² -R ⁵ , R ⁷ -R ¹² and C ^: -C ⁴ are defined as in general formula (I] including the substitutions and preferred definitions,

and wherein the compounds share the following structure (Ic-4]:

and wherein the compounds of structure (Ic-4] are - particularly without the proviso - preferred for use in human and veterinary medicine, in particular for the medical use described in the present invention, preferably for the use in immune system-related applications including immunotherapy and other immunotherapy methods as defined in the present invention, and in the treatment of immune system-related disorders, skin diseases, muscle diseases, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas, cancer of the skin, oral mucosa, tongue, lung, stomach, breast, cervix, ovaries, and cancer of the neuroendocrine system.

Examples are compounds XPW-0916, XPW-0924 and XPW-3052.

In some embodiments, the following compounds shown in Table 1 to Table 3 are explicitly excluded from the scope of the invention:

The compounds of Table 1 specifically indicated by CAS registry numbers have been identified by the inventors as state of the art. In embodiments where these compounds are encompassed by general formula (I] or any subgeneric formula as defined herein, they are explicitly excluded from the scope of the invention with regard to compound protection. To the best of the inventors’ knowledge, these compounds are not known for any medical use. Thus, the invention encompasses any medical use for compounds of Table 1.

Table 1:

The compounds of Table 2 specifically indicated by CAS registry numbers have been identified by the inventors as state of the art. In embodiments, where these compounds are encompassed by general formula (I] or any subgeneric formula as defined herein, they are explicitly excluded from the scope of the invention with regard to compound protection. To the best of the inventors’ knowledge, these compounds are not known for any medical use as defined in the invention. Thus, the compounds of Table 2 are explicitly included into the scope of the invention with regard to medical ° use as defined herein, particularly in the treatment of non-malignant or malignant hyperproliferative diseases.

Table 2:

The compounds of Table 3 specifically indicated by CAS registry numbers have been identified by the inventors as state of the art. In embodiments, where these compounds are encompassed by general formula (I] or any subgeneric formula as defined herein, they are explicitly excluded from the scope of the invention with regard to compound protection. Further, these compounds are, to the best of the inventors’ knowledge, known for a medical use, which in some embodiments may be encompassed by a medical use as defined herein. Thus, the compounds of Table 3 may be explicitly excluded from the scope of the invention with regard to compound protection and with regard to certain medical use in some embodiments as defined herein.

Table 3:

257605-09- 7 W02000005198 A1 1009100-88-2 W02008024746 A1 2199623-41-9 PCT/EP2018/054686

Ux

257605-10- 0 W02000005198 A1 1009100-89-3 W02008024746 A1 2243096-86-6 PCT/EP2018/054686 W

Ux

Specific examples of compounds falling under the scope of compounds contained in pending application PCT/EP2018/054686 have been identified in the present application to have novel medical use, in particular to have growth inhibitory properties on muscle cells, keratinocytes, and cells and malignant cells selected from cervical cancer, cutaneous T-cell lymphoma, acute promyelocytic leukemia, acute myeloid leukemia, oral and tongue squamous cell carcinoma, epidermoid squamous cell carcinoma and lung squamous cell carcinoma cells.

Thus, these compounds as well as salts and solvates thereof are particularly suitable for the treatment of hyperproliferative muscle diseases, hyperproliferative skin diseases as defined herein as well as for the treatment of cervical cancer, cutaneous T-cell lymphoma, acute promyelocytic leukemia, acute myeloid leukemia, epidermoid skin cancer such as non melanoma skin cancer, cancer of the oral cavity, cancer of the tongue and lung cancer as defined herein.

Specific examples of compounds falling under the scope of compounds contained in pending application PCT/EP2018/054686 have been identified in the present application to have further novel medical use, in particular to have growth inhibitory properties on cells and malignant cells selected from T-cell leukemia, B-cell leukemia, gastric cancer, breast cancer, ovarian cancer and medullary thyroid cancer.

Thus, these compounds as well as salts and solvates thereof are particularly suitable for the treatment of diseases of the haematopoietic system including the haematologic system such as T-cell leukemia, B-cell leukemia, as well as for the treatment of gastric cancer, breast cancer, ovarian cancer and cancer of the neuroendocrine system as defined herein.

The herein identified novel medical use for specific compounds falling under the scope of compounds contained in pending application PCT/EP2018/054686 are shown in Table 4 and Table 5, wherein the medical applications are selected from the treatments of hyperproliferative muscle diseases [A], hyperproliferative skin diseases as defined herein (B), cervical cancer (C), cutaneous T-cell lymphoma (D), acute promyelocytic leukemia (E], acute myeloid leukemia [F], epidermoid skin cancer (G], cancer of the oral cavity (H), cancer of the tongue (I], lung cancer (J), T-cell leukemia (K), B-cell leukemia [L , gastric cancer (M), breast cancer (N), ovarian cancer [0] and cancer of the neuroendocrine system (P).

The following compounds described in PCT/EP2018/054686 are specifically claimed for the indicated medical use.

Table 4:

The following compounds described in PCT/EP2018/054686 are specifically claimed for the indicated medical use.

Table 5:

Specific examples of compounds falling under the scope of formula [I) are shown in Table 6 to Table 54. Intermediates are denoted as "XPW-I".

Table 6:

'Jl

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 7:

os o

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 8:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 9:

os

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 10:

os

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 11:

os

4

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 12:

rt

os

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 13:

os os

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 14:

os

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 15:

os

00

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 16:

os so

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 17:

O

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 18:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 19:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

T

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 21:

4

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 22:

C/I

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 23:

Os

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 24:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 25:

00

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 26:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 27:

oo o

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 28:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 29:

oo

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 30:

oo

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 31:

oo

4

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 32:

oo

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 33:

oo o\

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 34: oo

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 35:

oo

00

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 36:

oo

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 37:

o

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 38:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 39:

VO

The above table constitutes an individualized description of each of the specifically indicated intermediates used for the synthesis of XPW-0001 to XPW-5062 as well as their salts and solvates. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 40:

w

The above table constitutes an individualized description of each of the specifically indicated intermediates used for the synthesis of XPW-0001 to XPW-5062 as well as their salts and solvates. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 41:

4

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 42:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 43:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates

Table 44:

o\

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates.

Table 45:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates

_"

Table 46:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates

Table 47:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 4B:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 49:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 50:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 51:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 52:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 53:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Table 54:

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates used as intermediates for the synthesis. Intermediates as such as well as their salts and solvates are also part of the invention, also in the frame of the process of generating the final compounds.

Also included are isomers, e.g. enantiomers or diastereomers or mixtures of isomers, salts, particularly pharmaceutically acceptable salts, and solvates of the compounds listed above. o

Further definitions:

The term "C ₁ -C ₁₂ alkyl" comprises all isomers of the corresponding saturated aliphatic hydrocarbon groups containing one to twelve carbon atoms; this includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, sec-pentyl, 3- pentyl, 2-methylbutyl, iso-pentyl, 2-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.

The term "C ₂ -C ₁₂ alkenyl" comprises all isomers of the corresponding unsaturated olefinic hydrocarbon groups containing two to twelve carbon atoms linked by (i.e. comprising] one or more double bonds; this includes vinyl, all propenyl-isomers, all butenyl-isomers, all pentenyl-isomers, all hexenyl-isomers, all heptenyl-isomers, all octenyl-isomers, all nonenyl-isomers, all decenyl-isomers, all undecenyl-isomers and all dodecenyl-isomers.

The term "C ₂ -C ₁₂ alkynyl" comprises all isomers of the corresponding unsaturated acetylenic hydrocarbon groups containing two to twelve carbon atoms linked by (i.e. comprising] 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.

The term "C ₃ -C ₈ cycloalkyl” comprises the corresponding saturated hydrocarbon groups containing three to eight carbon atoms arranged in a monocyclic ring structure; this includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The term "Cs-Cs cycloalkenyl” comprises the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing five to eight carbon atoms, of which at least one is sp ³ -hybridized, and which are arranged in a monocyclic ring structure and linked by (i.e. comprising] one or more double bonds; this includes all cyclopentenyl-isomers, all cyclohexenyl-isomers, all cycloheptenyl-isomers, all cyclooctenyl-isomers.

The term "C5-C 12 bicycloalkyl" comprises the corresponding saturated hydrocarbon groups containing five to twelve carbon atoms arranged in a bicyclic ring structure; wherein these bicyclic ring structures include fused, bridged and spiro systems;

The term "C ₇ -C ₁₂ bicycloalkenyl" comprises the corresponding unsaturated non aromatic and non-heteroaromatic hydrocarbon groups containing seven to twelve carbon atoms arranged in a bicyclic ring structure and linked by [i.e. comprising] one or more double bonds; wherein these bicyclic ring structures include fused, bridged and spiro systems;

The term "Cg-Ci ₄ tricycloalkyl" comprises the corresponding saturated hydrocarbon groups containing eight to fourteen carbon atoms arranged in a tricyclic ring structure; wherein these tricyclic ring structures include fused, bridged and spiro systems;

The terms "cyclic”, "bicyclic", "tricyclic", "cycloalkyl", "cycloalkenyl", "bicycloalkyl", "bicycloalkenyl” and "tricycloalkyl" for R ¹ mean that such cyclic, bicyclic or tricyclic residue is directly linked by a chemical bond to the aromatic ring to which R ¹ is bound, and wherein the terms "cyclic", "bicyclic", "tricyclic", "cycloalkyl", "cycloalkenyl", "bicycloalkyl", "bicycloalkenyl" and "tricycloalkyl" for a substituent of R ¹ mean that such cyclic, bicyclic or tricyclic residue is directly linked by a chemical bond to one of the C- atoms or N-atoms or O-atoms or S-atoms contained in R ¹ ; e.g. "R ¹ is cyclohexyl” means that the cyclohexyl residue is linked to the aromatic ring to which R ¹ is bound; and "R ¹ is methyl and R ¹ is substituted with cyclohexyl” means that the resulting -CH ₂ (cyclohexyl) residue is linked to the aromatic ring to which R ¹ is bound.

In case a carbon atom is replaced by a heteroatom selected from 0, N, or S, the number of substituents on the respective heteroatom is adapted according to its valency, e.g. a - CR ₂ - group may be replaced by a -NR-, -NR ₂ ⁺ -, -O- or -S- group.

The term "perhalogenated” relates to the exhaustive halogenation of the carbon scaffold; according residues comprise the corresponding perfluorinated, perchlorinated, perbrominated and periodinated groups. Preferably, the term "perhalogenated” relates to perfluorinated or perchlorinated groups, more preferably to perfluorinated groups.

The following contains definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.

The compounds of the present invention may form salts, which are also within the scope of this invention. Reference to a compound of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt[s) , as employed herein, denotes acidic and/or basic salts formed with inorganic and/or organic acids and bases. Zwitterions (internal or inner salts) are included within the term "salt(s)" as used herein (and may be formed, for example, where the substituents comprise an acid moiety such as a carboxyl group and an amino group). Also included herein are quaternary ammonium salts such as alkylammonium salts. Salts of the compounds may be formed, for example, by reacting a compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

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

Exemplary salts resulting from the addition of a base (formed, for example, where the substituents comprise 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 (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines, N-methyl-D- glucamines, N-methyl-D-glucamides, tert-butyl amines, and salts with amino acids such as arginine, lysine and the like. The basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides], dialkyl sulfates [e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates], long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides], aralkyl halides (e.g. benzyl and phenethyl bromides], and others.

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

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

Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom or an atropoisomeric bond, the invention relates to the D form, the L form and D,L mixtures and also, where more than one asymmetric carbon atom or atropoisomeric bond is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms or atropoisomeric bonds, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product.

Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

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

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

Also included are solvates and hydrates of the compounds of the invention and solvates and hydrates of their pharmaceutically acceptable salts.

The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers, rotamers, and isotopes of the structures depicted, unless otherwise indicated.

In some embodiments, the compound can be provided as a prodrug. The term "prodrug”, as employed herein, denotes a compound, which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of the invention, or a salt and/or solvate thereof.

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

Pharmaceutical Methods

The compounds according to the invention have been found to have pharmacologically important properties, which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other or in combination with other active compounds.

In certain embodiments, compounds of the present invention may exhibit growth inhibiting properties in hyperproliferative processes.

The antiproliferative activities of compounds falling under formula (la), (lb) and (Ic), respectively, were investigated on cells or cell lines originating from a disorder of the haematopoietic system, including the myeloid cell compartment and the lymphoid cell compartment (T-cells and B-cells), the neuroendocrine system, the cervix, the breast, the ovaries, the lung, the gastrointestinal tract, and the mucosal epithelium, as well as from the skin epithelium and from the muscle. To this end, HL-60 cells, NB-4 cells, HH cells, RPMI-8402 cells, TANOUE cells, TT cells, HeLa cells, MDA-MB-231 cells, FU-OV-1 cells, LOU-NH91 cells, 23132/87 cells, CAL-27 cells, BHY cells, SCC-25 cells, A-431 cells, human primary epidermal keratinocytes (HPEK), and C2C12 cells were seeded into 96- well plates suitable for fluorescence assays (CORNING #3598) at 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 with compounds at indicated final concentrations (diluted from the lOOOx stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v in H2O (Water For Injection, WFI, Fisherscientific #10378939)) or with the empty carrier DMSO at 0.1% v/v as control for 5 days. At day 5 after starting the treatments the cells were subjected to the alamarBlue® Proliferation Assay (Bio-Rad Serotec GmbH, BUF012B) according to the protocol of the manufacturer. The readout was taken with a multi-well plate-reader in the fluorescence mode with applying a filter for excitation at 560 nm (band width 10 nm) and for emission at 590 nm (band width 10 nm). Control treatments for growth inhibition with commercial compounds such as Methotrexate (MTREX) and Resveratrol (RES) were included on every plate. Some of the test compounds of the present invention were obtained and applied as their salts. According cases are indicated in the column "Specification" in Table 55 to Table 92 and by their sum formula in Table 93.

The assays were performed in duplicate or more replicates of independent single experiments each containing a six-fold replicate for every condition. For every individual plate, the measured fluorescence intensity values of the conditions with compound treatment were normalized against the corresponding equally weighted arithmetic mean of the fluorescence intensity values of the six DMSO treated control wells in order to obtain the relative values to a baseline level of 1.0.

Two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean (here abbreviated as AVE _W ) for each compound was calculated from the normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Muhlig, Taschenbuch der Mathematik, 5 ^th edition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the GauR' error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as "combined standard deviation”.

In cases with considerable variation in the normalized equally weighted arithmetic means derived from two independent replicates, the number of independent replicates was increased to three or more. In the cases of four or more independent replicates, a second-line outlier analysis was applied on all normalized equally weighted arithmetic means according to the methods by Peirce and Chauvenet as described above.

In certain embodiments, the compounds of the present invention may be growth inhibitors in hyperproliferative processes, including malignant and non-malignant hyperproliferative processes. In one embodiment, several compounds of the invention were found to inhibit the growth of HL-60 cells (human acute myeloid leukemia cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 3. HL-60 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of HL-60 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10 ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la), (lb) and (Ic), respectively, have been identified as growth inhibitors of HL-60 cells. The so far identified HL-60 growth inhibitors relate to the compounds listed in Table 55 and Table 56. The entries of Table 55 and Table 56 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 55: Proliferation assay with HL-60 cells at 20 uM

Table 56: Proliferation assay with HL-60 cells at 20 mM

The data in Table 55 relate to novel compounds, wherein the data in Table 56 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of NB-4 cells [human acute promyelocytic leukemia cells] obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ] under the accession number ACC 207. NB-4 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526] containing 10% fetal bovine serum [Fisherscientific, #15517589] at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of NB-4 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than l lO ² . According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb) and [Ic], respectively, have been identified as growth inhibitors of NB-4 cells. The so far identified NB-4 growth inhibitors relate to the compounds listed in Table 57 and Table 58. The entries of Table 57 and Table 58 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 57: Proliferation assay with NB-4 cells at 20 uM

Table 58: Proliferation assay with NB-4 cells at 20 iiM

The data in Table 57 relate to novel compounds, wherein the data in Table 58 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of HH cells [human cutaneous T-cell lymphoma cells] obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ] under the accession number ACC 707. HH cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526] containing 10% fetal bovine serum (Fisherscientific, #15517589] at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of HH cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than l lO ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula [la], [lb] and [Ic], respectively, have been identified as growth inhibitors of HH cells. The so far identified HH growth inhibitors relate to the compounds listed in Table 59 and Table 60. The entries of Table 59 and Table 60 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 59: Proliferation assay with HH cells at 20 uM

Table 60: Proliferation assay with HH cells at 20 uM

The data in Table 59 relate to novel compounds, wherein the data in Table 60 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

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

A compound is considered as a growth inhibitor of RPMI-8402 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10- ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula [la], [lb] and [Ic], respectively, have been identified as growth inhibitors of RPMI-8402 cells. The so far identified RPMI-8402 growth inhibitors relate to the compounds listed in Table 61 and Table 62. The entries of Table 61 and Table 62 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 61: Proliferation assay with RPMI-8402 cells at 20 mM

Table 62: Proliferation assay with RP I-8402 cells at 20 mM

The data in Table 61 relate to novel compounds, wherein the data in Table 62 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

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

A compound is considered as a growth inhibitor of TANOUE cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10- ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb) and (Ic), respectively, have been identified as growth inhibitors of TANOUE cells. The so far identified TANOUE growth inhibitors relate to the compounds listed in Table 63 andTable 64. The entries of Table 63 and Table 64 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 63 : Proliferation assay with TANOUE cells at 20 mM

Table 64: Proliferation assay with TANOUE cells at 20 u

The data in Table 63 relate to novel compounds, wherein the data in Table 64 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

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

A compound is considered as a growth inhibitor of TT cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than l lO ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la), (lb) and (Ic), respectively, have been identified as growth inhibitors of TT cells. The so far identified TT growth inhibitors relate to the compounds listed in Table 65 and Table 66. The entries of Table 65 and Table 66 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 65: Proliferation assay with TT cells at 20 mM

Table 66: Proliferation assay with TT cells at 20 uM

The data in Table 65 relate to novel compounds, wherein the data in Table 66 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of HeLa cells (human cervical adenocarcinoma cells) obtainable from the American Type Culture Collection (ATCC) under the accession number ATCC-CCL-2. HeLa cells were cultivated in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% CO2.

A compound is considered as a growth inhibitor of HeLa cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than l lO ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb) and (Ic), respectively, have been identified as growth inhibitors of HeLa cells. The so far identified HeLa growth inhibitors relate to the compounds listed in Table 67 and Table 68. The entries of Table 67 and Table 68 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 67: Proliferation assay with HeLa cells at 20 mM

Table 68: Proliferation assay with HeLa cells at 20 mM

The data in Table 67 relate to novel compounds, wherein the data in Table 68 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of MDA-MB-231 cells [human breast carcinoma cells] obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ] under the accession number ACC 732. MDA-MB-231 cells were cultivated in Leibovitz's L-15 (no phenol red] medium (Fisherscientific, #11540556] containing 10% fetal bovine serum (Fisherscientific, #15517589] at 37°C and 0% CO2. A compound is considered as a growth inhibitor of MDA-MB-231 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10 ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb) and (Ic), respectively, have been identified as growth inhibitors of MDA-MB-231 cells. The so far identified MDA-MB-231 growth inhibitors relate to the compounds listed in Table 69 andTable 70. The entries of Table 69 and Table 70 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 69: Proliferation assay with MDA-MB-231 cells at 20 mM

Table 70: Proliferation assay with MDA-MB-231 cells at 20 mM The data in Table 69 relate to novel compounds, wherein the data in Table 70 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of FU-OV-1 cells [human ovarian carcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ] under the accession number ACC 444. FU-OV-1 cells were cultivated in Ham's F-12/DMEM (1:1) medium (Fisherscientific, #11514436) containing 10% fetal bovine serum (Fisherscientific, #15517589) and ImM sodium pyruvate (Fisherscientific, #11501871) at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of FU-OV-1 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10- ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (lb) have been identified as growth inhibitors of FU-OV-1 cells. The so far identified FU-OV-1 growth inhibitors relate to the compounds listed in Table 71 and Table 72. The entries of Table 71 and Table 72 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 71: Proliferation assay with FU-OV-1 cells at 20 uM

Table 72: Proliferation assay with FU-OV-1 cells at 20 u

The data in Table 71 relate to novel compounds, wherein the data in Table 72 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of LOU-NH91 cells (human lung squamous cell carcinoma cells] obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ] under the accession number ACC 393. LOU-NH91 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526] containing 10% fetal bovine serum (Fisherscientific, #15517589] at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of LOU-NH91 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10 ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb] and (Ic], respectively, have been identified as growth inhibitors of LOU-NH91 cells. The so far identified LOU-NH91 growth inhibitors relate to the compounds listed in Table 73 and Table 74. The entries of Table 73 and Table 74 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated. Table 73: Proliferation assay with LOU-NH91 cells at 20 m

Table 74: Proliferation assay with LOU-NH91 cells at 20 uM

The data in Table 73 relate to novel compounds, wherein the data in Table 74 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of 23132/87 cells [human gastric adenocarcinoma cells) obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSMZ) under the accession number ACC 201. 23132/87 cells were cultivated in RPMI 1640 medium (Fisherscientific, #11554526) containing 10% fetal bovine serum (Fisherscientific, #15517589) at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of 23132/87 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10- ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la), (lb) and (Ic), respectively, have been identified as growth inhibitors of 23132/87 cells. The so far identified 23132/87 growth inhibitors relate to the compounds listed in Table 75 and Table 76. The entries of Table 75 and Table 76 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 75: Proliferation assay with 23132/87 cells at 20 uM

Table 76: Proliferation assay with 23132 /87 cells at 20 mM

The data in Table 75 relate to novel compounds, wherein the data in Table 76 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686. In one embodiment, several compounds of the invention were found to inhibit the growth of CAL-27 cells [human tongue squamous cell carcinoma cells] obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ] under the accession number ACC 446. CAL-27 cells were cultivated in DMEM medium (Fisherscientific, #11584456] containing 10% fetal bovine serum (Fisherscientific, #15517589] at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of CAL-27 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10 ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula [la], [lb] and [Ic], respectively, have been identified as growth inhibitors of CAL-27 cells. The so far identified CAL-27 growth inhibitors relate to the compounds listed in Table 77 and Table 78. The entries of Table 77 and Table 78 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 77: Proliferation assay with CAL-27 cells at 20 tiM

Table 78: Proliferation assay with CAL-27 cells at 20 mM

The data in Table 77 relate to novel compounds, wherein the data in Table 78 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of BHY cells (human oral squamous cell carcinoma cells] obtainable from the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH [DSMZ] under the accession number ACC 404. BHY cells were cultivated in DMEM medium (Fisherscientific, #11584456] containing 10% fetal bovine serum (Fisherscientific, #15517589] at 37°C and 5% C0 ₂ .

A compound is considered as a growth inhibitor of BHY cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10 ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb] and (Ic], respectively, have been identified as growth inhibitors of BHY cells. The so far identified BHY growth inhibitors relate to the compounds listed in Table 79, Table 80 and Table 81. The entries of Table 79, Table 80 and Table 81 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 79: Proliferation assay with BHY cells at 20 mM

Table 80: Proliferation assay with BHY cells at 20 uM

Table 81: Proliferation assay with BHY cells at 20 mM

The data in Table 79 relate to novel compounds, wherein the data in Table 80 and Table 81 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

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

A compound is considered as a growth inhibitor of SCC-25 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than l lO ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb] and (Ic], respectively, have been identified as growth inhibitors of SCC-25 cells. The so far identified SCC-25 growth inhibitors relate to the compounds listed in Table 82 and Table 83. The entries of Table 82 and Table 83 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 82: Proliferation assay with SCC-25 cells at 20 uM

Table 83: Proliferation assay with SCC-25 cells at 20 mM

The data in Table 82 relate to novel compounds, wherein the data in Table 83 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of A-431 cells [human epidermoid squamous cell carcinoma cells] obtainable from the Cell Lines Service GmbH [CLS] under the accession number 300112. A-431 cells were cultivated in DMEM medium (Fisherscientific, #11584456] containing 10% fetal bovine serum [Fisherscientific, #15517589] at 37°C and 5% CO2. A compound is considered as a growth inhibitor of A-431 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10 ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb) and (Ic], respectively, have been identified as growth inhibitors of A-431 cells. The so far identified A-431 growth inhibitors relate to the compounds listed in Table 84 and Table 85. The entries of Table 84 and Table 85 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 84: Proliferation assay with A-431 cells at 20 mM

Table 85 : Proliferation assay with A-431 cells at 20 mM

The data in Table 84 relate to novel compounds, wherein the data in Table 85 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In one embodiment, several compounds of the invention were found to inhibit the growth of human epidermal keratinocyte progenitors, (HPEKp, pooled), obtainable from CELLnTEC Advanced Cell Systems AG under the accession number HPEKp. HPEKp cells were cultivated in CnT-Prime epithelial culture medium [CELLnTEC, #CnT-PR, a fully defined, low calcium formulation, completely free of animal or human-derived components) without addition of further components at 37°C and 5% CO2.

A compound is considered as a growth inhibitor of HPEKp cells, if - at a reference concentration of 10 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10 ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la), (lb) and (Ic), respectively, have been identified as growth inhibitors of HPEKp cells. The so far identified HPEKp growth inhibitors relate to the compounds listed in Table 86, Table 87 and Table 88. The entries of Table 86, Table 87 and Table 88 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 86: Proliferation assay with HPEKp cells at 10 mM

Table 87: Proliferation assay with HPEKp cells at 10 mM

Table 88: Proliferation assay with HPEKo cells at 10 uM _ _ _ _

The data in Table 86 relate to novel compounds, wherein the data in Table 87 and Table 88 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

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

A compound is considered as a growth inhibitor of C2C12 cells, if - at a reference concentration of 20 mM - the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation amounts to 0.9 or lower, in particular to 0.8 or lower, 0.7 or lower, 0.6 or lower, 0.4 or lower, and 0.2 or lower, relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all normalized values from the DMSO control measurements in analogy to the calculations performed for the test-compounds. The corresponding combined standard deviation for the DMSO values amounts to less than l lO ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula (la], (lb) and (Ic), respectively, have been identified as growth inhibitors of C2C12 cells. The so far identified C2C12 growth inhibitors relate to the compounds listed in Table 89, Table 90 and Table 91. The entries of Table 89, Table 90 and Table 91 are categorized by the corresponding weighted arithmetic means of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 89: Proliferation assay with C2C12 cells at 20 mM

Table 90: Proliferation assay with C2C12 cells at 20 uM

Table 91: Proliferation assay with C2C12 cells at 20 uM

The data in Table 89 relate to novel compounds, wherein the data in Table 90 and Table 91 relate to a novel medical use of compounds disclosed in PCT/EP2018/054686.

In certain embodiments, compounds of the present invention may be modulators, in particular enhancers of Notch signalling.

The communication between cells via Notch signaling [reviewed in Kopan et al., Cell 2009, 137, 216-233; Bray, Nat. Rev. Mol. Cell Biol. 2016, 17, 722-735] is in the first step mediated by two types of transmembrane proteins: The Notch receptors being distributed across the cell membrane of the signal-receiving cell and the Notch ligands covering the membrane of the signal-sending cell. Mechanistically, Notch signaling is activated by receptor-ligand interaction, which leads to the proteolytic release of the intracellular domain (NICD) of the membrane bound Notch receptor into the inside of the signal-receiving cell. Subsequent translocation of NICD into the nucleus in turn leads to the transcriptional activation of certain and cell type specific genes. The Notch- mediated alteration of the previous gene-expression program of a cell is manifested in according cellular changes, which represent the response of the cell to a Notch signal.

The activation level of Notch signaling can be quantified in vitro reliably by measuring the expression levels of Notch specific target genes. This can be accomplished by the quantification of corresponding mRNA or protein of a particular Notch target gene. Alternatively, cells can be genetically modified to carry a luciferase gene as an artificial Notch target gene, which is expressed in dependence of Notch activity. In this setting, Notch signaling levels can be quantified by measuring the luciferase-derived bioluminescence values.

An according Notch-reporter assay, i.e. a luciferase-based luminescence readout, was used here to quantify the ability of the claimed compounds to augment Notch signaling in a cellular system. For this purpose, HeLa cells, obtainable from the American Type Culture Collection [ATCC] under the accession number ATCC-CCL-2, were transiently transfected for 24 hours using FuGENE® HD (Promega, #E2311] as transfection reagent with expression vectors of a membrane-tethered form of the constitutively active intracellular domain of the human Notchl receptor (hNotchlAE) to activate the Notch signaling cascade [BPS Bioscience, customized human analogue to Notch Pathway Reporter Kit #60509 component C), a Firefly luciferase being expressed under the control of a Notch-responsive promoter to monitor Notch signaling (BPS Bioscience, Notch Pathway Reporter Kit #60509, CSL luciferase reporter vector from component A not premixed with Renilla luciferase vector), and a Renilla luciferase being constitutively expressed in a Notch signaling independent manner to include a measure for the cell number per sample (Promega, pRL-SV40, #E2231). HeLa cells were cultivated in DMEM medium (Fisherscientific, #11584456) containing 10% fetal bovine serum (Fisherscientific, #15517589). The transfection was carried out in a 100 mm- culture dish (StarLab, #CC7682-3394) with cells being properly attached to the plate at a cell confluency of 80-90% in a total volume of 7 mL culture medium. Per dish to be transfected, a transfection mix was prepared by adding to 238 pL Opti-MEM (Fisherscientific, #10149832) 40 pL of the hNotchlAE expression vector (100 ng/pL), 80 pL of the CSL luciferase reporter vector (40 ng/pL), 4 pL of the pRL-SV40-Renilla luciferase vector (10 ng/pL), and in the last step 18.1 pL of FuGENE® HD. After addition of FuGENE® HD the transfection mix was let stand for 15 min at room temperature and hereafter equally distributed into the culture dish. After 24 hours of transfection, the transfected cells were carefully detached from the dish using 0.5 mM EDTA in PBS and seeded into 96-well plates suitable for luminescence readouts (CORNING, #3610) at 10Ό00 cells per well. The cells were then incubated with the test-compounds at a final concentration of 10 pM (diluted from 10 mM stock-solutions in DMSO to a final DMSO concentration of 0.1% v/v in H2O (Water For Injection, WFI, Fisherscientific #10378939)) or with the empty carrier DMSO at 0.1% v/v as control for 20 hours. Hereafter, the cells were washed once with PBS and then lysed with 30 pL per well of Passive Lysis Buffer (Promega, #E194A, component of Dual-Luciferase® Reporter Assay System, #E1910) by gently shaking the plates for 20 min at room temperature with an orbital plate shaker. Directly after the lysis, first the Firefly and then the Renilla luciferase values were measured consecutively from the same well with a luminescence reader immediately after applying 15 pL per well each of the corresponding enzyme substrates needed to create the luminescence signals (Promega, Dual-Luciferase® Reporter Assay System, #E1910).

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

Per single experiment the measurement was performed in six replicates per compound. For every compound, this experiment was repeated in three or more independent replicates. The values of the Notch-reporter luciferase were normalized by division through the corresponding individual Notch-independent Renilla values in order to eliminate the impact of variation in the absolute cell numbers in between the samples. For every individual plate, a second normalization was performed against the equally weighted arithmetic mean (here abbreviated as AVE) of the six associated Renilla- normalized DMSO-control values within a single experiment in order to obtain the relative values to a baseline level of 1.0. The statistical calculations were performed in analogy to the proliferation assay as described above. To this end, two independent outlier analyses were performed according to the methods by Peirce and Chauvenet (Ross, Journal of Engineering Technology 2003, 1-12). Outliers confirmed by at least one of the methods were excluded from the calculations but not more than one value out of six per compound within a single experiment. The weighted arithmetic mean AVE _W for each compound was calculated from the double-normalized values over all independent replicates of the single experiments comprising the six replicates each. The corresponding standard deviation for the weighted arithmetic mean was calculated according to the method described by Bronstein et al. (Bronstein, Semendjajew, Musiol, Miihlig, Taschenbuch der Mathematik, 5 ^th edition 2001 (German], publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun] and was combined with the Gaui¾' error propagation associated with the performed calculation for the normalization. The resulting standard deviation is herein referred to as "combined standard deviation".

In cases with considerable variation in the double-normalized equally weighted arithmetic means derived from three independent replicates, the number of independent replicates was increased to four or more. In the cases of four or more independent replicates, a second-line outlier analysis was applied on all double- normalized equally weighted arithmetic means according to the methods by Peirce and Chauvenet as described above.

A compound is considered as a Notch signaling augmenting molecule, i.e. an enhancer of Notch signaling, if the weighted arithmetic mean of the luminescence values after subtraction of the corresponding combined standard deviation amounts to 1.1 or higher, in particular to 1.2 or higher, 1.3 or higher, 1.4 or higher, 1.5 or higher, 1.7 or higher, and 2.0 or higher relative to the overall basis level of 1.0. The overall basis level was calculated as the weighted arithmetic mean of all double-normalized values from the DMSO control measurements in analogy to the calculations performed for the test- compounds. The corresponding combined standard deviation for the DMSO values amounts to less than 1-10- ² .

According to the method described above, several molecules falling under the scope of the compounds herein defined in formula [lb] and [Ic], respectively, have been identified as enhancers of Notch signaling. The so far identified Notch enhancers relate to the compounds listed in Table 92. The entries of Table 92 are categorized by the corresponding weighted arithmetic mean of the compounds without consideration of the respective standard deviations, hence falling into the activity ranges as indicated.

Table 92: Notch reporter assay

Several other molecules have not been identified as enhancers of Notch signaling according to the above method.

In some cases, the growth inhibiting properties correlate with Notch enhancing properties, in other cases the growth inhibiting properties do not correlate with Notch enhancing properties.

The biological activity of the claimed compounds can be attributed to but may not be limited to Notch signaling enhancing activity. The Notch regulating properties of the claimed compounds can be used alternatively or in combination with the mechanisms leading to antiproliferative effects in medicinal treatments, preferably in the treatment of hyperproliferative disorders including cancer and non-malignant hyperproliferative disorders.

In one aspect, the present invention relates to the treatment of skin, skin appendages, mucosa, mucosal appendages, cornea, and all kinds of epithelial tissue. The term "skin" relates to tissue including epidermis and dermis. The term“mucosa" relates to mucous and submucous tissues including oral mucosa, nasal mucosa, ocular mucosa, mucosa of the ear, respiratory mucosa, genital mucosa, urothelial mucosa, anal mucosa and rectal mucosa. The term "appendages" relates to tissue including hair follicles, hair, fingernails, toenails and glands including sebaceous glands, sweat glands, e.g. apocrine or eccrine sweat glands and mammary glands.

In one embodiment, the present invention relates to treatment of non-melanoma skin cancer and pre-cancerous 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 cancer and pre-cancerous lesions of other squamous epithelia e.g. cutaneous SCC, lung SCC, head and neck SCC, oral SCC, tongue SCC, esophageal SCC, cervical SCC, periocular SCC, SCC of the thyroid, SCC of the penis, SCC of the vagina, SCC of the prostate and SCC of the bladder.

In a further embodiment, the present invention relates to the treatment of skin and mucosal disorders with cornification defects [keratoses) and/or abnormal keratinocyte proliferation, such as Psoriasis, Darier's disease, Lichen planus, Lupus erythematosus, Ichthyosis or Verruca vulgaris [senilis).

In a further embodiment, the invention relates to the treatment of skin and mucosal diseases, and skin and mucosal cancer each related to and/or caused by viral infections, such as warts, and warts related to HPV (human papilloma virus), papillomas, HPV- related papillomas, papillomatoses and HPV-related papillomatoses, e.g. Verruca (plantar warts), Verruca plana (flat warts/plane warts), Verruca filiformis (filiform warts), mosaic warts, periungual warts, subungual warts, oral warts, genital warts, fibroepithelial papilloma, intracanalicular papilloma, intraductal papilloma, inverted papilloma, basal cell papilloma, squamous papilloma, cutaneous papilloma, fibrovasular papilloma, plexus papilloma, nasal papilloma, pharyngeal papilloma, Papillomatosis cutis carcinoides, Papillomatosis cutis lymphostatica, Papillomatosis confluens et reticularis or laryngeal papillomatosis (respiratory papillomatosis), Herpes -related diseases, e.g. Herpes labialis, Herpes genitalis, Herpes zoster, Herpes corneae or Kaposi's sarcoma and HPV-related cancer of the cervix, vulva, penis, vagina, anus, oropharynx, tongue and oral cavity.

In a further embodiment, the invention relates to the treatment of atopic dermatitis. In a further embodiment, the invention relates to the treatment of acne.

In a further embodiment, the invention relates to the treatment of wounds of the skin, wherein the process of wound healing is accelerated.

In a further embodiment, the invention relates to the treatment of cancer related to and/or caused by viral infections, i.e. oncoviral infections, e.g. cancer related to HBV- and HCV (hepatitis virus B and C] such as liver cancer, cancer related to EBV (Epstein- Barr virus] such as Burkitt lymphoma, Hodgkin's and non-Hodgkin's lymphoma and stomach cancer, cancer related to HPV (human papilloma virus] such as cervical cancer, cancer related to HHV (human herpes virus] such as Kaposi's sarcoma, and cancer related to HTLV (human T-lymphotrophic virus] such as T-cell leukemia and T-cell lymphoma.

A further aspect of the present invention relates to the treatment of immune system- related disorders. The term " immune system-related disorders" as used herein applies to a pathological condition of the haematopoietic system including the haematologic system, in particular a pathological condition of immune cells belonging to the inate or adaptive immune system.

A further aspect of the present invention relates to the therapeutic use in immune system-related applications. The term "immune system-related application" as used herein applies to the intervention into proliferation, differentiation and/or activation of cell lineages of the haematopoietic system including the haematologic system in order to modulate an immune response (immune modulation]. The term "immune system-related application" as used herein also applies to the intervention into the cellular and non- cellular microenvironment of sites of action of immune cells in order to support and/or enable immune cells in their performance. In particular, the interventions as here defined with the term "immune system-related application” relate to immune cells belonging to the inate or adaptive immune system.

Thus, the compounds of the invention may be used in immunotherapy, alone or together with other immunotherapeutic methods or compounds, as immunologic adjuvant, e.g. as vaccine adjuvant, or as adjuvant for immunotherapy. The term“immunotherapy” as used herein applies to activation-immunotherapy in patients without immune deficiency or with acquired or congenital immune deficiency, and as immune recovery to enhance the functionality of the immune system in the response against pathogens or pathologically transformed endogenous cells, such as cancer cells.

The term "other immunotherapy methods" as used herein applies to vaccinations, antibody treatment, cytokine therapy, the use of immune checkpoint inhibitors and immune response-stimulating drugs, as well as to autologous transplantations of genetically modified or non-modified immune cells, which may be stimulated with intercellular signals, or signaling molecules, or antigens, or antibodies, i.e. adoptive immune-cell transfer.

The method of use of the present invention in immune system-related applications and other immunotherapy methods relates to the use in vivo, in vitro, and ex vivo, respectively.

Specific examples are activation and/or enhancement of activation of peripheral T- lymphocytes, including T-helper cells and cytotoxic T-cells, in order to amplify an immune response, particularly the stimulation of proliferation and/or production and/or secretion of cytokines and/or cytotoxic agents upon antigen recognition in order to amplify an immune response, such as the activation and/or enhancement of activation of B-lymphocytes in order to amplify an immune response, particularly the stimulation of proliferation and/or antibody production and/or secretion, such as the enhancement of an immune response through augmentation of the number of specific immune-cell subtypes, by regulation of differentiation and/or cell fate decision during immune-cell development, as for example to regulate, particularly to augment the number of immune cells belonging to the T- and B-cell lineage, including marginal zone B-cells, cytotoxic T-cells or T-helper [Th] subsets in particular Thl, Th2, Thl7 and regulatory T-cells; or the use as immunologic adjuvant such as vaccine adjuvant.

A still further aspect of the invention relates to the treatment of muscular diseases including diseases of skeletal muscle, cardiac muscle and smooth muscle.

In one embodiment, the invention relates to the treatment of muscular dystrophies (MD).

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

In a further embodiment, the invention relates to the treatment of hyperproliferative disorders of the muscle, including myoblastoma, rhabdomyoma, and rhabdomyosarcoma, as well as muscle hyperplasia and muscle hypertrophy.

In a further embodiment, the compounds of the invention may be used for muscle regeneration after pathologic muscle degeneration or atrophy, e.g. caused by traumata, caused by muscle ischemia or caused by inflammation, in aging-related muscle-atrophy or in disease-related muscle atrophy such as myositis and fibromyositis or poliomyelitis.

A still further aspect relates to the treatment of disorders of the neuroendocrine system such as cancer of the neuroendocrine system, comprising neuroendocrine small cell carcinomas, neuroendocrine large cell carcinomas and carcinoid tumors, e.g. of the brain, thyroid, pancreas, gastrointestinal tract, liver, esophagus, and lung, such as neuroendocrine tumor of the pituitary gland, neuroendocrine tumor of the adrenal gland, medullary thyroid cancer (MTC), C-cell hyperplasia, anaplastic thyroid cancer (ATC), parathyroid adenoma, intrathyroidal nodules, insular carcinoma, hyalinizing trabecular neoplasm, paraganglioma, lung carcinoid tumors, neuroblastoma, gastrointestinal carcinoid, Goblet-cell carcinoid, pancreatic carcinoid, gastrinoma, glucagenoma, somatostatinoma, VIPoma, insulinoma, non-functional islet cell tumor, multiple endocrine neoplasia type-1, or pulmonary carcinoid.

A still further aspect relates to the treatment of disorders of the lung such as cancer of the lung, comprising small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), including lung squamous cell carcinoma, lung adenocarcinoma and lung large cell carcinoma.

A still further aspect relates to the treatment of cancers or precancerous lesions of the brain, pancreas, breast, ovaries, liver, thyroid, genitourinary tract, gastrointestinal tract, and endothelial tissue, including glioma, mixed glioma, glioblastoma multiforme, astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma, brain stem glioma, optic nerve glioma, and forebrain tumors, pancreatic adenocarcinoma, pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma, pancreatic pseudopapillary neoplasm, pancreatic intraductal papillary-mucinous neoplasm, pancreatic mucinous cystadenocarcinoma, pancreatoblastoma and pancreatic intraepithelial neoplesia, hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, papillary thyroid cancer and follicular thyroid cancer, cervical cancer, hormone receptor-positive breast cancer and hormone receptor-negative breast cancer, ovarian cancer, gastric cancer and angiosarcoma.

As used herein, the term "treating” or "treatment" refers to one or more of [1] inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder [i.e., arresting further development of the pathology and/or symptomatology]; and (2] ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder [i.e., reversing the pathology and/or symptomatology] such as decreasing the severity of disease. The term "treating" also encompasses post-treatment care.

In some embodiments, administration of a compound of the invention, or pharmaceutically acceptable salt thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

The compounds of the invention may be used in human and veterinary medicine, which includes the treatment of companion animals, e.g. horses, dogs, cats, rabbits, guinea pigs, fishes e.g. koi, birds e.g. falcon; and livestock, e.g. cattle, poultry, pig, sheep, goat, donkey, yak and camel.

Pharmaceutical Compositions

The present invention further provides pharmaceutical compositions comprising a compound as described herein or a pharmaceutically acceptable salt thereof for use in medicine, e.g. in human or veterinary medicine. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

An effective dose of the compounds according to the invention, or their salts, solvates or prodrugs thereof is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1-500 mg, e.g. 0.1-100 mg.

Suitable administration forms are topical or systemical including enteral, oral, rectal, and parenteral, as infusion and injection, intravenous, intra-arterial, intraperitoneal, intramuscular, intracardial, epidural, intracerebral, intracerebroventricular, intraosseous, intra-articular, intraocular, intravitreal, intrathecal, intravaginal, intracavernous, intravesical, subcutaneous, intradermal, transdermal, transmucosal, inhalative, intranasal, buccal, sublingual and intralesional preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal preparations, e.g. dry powder or sublingual, of the compounds according to the invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, gels, hydrogels, ointments, creams, lotions, shampoos, lip balms, mouthwashs, foams, pastes, tinctures, dermal patches and tapes, forms in occlusion or in combination with time release drug delivery systems, with electrophoretic dermal delivery systems including implants and devices, and with jet injectors, liposome and transfersome vesicles, vapors, sprays, syrups, juices or drops and eye drops, can be used.

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

Liquid medicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators. Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts]. High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid], gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.

Oily suspensions for parenteral or topical applications can be vegetable, synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.

Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc. Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.

Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl-b- iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween], cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.

Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.

Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.

Inhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose.

The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions.

As indicated above, the compounds of the invention may be administered as a combination therapy, as sequence therapy or as simultaneous combination therapy, with further active agents, e.g. therapeutically active compounds useful in the treatment of the above indicated disorders. These therapeutically active compounds may include but are not limited to chemotherapeutic agents such as nucleoside and nucleobase analogs, e.g. Cytarabin, Gemcitabine, Azathioprine, Mercaptopurine, Fluorouracil, Thioguanine, Azacitidine, Capecitabine, Doxifluridine; such as platinum-based drugs, e.g. Cisplatin, Oxaliplatin, Carboplatin and Nedaplatin; such as anthracyclines, e.g. Doxorubicin, Epirubicin, Valrubicin, Idarubicin, Daunorubicin, Sabarubicin, Pixantrone and Mitoxantrone; such as peptide antibiotics, e.g. Actinomycin and Bleomycin; such as alkylating agents e.g. Mechlorethamine, Chlorambucil, Melphalan, Nitrosoureas, Dacarbazine, Temozolomide and Cyclophosphamide; such as antimitotic agents including taxanes and vinca alkaloids, e.g. Docetaxel, Paclitaxel, Abraxane, Cabazitaxel, Vinblastine, Vindesine, Vinorelbine and Vincristine; such as topoisomerase inhibitors, e.g. Irinotecan, Topotecan, Teniposide and Etoposide; such as other cytostatic agents e.g. Hydroxyurea and Methotrexate; such as proteasome inhibitors, e.g Bortezomib, Ixazomib; and other targeted therapeutic agents such as kinase inhibitors, cell cycle inhibitors, regulators i.e. inhibitors and activators of signaling pathways including growth factor signaling, cytokine signaling, NF-kappaB signaling, API signaling, JAK/STAT signaling, EGFR signaling, TGF-beta signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g. Erlotinib, Lapatinib, Dasatinib, Imatinib, Afatinib, Vemurafenib, Dabrafenib, Nilotinib, Cetuximab, Trametinib, Palbociclib, Cobimetinib, Cabozantinib, Pegaptanib, Crizotinib, Olaparib, Panitumumab, Cabozantinib, Ponatinib, Regorafenib, Entrectinib, Ranibizumab, Ibrutinib, Trastuzumab, Rituximab, Alemtuzumab, Gefitinib, Bevacizumab, Lenvatinib, Bosutinib, Axitinib, Pazopanib, Everolimus, Temsirolimus, Ruxolitinib, Tofacitinib, Sorafenib, Sunitinib, Aflibercept, Vandetanib; Vismodegib and Sonidegib; retinoids such as retinol, tretinoin, isotretinoin, alitretinoin, bexarotene, tazarotene, acitretin, adapalene and etretinate; hormone signaling modulators including estrogen receptor modulators, androgen receptor modulators and aromatase inhibitors e.g. Raloxifene, Tamoxifen, Fulvestrant, Lasofoxifene, Toremifene, Bicalutamide, Flutamide, Anastrozole, Letrozole and Exemestane; histone deacetylase inhibitors, e.g. Vorinostat, Romidepsin, Panobinostat, Belinostat and Chidamide; and Ingenol mebutate; and other Notch enhancers not encompassed by the compounds of the present invention, e.g. Valproic acid, Resveratrol, hesperetin, chrysin, phenethyl isothiocyanate, thiocoraline, N- methylhemeanthidine chloride and Notch Signaling-activating peptides or antibodies; and immune response modulating agents including immune checkpoint inhibitors e.g. Imiquimod, Ipilimumab, Atezolizumab, Ofatumumab, Rituximab, Nivolumab and Pembrolizumab; and anti-inflammatory agents including glucocorticoids and non steroidal anti-inflammatory drugs, e.g. cortisol-based preparations, Dexamethason, Betamethason, Prednisone, Prednisolone, Methylprednisolone, Triamcinolon- hexacetonid, Mometasonfuroat, Clobetasolpropionat, 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 beta-blockers; and myostatin inhibitors; and PDE-5 inhibitors; and antihistamines. For a combination therapy, the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active ingredients in separate dose forms. The active ingredients used in combination therapy may be co-administered or administered separately.

The compounds of the invention may be administered as antibody-drug conjugates.

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

Abbreviations:

Ac Acetyl

aq Aqueous

Aik Alkyl

Bn Benzyl

BRSM Based on Recovered Starting Material [yield]

Bu Butyl

mCPBA meta chloroperoxybenzoic acid

NMR Nulcear Magnetic Resonance Spectroscopy

DCE 1,2-dichloroethane

DCM Dichloromethane

DIBAL-H Diisobutylaluminium hydride

DMF N,N-dimethylformamide

DMSO Dimethyl sulfoxide

DMAP Dimethylaminopyridine

Equiv Equivalent

ESI Electron Spray Ionization

EDC N-[3dimethylaminopropyl]-N’-ethylcarbodimide

HOBt 1-hydroxybenzotriazole

HATU Hexafluorophosphate azabenzotriazole tetramethyl uronium

Et Ethyl

LiHMDS Lithium bis(trimetylsilyl]amide

Me Methyl

Ms Methanesulfonyl

PE Petroleum Ether

PG Protecting group

PTSA p-Toluenesulfonic acid

sat Saturated

TBAF Tetrabutylammonium Fluoride

Tf Trifluoromethanesulfonyl

THF Tetrahydrofuran

TLC Thin Layer Chromatography

TMS Trimethylsilyl

Ts p-Toluenesulfonyl

UV Ultraviolet

General considerations:

The compounds listed in Table 93 and Table 94 have been identified by TLC using pre coated silica TLC sheets and common organic solvents such as petroleum ether, ethyl acetate, dichloromethane, methanol, toluene, triethylamine or acetic acid as eluent, preferably as binary or tertiary solvent mixtures thereof. UV light at a wavelength of 254 or 366 nm, and/or common staining solutions such as phosphomolybdic acid, potassium permanganate, or ninhydrin were used to visualize the compounds. Reactions were also monitered for completion this way. Reactions were run under inert atmosphere unless otherwise stated. Dry solvents were used wherever required. All reactions were stirred using a stir plate and magnetic stir bar.

The compounds listed in Table 93 have furthermore been identified by mass spectrometry using formic acid in the mobile phase for detection of positive ions, while no additive was used for negative ions. Ammonium Carbonate was used if the molecule was difficult to ionize in negative mode. Representative compounds and those which showed poor ionization in mass spectrometry were also identified by nuclear magnetic resonance spectroscopy (Table 94). Chemical shifts (d) were reported in parts per million (ppm) relative to residual solvent peaks rounded to the nearest 0.01 ppm for proton and 0.1 ppm for carbon (ref.: CHCI ₃ [ ^: H: 7.26 ppm, ¹³ C: 77.2 ppm], DMSO [ ^a H: 2.50 ppm, ¹³ C: 39.5 ppm]). Coupling constants (/) were reported in Hz to the nearest 0.1 Hz. Peak multiplicity was indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), hept (heptet), m (multiplet), and br (broad).

Synthesis of described compounds:

The aforementioned compounds of the invention falling under the scope of formula I can be synthesized and purified by those persons skilled in the art and are preferably synthesized according to the general procedures (A to R) mentioned herein as illustrated in Scheme 1.

A To the corresponding mono or bisubstituted phenol (1.0-1.5 equiv) and 4-alkyl ester halo(hetero)aryl (1 equiv), dissolved in DMSO (0.5 M) under argon and stirring, was added K ₂ CO ₃ (1.5 equiv) and the mixture was either stirred at room temperature or heated between 40 °C and 160 °C until full conversion. The mixture was allowed to return to room temperature and was partitioned between an organic solvent, preferably petroleum ether and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with NaOH (aq, 2M) followed by Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt, DCM/MeOH or petroleum ether/AcOEt/NEt3) to yield the desired bi(hetero)aryl ether ethyl ester.

B) The corresponding bis(hetero)aryl ether alkyl ester (1 equiv) was dissolved in dry THF [0.2 M) under argon and stirring and the resulting solution was cooled to 0 °C with an ice bath. DIBAL-H (2.5 equiv, 1.2 M in toluene) was then added dropwise and the mixture left to stir at that temperature till full conversion. The reaction was quenched via the Fieser method, filtered, concentrated under vacuum and the residue was then purified by flash chromatography (Si02, gradient petroleum ether/AcOEt) to yield the desired alcohol.

C) Depending on the scale and substrate, either of these procedures were used.

To the corresponding alcohol (1 equiv), dissolved in DCM (0.2 M) under vigorous stirring, was added Mn0 ₂ (2-4 equiv). The resulting suspension was stirred at room temperature or 40 °C till full conversion. The reaction was then diluted with AcOEt, filtered over celite and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt) to yield the desired aldehyde.

To the corresponding alcohol (1 equiv), dissolved in DCM or DMSO (0.2 M) under vigorous stirring, was added Dess Martin Periodinane (1.2 equiv). The resulting suspension was stirred at room temperature till full conversion. The solution was diluted in AcOEt and quenched with aq. sat. NaHC03 and the phases seperated. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt) to yield the desired aldehyde.

To a solution of oxalyl chloride (2 equiv) in DCM (0.2 M) at -78 °C was added dry DMSO (4 equiv) and the mixture was stirred for 30 min. A solution in DCM (0.2 M) of the corresponding alcohol (1 equiv) was then added followed by freshly distilled NEt3 (8 equiv). The resulting solution was stirred for 1 hour before being slowly returned to room temperature. The solution was diluted in AcOEt and quenched with aq HC1 1M and the phases seperated. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt) to yield the desired aldehyde.

D) To the corresponding aldehyde (1 equiv), dissolved in dry THF (0.2 M) at 0 °C under argon and stirring, was added either TMSCF3 (2 equiv) followed by TBAF (1 mol%) to obtain the corresponding CF3 bearing secondary alcohol or a Grignard reagent (2 equiv) to obtain the corresponding secondary alkyl alcohol. In both cases, the resulting solution was left to stir at that temperature till full conversion. HC1 aq (2.5 M) was then added and the reaction left to stir for a further hour. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt) to yield the desired secondary alcohol. E] To a stirred solution of the corresponding secondry alcohol [1 equiv] in chloroform (0.2 M] at 0 °C was added Dess-Martin Periodinane (1.5 equiv]. After completion of the reaction, it was partitioned between AcOEt and NaHC0 ₃ aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt) to yield the desired ketone.

F] To a stirred solution of the corresponding ketone (1 equiv] in ethanol (0.2 M] was added the amine (2.5-40 equiv] followed by either a catalytic amount of PTSA in the case of aliphatic amines, or a base (2.5-40 equiv] in the case of hydroxylamines. The reaction was then refluxed for 24-72 h. After this time, Celite was added and the volatiles evaporated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] to yield the desired imines.

G] To the corresponding aldehyde or crude imine solution, obtained before purification during procedure (F], in DCM (0.25 M] was added sodium borohydride (4 equiv] and the solution left to stir for a further 2 hours. The reaction was then partitioned between AcOEt and NaHC0 ₃ aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] to yield the desired product.

H] To a stirred solution under argon of the corresponding aldehyde (1 equiv] in toluene (0.2 M] was added the amine (2 equiv] followed by TMSCN (2 equiv] and the reaction was stirred for 16 h. The reaction was then partitioned between AcOEt and NaHC0 ₃ aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] to yield the desired cyanoamine.

I] To the corresponding bis (hetero] aryl ether alkyl ester (1 equiv], dissolved in EtOH or THF (0.5 M] was added NaOH aq 2 M (2 equiv] and the reaction was left to stir till completion. The reaction was then partitioned between AcOEt and HC1 aq (1 M] The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified either by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] or by recrystallization (AcOEt] to yield the desired carboxylic acid.

J] Depending on the amine used, either of these procedures were employed.

To the corresponding bis(hetero]aryl ether carboxylic acid (1 equiv], suspended in stirred toluene (0.2 M], under argon, was added first S0C1 ₂ (2.5 equiv] then DMF (1 mol%] and the mixture was heated to 80 °C for 3 hours. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THF (0.2 M]. To this was added in order, trimethylamine (2.5 equiv], DMAP (1 mol%] and the corresponding amine or amide (1.2-1.5 equiv] and the suspension was stirred for 16 hours. The reaction was then partitioned between AcOEt and HC1 aq (1 M]. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt or petroleum ether/AcOEt/AcOH or DCM/MeOH) to yield the desired amide.

To the corresponding bis(hetero)aryl ether carboxylic acid [1 equiv) in DCM [0.2 M) was added in order NEt3 (3 equiv) and HOBt/EDCI (1.5 equiv/1.5 equiv) or HATU (1.5 equiv). The reaction mixture was then stirred 5 to 60 min before the corresponding amine (1.25 equiv) was added and the mixture stirred till completion. The reaction was then partitioned between AcOEt and HC1 aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ SC>4, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt or petroleum ether/AcOEt/AcOH or DCM/MeOH) to yield the desired amide.

To the corresponding bis(hetero)aryl ether carboxylic acid (1 equiv), suspended in stirred toluene (0.2 M), under argon, was added first S0C1 ₂ (2.5 equiv) then DMF (1 mol%) and the mixture was heated to 80 °C for 3 hours. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in toluene (0.2 M). This was added to a solution of the corresponding hydroxylamine in aq. sat. NaHC03 and the reaction mixture was stirred till completion. The reaction was then partitioned between AcOEt and aq HC1 1 M or water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt or petroleum ether/AcOEt/AcOH or DCM/MeOH) to yield the desired amide.

K) To the corresponding 4-substituted phenol (1 equiv) and 1,4-dibromoaryl (2.5 equiv), dissolved in DMF (0.2 M), was added Cs ₂ C03 (2 equiv), Cul (10 mol%) and tBuXPos (20 mol%). The mixture was degassed using the freeze- pump-thaw method, placed under argon, vigorously stirred and refluxed (165 °C) for 72 h. The mixture was allowed to return to room temperature and was partitioned between petroleum ether and NaOH aq 2 M. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt) to yield the desired bisaryl ether bromide.

L) To the corresponding 4-substituted phenol (1.2-1.5 equiv) and l,4-diromo(hetero)aryl (1 equiv), dissolved in DMSO (0.5 M) under argon and stirring, was added K ₂ C03 (1.5 equiv) and the mixture was heated between 80 °C and 160 °C until full conversion. The mixture was allowed to return to room temperature and was partitioned between petroleum ether and NaOH aq 2M. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt) to yield the desired bis (hetero) aryl ether bromide.

M) The corresponding bi (hetero) aryl ether bromide (1 equiv) was dissolved in dry THF (0.2 M) under argon and stirring and the resulting solution was cooled to -78 °C with a dry ice/acetone bath n- or t-BuLi [1.1-2.2 equiv, 1.9-2.5 M in hexane or pentane] was then added dropwise and the mixture left to stir at that temperature for 30 min then at -50 °C till full consuption of the starting material [monitored by TLC in pentane]. The mixture was then cooled back down to -78 °C, a solution in dry THF of the corresponding electrophile (2 equiv, 0.5 M] was added, and the reaction was allowed to return to room temperature slowly over 16 h. The reaction was then partitioned between AcOEt and NH4CI aq. sat., the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt/NEts] to yield the desired compound.

N] To the corresponding protected amine compound [1 equiv], dissolved in THF

[0.1-0.2 M] was added HC1 (0.5 M in MeOH, 2-6 equiv] and the reaction was left to stir till completion. Then either the reaction was evaporated to dryness to yield the desired amine as HC1 salt or the reaction was partitioned between AcOEt and NaHCOs aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt/MeOH or DCM/MeOH] to yield the desired free amine.

O] To the corresponding 4-substituted phenol (1 equiv] and 4-cyano(hetero]haloaryl (2.5 equiv], dissolved in DMSO (0.5 M] under argon and stirring, was added K ₂ C03 (1.5 equiv] and the mixture was heated between 80 °C and 160 °C until full conversion. The mixture was allowed to return to room temperature and was partitioned between petroleum ether and NaOH aq 2M. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] to yield the desired bis(hetero]aryl ether cyanide.

P] To the corresponding bis(hetero]aryl ether cyanide (1 equiv], dissolved in THF/MeOH (1:1, 0.1 M], at 0 °C under argon and stirring, was added NaH (1.1 equiv]. After 4 h, the ice bath was removed and cyanamide (1.5 equiv] was added and the mixture stirred for a further 16 h. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt/MeOH] to yield the desired amine.

Q] To the corresponding bis (hetero] aryl ether alcohol, hydroxamic acid or amide (1 equiv], dissolved in THF/DMF (1:0 to 2:8 mixture, 0.2 M], under argon and stirring, was added NaH, NaOAc or Cs ₂ C03 (1.2-2 equiv]. After 30 min, the alkyl (di]halide or acyl chloride (1.2- 2 equiv] was added, with KI (1.2 equiv] in the cases of alkyl (di]bromides. The mixture then stirred for a further 16 h at room temperature or 50 °C in the cases of alkyl (di]bromides. The reaction was then partitioned between AcOEt and HC1 aq (1 M] The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt/AcOH] to yield the desired amide. R] To the corresponding bis(hetero]aryl ether amide (1 equiv], dissolved in THF [0.2 M], at 0 °C under argon and stirring, was added NaBFU (1.1 equiv]. After 1 h, The reaction was then partitioned between AcOEt and NaHCOs aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt] to yield the desired amide.

S] To the corresponding aldehyde (1 equiv] in dry THF (0.2 M] was added the corresponding Wittig reagent (1.5 equiv] at 0 °C. To this stirred mixture was added dropwise LiHMDS (1.3 equiv, 1 M in THF]. The reaction was stirred untill completion before being partitioned between AcOEt and HC1 aq (1 M] The aqueous layer was extracted twice more and the combined organic phases were then washed with aq. sat. NaHCOs, Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt] to yield the desired olefin.

T] For adding methyl groups to the amine:

To the corresponding free amine (1 equiv] in acetonitrile (0.2 M] was added formaldehyde (6 equiv, 37% w/w in water] followed by NaBHsCN (2 equiv]. The reaction mixture was stirred till completion before being partitioned between AcOEt and aq. sat. NaHCOs, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient DCM/MeOH/NEts] to yield the desired compound.

For adding isopropyl groups to the amine:

To the corresponding free amine (1 equiv] in acetone (0.2 M] was added NaBHsCN (10 equiv] in five portions every 15 min while keeping the pH at approximativly 5 with acetic acid. The reaction mixture was then partitioned between AcOEt and aq. sat. NaHCOs, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient DCM/MeOH/NEts] to yield the desired compound.

U] To the corresponding amine (1 equiv] in DCM (0.1 M] was added mCPBA (1.2 equiv] and the mixture was stirred at room temperature till full conversion. The reaction mixture was then partitioned between AcOEt and aq. sat. NaHCOs, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt] to yield the desired compound.

V] To the corresponding nitrile (1 equiv] in ethanol (0.2 M] was added hydroxylamine hydrochloride (2.5 equiv] and sodium hydroxide (2.5 equiv]. The reaction was heated to 80 °C overnight before being filtered over celite, concentrated under under vacuum and the residue purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt) to yield the desired compound.

W) To the corresponding aldehyde (1 equiv in methanol (0.1 M) was added K ₂ CO ₃ (2 equiv] followed by the Ohira-Bestmann reagent (1.1 equiv] and the reaction stirred till completion. The reaction was then partitioned between AcOEt and NaHC03 aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] to yield the desired alkyne.

Analytical Data

The following compounds were synthetized according to the aforementioned protocols and characterized via mass spectrometry (Table 93] or NMR (Table 94],

Table 93:

Compound m/z Ion m/z Ion

Formula Procedure No. [ESP] [ESP] JS5LL iºl

XPW-0014 C24H26F3NO 385.6 [M+NH2] N

C21H24F3NO-

XPW-0020 364 [M+H] G

HC1

C25H2 _S F3NO-

XPW-0028 416.7 [M+H] N

HC1

XPW-0042 C26H30F3NO 430.7 [M+H] ⁺ T

[M+H] ⁺ [minor]

335.31

[M-CN] ⁺ [major]

XPW-0314 C22H26N2O 308.24 H

[M-NMe ₂ ] ⁺

290.14

[major]

XPW-0506 C17H19NO2 270.1 [M+H] ⁺ J

XPW-0509 C17H14F3NO2 322.2 [M+H] ⁺ J

XPW-0510 C19H21NO2 296.2 [M+H] ⁺ J

XPW-0515 C20H21NO2 308.2 [M+H] ⁺ J

XPW-0516 C21H23NO2 322.3 [M+H] ⁺ I

XPW-0518 C23H25NO2 348.3 [M+H] ⁺ I

XPW-0520 C18H21NO2 284.2 [M+H] ⁺ I

XPW-0523 C18H16F3NO2 336.2 [M+H] ⁺ I

XPW-0524 C20H23NO2 310.2 [M+H] ⁺

XPW-0529 C21H23NO2 322.3 [M+H] ⁺

XPW-0530 C22H25NO2 336.3 [M+H] ⁺

XPW-0532 C24H27NO2 362.3 [M+H] ⁺ J

XPW-0533 C19H23NO2 298.2 [M+H] ⁺ I

XPW-0534 C19H23NO2 298.2 [M+H] ⁺ I

XPW-0535 C18H21NO3 300.2 [M+H] ⁺ I

XPW-0536 C19H24N2O2 313.3 [M+H] ⁺ I

XPW-0537 C19H18F3NO2 350.2 [M+H] ⁺

XPW-0538 C21H25NO2 324.3 [M+H] ⁺

XPW-0539 C20H23NO3 326.2 [M+H] ⁺

XPW-0541 C19H22N2O3 327.5 [M+H] ⁺

XPW-0543 C22H25NO2 336.3 [M+H] ⁺ J

XPW-0544 C23H27NO2 350.3 [M+H] ⁺ J

XPW-0546 C25H29NO2 376.3 [M+H] ⁺ J

XPW-0547 C18H21NO4S 348.2 [M+H] ⁺ 346.24 [M-H] J

XPW-0548 C18H21NO4S 348.2 [M+H] ⁺ 346.23 [M-H] I

XPW-0552 C20H23NO4S 374.3 [M+H] ⁺ 372.27 [M-H] I Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI-] [ESI ]

XPW-0560 C24H27NO4S 426.3 [M+H] ⁺ 424.3 [M-H] I

XPW-0566 C21H25NO4S 388.3 [M+H] ⁺ Q

XPW-0574 C25H29NO4S 440.3 [M+H] ⁺ Q

XPW-0575 C18H18F3NO4S 402.3 [M+H] ⁺ 400.21 [M-H] J

XPW-0576 C18H18F3NO4S [M+H] ⁺ 400.23 [M-H] I

XPW-0580 C20H20F3NO4S [M+H] ⁺ 426.24 [M-H] I

XPW-0588 C24H24F3NO4S [M+H] ⁺ 478.24 [M-H] I

XPW-0603 C24H25NO4S 424.3 [M+H] ⁺ 422.27 [M-H] I

XPW-0604 C24H25NO4S 424.3 [M+H] ⁺ 422.28 [M-H] 0

XPW-0608 C26H27NO4S 450.3 [M+H] ⁺ 448.32 [M-H]

XPW-0616 C30H31NO4S 502.2 [M+H] ⁺ 500.25 [M-H]

XPW-0636 C20H20N2O2 [M+H] ⁺ 319.28 [M-H]

XPW-0659 C17H19NO3 286.2 [M+H] ⁺

XPW-0660 C17H19NO3 286.2 [M+H] ⁺ I

XPW-0661 C16H17NO4 288.2 [M+H] ⁺ 286.14 [M-H] A

XPW-0663 C17H14F3NO3 338.2 [M+H] ⁺ J

XPW-0664 C19H21NO3 312.2 [M+H] ⁺ J

XPW-0665 C18H19NO4 314.2 [M+H] ⁺ 312.19 [M-H]

XPW-0667 C17H18N2O4 315.5 [M+H] ⁺

XPW-0669 C20H21NO3 324.2 [M+H] ⁺

XPW-0670 C21H23NO3 338.3 [M+H] ⁺

XPW-0672 C23H25NO3 364.4 [M+H] ⁺ J

XPW-0674 C18H21NO3 300.2 [M+H] ⁺ J

XPW-0675 C17H19NO4 302.2 [M+H] ⁺ J

XPW-0678 C20H23NO3 326.3 [M+H] ⁺ J

XPW-0679 C19H21NO4 328.2 [M+H] ⁺

XPW-0686 C24H27NO3 378.3 [M+H] ⁺

XPW-0700 C26H31NO3 406.6 [M+H] ⁺

XPW-0702 C18H21NO3 300.2 [M+H] ⁺

XPW-0703 C17H19NO4 302.2 [M+H] ⁺ A

XPW-0704 C18H22N2O3-HCI 315.2 [M+H] ⁺ J

XPW-0706 C20H23NO3 326.3 [M+H] ⁺ J

XPW-0714 C24H27NO3 378.3 [M+H] ⁺ J

XPW-0716 C19H23NO3 314.2 [M+H] ⁺ I

XPW-0717 C18H21NO4 316.2 [M+H] ⁺ I

XPW-0718 C19H24N2O3-HCI 329.3 [M+H] ⁺ I

XPW-0720 C21H25NO3 340.3 [M+H] ⁺ I

XPW-0728 C24H29NO3 392.4 [M+H] ⁺ I

XPW-0734 C26H27NO3 402.4 [M+H] ⁺ J

XPW-0742 C30H31NO3 454.3 [M+H] ⁺ J

XPW-0762 C23H27NO3 366.3 [M+H] ⁺ I

XPW-0770 C27H31NO3 418.4 [M+H] ⁺ I

XPW-0776 C22H25NO3 352.3 [M+H] ⁺ R

XPW-0784 C26H29NO3 404.4 [M+H] ⁺ R

XPW-0790 C22H23NO3 350.3 [M+H] ⁺ I

XPW-0798 C26H27NO3 402.4 [M+H] ⁺

XPW-0818 C24H27NO3 387.7 [M+H] ⁺

XPW-0832 C20H21N3O 320.3 [M+H] ⁺ p

XPW-0902 C25H33NO3S 428.4 [M+H] ⁺ M

XPW-0916 C21H25NO2 324.3 [M+H] ⁺ N

379.32 min [M+l] ⁺ (minor]

XPW-0924 C25H29NO2 M

359.28 maj [M-NH2] ⁺ [major]

XPW-0930 C22H27NO2 338.64 [M+H] ⁺ N Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI ] [ESI ]

307.53 [M-NHMe]

XPW-1582 C23H24FNO2 366.3 [M+H] ⁺ J

XPW-1587 C18H15F4NO2 354.2 [M+H] ⁺ J

XPW-1588 C20H22FNO2 328.3 [M+H] ⁺ J

XPW-1596 C24H26FNO2 380.3 [M+H] ⁺ I

XPW-1601 C19H17F4NO2 368.2 [M+H] ⁺ I

XPW-1602 C21H24FNO2 342.3 [M+H] ⁺ I

XPW-1610 C25H28FNO2 394.3 [M+H] ⁺ I

XPW-1727 C17H13F4NO3 356.2 [M+H] ⁺ I

XPW-1728 C19H20FNO3 330.2 [M+H] ⁺

XPW-1736 C23H24FNO3 382.3 [M+H] ⁺

XPW-1750 C24H26FNO3 396.3 [M+H] ⁺

XPW-2633 C16H18N2O2 271.1 [M+H] ⁺

XPW-2634 C16H18N2O2 271.1 [M+H] ⁺ I

XPW-2637 C16H13F3N2O2 323.2 [M+H] ⁺ J

XPW-2643 C19H20N2O2 309.2 [M+H] ⁺ J

XPW-2644 C20H22N2O2 323.3 [M+H] ⁺ J

XPW-2646 C22H24N2O2 349.3 [M+H] ⁺

XPW-2648 C17H20N2O2 285.2 [M+H] ⁺

XPW-2651 C17H15F3N2O2 337.2 [M+H] ⁺

XPW-2652 C19H22N2O2 311.2 [M+H] ⁺

XPW-2657 C20H22N2O2 323.3 [M+H] ⁺ J

XPW-2658 C21H24N2O2 337.3 [M+H] ⁺ J

XPW-2660 C23H26N2O2 363.3 [M+H] ⁺ J

XPW-2661 C18H22N2O2 299.2 [M+H] ⁺ J

XPW-2662 C18H22N2O2 299.2 [M+H] ⁺

XPW-2665 C18H17F3N2O2 351.2 [M+H] ⁺

XPW-2666 C20H24N2O2 325.3 [M+H] ⁺

XPW-2671 C21H24N2O2 337.3 [M+H] ⁺

XPW-2672 C22H26N2O2 351.3 [M+H] ⁺ J

XPW-2674 C24H28N2O2 377.3 [M+H] ⁺ J

XPW-2675 C17H20N2O4S 349.2 [M+H] ⁺ 347.22 [M-H] J

XPW-2676 C17H20N2O4S 349.2 [M+H] ⁺ 347.24 [M-H] J

XPW-2688 C23H26N2O4S 427.3 [M+H] ⁺ 425.29 [M-H]- J

XPW-2703 C17H17F3N2O4S 403.2 [M+H] ⁺ 401.21 [M-H]- J

XPW-2704 C17H17F3N2O4S 403.2 [M+H] ⁺ 401.23 [M-H]- J

XPW-2708 C19H19F3N2O4S 429.2 [M+H] ⁺ 427.24 [M-H]- J

XPW-2716 C23H23F3N2O4S 480.5 [M+H] ⁺ 479.23 [M-H]- J

XPW-2731 C23H24N2O4S 425.3 [M+H] ⁺ 423.33 [M-H] J

XPW-2732 C23H24N2O4S 425.3 [M+H] ⁺ 423.28 [M-H]- J

XPW-2744 C29H30N2O4S 503.2 [M+H] ⁺ 501.26 [M-H]- J

XPW-2787 C16H18N2O3 287.1 [M+H] ⁺ I

XPW-2788 C16H18N2O3 287.1 [M+H] ⁺ I

XPW-2791 C16H13F3N2O3 339.2 [M+H] ⁺ 337.22 [M-H]- J

XPW-2792 C18H20N2O3 313.2 [M+H] ⁺ I

XPW-2795 C16H17N3O4 316.5 [M+H] ⁺ I

XPW-2797 C19H20N2O3 325.2 [M+H] ⁺ 323.29 [M-H]- J

XPW-2798 C20H22N2O3 339.2 [M+H] ⁺ 337.31 [M-H]- J

XPW-2800 C22H24N2O3 365.3 [M+H] ⁺ I

XPW-2805 C17H15F3N2O3 353.2 [M+H] ⁺ 351.2 [M-H]- J

XPW-2806 C19H22N2O3 327.3 [M+H] ⁺ J

XPW-2833 C17H15F3N2O3 353.2 [M+H] ⁺ J Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI] [ESI]

Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI] [ESI]

XPW-4545 C H N O 313.3 [M+H] j

XPW-4546 C H FN O 331.3 [M+H] J

XPW-4547 C H N O 257.1 [M+H] J

XPW-4548 C H N O 271.1 [M+H] J

XPW-4549 C H N O 285.2 [M+H]

XPW-4550 C H FN O 329.3 [M+H] I

XPW-4551 C H FN O 343.3 [M+H] I

XPW-4552 C H N O 229.1 [M+H] I

XPW-4553 C H N O 243.1 [M+H] I

XPW-4554 C H N O 257.1 [M+H]

XPW-4555 C H N O 243.1 [M+H]

XPW-4556 C H N O 257.1 [M+H]

XPW-4557 C H N O 271.1 [M+H]

XPW-4558 C H N O 257.1 [M+H] I

XPW-4559 C H N O 285.2 [M+H] J

XPW-4560 C H NO 284.2 [M+H] J

XPW-4561 C H NO 298.2 [M+H] J

XPW-4562 C H NO 312.2 [M+H]

XPW-4563 C H NO 270.1 [M+H]

XPW-4564 CiaH2iN02 284.2 [M+H]

XPW-4565 C H NO 242.1 [M+H]

XPW-4566 C H F N O 341.2 [M+H] J

XPW-4567 C H F N O 369.2 [M+H] J

XPW-4568 C H F N O 283 [M+H] J

XPW-4569 C H F N O 297.1 [M+H] J

XPW-4570 C H F N O 311.1 [M+H]

XPW-4571 C H CIF N O 357.1 [M+H]

XPW-4572 C H CIF N O 371.2 [M+H]

XPW-4573 C H CIF N O 385.2 [M+H]

XPW-4574 C H N O 311.5 [M+H] V

XPW-4575 C H CINO 358.59/360.59 [M+H] J

XPW-4576 C H NO 380.6 [M+H] J

XPW-4577 C H NO 390.7 [M+H] R

XPW-4578 C H NO 396.7 [M+H] G

XPW-4579 C H N O 465.7 [M+H] G

XPW-4580 C H N O 409.7 [M+H] G

XPW-4581 C H NO 410.7 [M+H] Q

XPW-4583 C H CINO 400.7 [M+H] I

XPW-4584 C H CINO 346.5 [M+H] J

XPW-4585 C H CINO 410.7 [M+H] J

XPW-4586 C H CINO 452.7 [M+H] I

XPW-4587 C H CINO 398.6 [M+H] I

XPW-4588 C ₂ iH24BrN0 ₂ 402.57/404.58 [M+H] I

XPW-4589 C23H26BrN03 444.57/446.57 [M+H] I

XPW-4590 Ci9H2oBrN03 390.52/392.52 [M+H] I

XPW-4591 C25H28BrN02 454.59/456.58 [M+H]

XPW-4592 C27H3aBrN03 496.62/498.59 [M+H]

XPW-4593 C23H24BrN03 442.54/444.54 [M+H]

XPW-4594 C H NO 380.6 [M+H]

XPW-4595 C H NO 338.6 [M+H] J

XPW-4603 C H NO 312.5 [M+H] J

XPW-4605 C H NO 286.4 [M+H] J Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI] [ESI]

Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI-] [ESI]

XPW-I-0023 C H O 269.18 [M-H] I

XPW-I-0024 C H O 269.18 [M-H] I

XPW-I-0025 C H O 295.27 [M-H] I

XPW-I-0026 C H O 337.3 [M+H] A

XPW-I-0027 C H O 307.28 [M-H] I

XPW-I-0028 C H O 351.3 [M+H] A

XPW-I-0029 C H O 321.34 [M-H] I

XPW-I-0030 C H O 347.37 [M-H] I

XPW-I-0031 C H F O 321.22 [M-H] I

XPW-I-0032 C H F O 351.2 [M+H] A

XPW-I-0033 C H FO 317.2 [M+H] A

XPW-I-0034 C H FO 287.18 [M-H] I

XPW-I-0035 C H NO 300.2 [M+H] A

XPW-I-0036 C H NO 272.1 [M+H] 270.18 [M-H] I

XPW-I-0037 C H NO 300.2 [M+H] A

XPW-I-0038 C H NO 272.1 [M+H] 270.18 [M-H] I

XPW-I-0039 C H NO 326.3 [M+H] A

XPW-I-0040 C H NO 298.2 [M+H] 296.22 [M-H] I

XPW-I-0041 C H NO 338.2 [M+H] A

XPW-I-0042 C H NO 308.25 [M-H] I

XPW-I-0043 C H NO 352.3 [M+H] A

XPW-I-0044 C H NO 322.3 [M-H] I

XPW-I-0045 C H NO 378.3 [M+H] A

XPW-I-0046 C H NO 348.37 [M-H] I

XPW-I-0047 352.2 [M+H] A

XPW-I-0048 C H F NO 324.1 [M+H] 322.22 [M-H] I

XPW-I-0049 C H FO 317.2 [M+H] A

XPW-I-0050 C H FO 287.18 [M-H] I

XPW-I-0051 C H FO 343.3 [M+H] A

XPW-I-0052 C H FO 313.24 [M-H] I

XPW-I-0053 C H FO 395.3 [M+H] A

XPW-I-0054 C H F O 369.2 [M+H] A

XPW-I-0055 C H FO 301.24 [M-H]

XPW-I-0056 C H FO 259.15 [M-H]

XPW-I-0057 C H FO 245.13 [M-H]

XPW-I-0058 C H FO 273.15 [M-H] I

XPW-I-0059 C H F O 299.12 [M-H] I

XPW-I-0060 C H NO 286.2 [M+H] 284.2 [M-H] I

XPW-I-0062 C H O 313.3 [M+H] A

XPW-I-0063 C H O 283.21 [M-H] I

XPW-I-0064 257.1 [M+H] A

XPW-I-0065 C H O 271.1 [M+H] A

XPW-I-0066 C H O 241.17 [M-H] I

XPW-I-0067 C H O 285.2 [M+H] A

XPW-I-0068 255.18 [M-H] I

XPW-I-0069 C H O 285.2 [M+H] A Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI-] [ESI]

XPW-I-0073 C H NO 258.1 [M+H] A

XPW-I-0074 C H NO 230.1 [M+H] 228.15 [M-H] I

XPW-I-0075 C H NO 272.1 [M+H] A

XPW-I-0076 C H NO 244 [M+H] 242.15 [M-H] I

XPW-I-0077 Ci7HigN03 286.2 [M+H] A

XPW-I-0078 C H NO 258.1 [M+H] 256.17 [M-H] I

XPW-I-0079 C H NO 314.2 [M+H] A

XPW-I-0080 C H NO 286.2 [M+H] 284.2 [M-H] I

XPW-I-0081 C H NO 286.2 [M+H] A

XPW-I-0082 C H NO 258.1 [M+H] 256.17 [M-H] I

XPW-I-0083 C H NO 314.2 [M+H] A

XPW-I-0084 C H F NO 312.1 [M+H] A

XPW-I-0085 C H F NO 284 [M+H] 282.1 [M-H] I

XPW-I-0086 C H FO 331.3 [M+H] A

XPW-I-0087 C H O 227.16 [M-H] I

XPW-I-0088 C H FNO 332.2 [M+H] A

XPW-I-0089 C H SFNO 304.2 [M+H] 302.22 [M-H] I

XPW-I-0090 C H FNO 344.2 [M+H] A

XPW-I-0091 C H FNO 314.24 [M-H] I

XPW-I-0092 C H FNO 396.3 [M+H] A

XPW-I-0093 C H FNO 368.3 [M+H] 366.37 [M-H] I

XPW-I-0094 C H F NO 370.2 [M+H] A

XPW-I-0095 C H F NO 340.21 [M-H] I

XPW-I-0096 C H CIF O 355.21 [M-H] I

XPW-I-0097 C H CIF O 385.2 [M+H] A

XPW-I-0098 CiaHisClFsNOs 386.2 [M+H] A

XPW-I-0099 C H CIF NO 358.1 [M+H] 356.2 [M-H] I

XPW-I-0100 C H F O 401.3 [M+H] A

XPW-I-0101 C H F NO 402.3 [M+H] A

XPW-I-0102 C H F O n.a [M+H] 371.3 [M-H] I

XPW-I-0103 C H F NO 374.2 [M+H] 372.3 [M-H] I

XPW-I-0104 C H FO 275.1 [M+H] A

XPW-I-0105 C H FO 289.1 [M+H] A

XPW-I-0106 C H FO 303.2 [M+H] A

XPW-I-0107 C H F O 329.2 [M+H] A

XPW-I-0108 C H FO 331.2 [M+H] A

XPW-I-0109 C H FO 303.2 [M+H] A

XPW-I-0110 C H FO 301.21 [M-H] I

XPW-I-0111 C H FO 273.17 [M-H] I

XPW-I-0112 C H FNO 304.2 [M+H] A

XPW-I-0113 C H FNO 318.2 [M+H] A

XPW-I-0114 C H FNO 276.1 [M+H] A

XPW-I-0115 C H F NO 330.1 [M+H] A

XPW-I-0116 C H FNO 274.15 [M-H]

XPW-I-0117 CieHieFNOs 288.17 [M-H]

XPW-I-0118 C H FNO 246.12 [M-H]

XPW-I-0119 C H F NO 300.1 [M-H] I

XPW-I-0120 C H O 339.6 [M+H] A

XPW-I-0121 C H O 309.45 [M-H] I Compound m/z Ion m/z Ion

Formula Procedure

No. [ESI ⁺ ] [ESI ⁺ ] [ESI-] [ESI ]

To 4-(4-butylphenoxy]benzoic acid [104 mg, 0.38 mmol, 1 equiv], suspended in stirred toluene [1.85 mL, 0.2 M], under argon, was added first SOCI2 [67 pL, 0.93 mmol, 2.5 equiv] then DMF (0.3 pL, 3.7 pmol, 1 mol%] and the mixture was heated to 80 °C for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THF (1.85 mL, 0.2 M]. To this was added in order, trimethylamine (0.13 mL, 0.93 mmol, 2.5 equiv], DMAP (0.45 mg, 3.7 pmol, 1 mol%] and methansulfonamide (42.3 mg, 0.45 mmol, 1.2 equiv] and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and HC1 aq (1 M]. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over NazSC , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt] to yield 118 mg of 4-(4-butylphenoxy]-/V-(methylsulfonyl]benzamide [88%].

MS: m/z [M-H]-, calc for [CiaF oNC S] _^ 346.11; found 346.24

iH-NMR (300 MHz DMSO-d ₆ ] d 12.03 (s, 1H], 7.97 (d,/ = 8.9 Hz, 2H], 7.32 - 7.24 (m, 2H], 7.08 - 6.97 (m, 4H], 3.36 (s, 3H], 2.66 - 2.56 (m, 2H], 1.58 (tt,/ = 8.8, 6.8 Hz, 2H], 1.41 - 1.24 (m, 2H], 0.92 (t = 7.3 Hz, 3H]

¹³ C-NMR (75 MHz, DMSO-d ₆ ] d 166.1, 162.1, 153.2, 139.4, 131.4, 130.5, 126.3, 120.4, 117.2, 41.8, 34.6, 33.6, 22.2, 14.3.

XPW-2890 (6-(4-cyclohexylphenoxy]pyridin-3-yl](morpholino]methanone To 6-(4-cyclohexylphenoxy]nicotinic acid (50 mg, 0.17 mmol, 1 equiv], suspended in stirred toluene (0.85 mL, 0.2 M], under argon, was added first SOCI2 (31 gL, 0.43 mmol, 2.5 equiv] then DMF (0.14 gL, 1.7 gmol, 1 mol%] and the mixture was heated to 80 °C for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THF (0.85 mL, 0.2 M] To this was added in order, trimethylamine (9.4 gL, 0.68 mmol, 2.5 equiv], DMAP (0.2 mg, 1.7 gmol, 1 mol%] and morpholine (20 gL, 0.23 mmol, 1.5 equiv] and the suspension was stirred for 16 hours. The reaction was then partitioned between AcOEt and HC1 aq (1 M]. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] to yield 45 mg of (6-(4-cyclohexylphenoxy]pyridin-3- yl](morpholino]methanone (71%].

MS: m/z [M+H] ⁺ , calc for [C ₂₂ H ₂₇ N ₂ 0 ₃ ] ⁺ = 367.20; found 367.32

^! H-NMR (300 MHz, CDCI ₃ ] d 8.20 (d,/ = 2.3 Hz, 1H], 7.73 (dd,/ = 8.6, 2.2 Hz, 1H], 7.18 (d, = 7.7 Hz, 2H], 7.06 - 6.92 (m, 2H], 6.87 (d ,/ = 8.5 Hz, 1H], 3.63 (s, 8H], 2.50 - 2.37 (m, 1H], 1.89 - 1.62 (m, 5H], 1.38-1.08 (m, 5H]

¹³ C-NMR (75 MHz, CDC1 ₃ ] d 167.7, 164.7, 151.2, 146.6, 145.1, 139.5, 128.1, 125.5, 121.0, 111.3, 66.8, 53.4, 44.0, 34.5, 26.9, 26.1.

XPW-0636 N-cyano-4-(4-cyclohexylphenoxy]benzamide

To 4-(4-cyclohexylphenoxy]benzoic acid (60 mg, 0.2 mmol, 1 equiv], suspended in stirred toluene (0.8 mL, 0.2 M], under argon, was added first SOCI2 (37 gL, 0.0.5 mmol, 2.5 equiv] then DMF (0.15 gL, 2.0 gmol, 1 mol%] and the mixture was heated to 80 °C for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THF (0.8 mL, 0.2 M] To this was added in order, trimethylamine (57 gL, 0.5 mmol, 2.5 equiv], DMAP (0.24 mg, 2.0 gmol, 1 mol%] and cyanamide (12.6 mg, 0.3 mmol, 1.5 equiv] and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and HC1 aq (1 M]. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt] to yield 15.4 mg of N-cyano-4-(4-cyclohexylphenoxy]benzamide (24%].

MS: m/z [M-H]-, calc for [C ₂ oHi ₉ N ₂ 0 ₂ ]- = 319.15; found 319.28 ⁱ H-NMR, (300 MHz, CDCI3] d 7.93 (d = 8.8 Hz, 2H], 7.31 (d,/ = 8.5 Hz, 2H], 7.23 - 6.85 (m, 4H], 3.37 (brs, 1H], 2.59 - 2.51 (m, 1H ] 1.91 - 1.63 (m, 5H], 1.57 - 1.12 (m, 5H]

¹³ C-NMR, (75 MHz, CDC1 ₃ ] d 166.5, 161.8, 152.7, 144.2, 130.8, 128.4, 124.8, 119.9, 117.1, 110.0, 43.1, 34.0, 26.3, 25.5. XPW-0675 N-hydroxy-4-(4-(2-methoxyethyl]phenoxy]-N-methylbenzamide

To 4-(4-(2-methoxyethyl]phenoxy]benzoic acid (125 mg, 0.46 mmol, 1 equiv], suspended in stirred toluene (2.3 mL, 0.2 M], under argon, was added first SOCI2 (84 pL, 1.15 mmol, 2.5 equiv] then DMF (0.35 pL, 4.6 pmol, 1 mol%] and the mixture was heated to 80 °C for 3 h. The reaction mixture was then evaporated to dryness and the resulting residue placed under argon again and redissolved in THF (2.3 mL, 0.2 M]. To this was added in order, trimethylamine (144 pL, 1.13 mmol, 2.5 equiv], DMAP (0.56 mg, 4.6 pmol, 1 mol%] and N-methylhydroxylamine hydrochloride (58 mg, 0.69 mmol, 1.5 equiv] and the suspension was stirred for 16 h. The reaction was then partitioned between AcOEt and HC1 aq (1 M]. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt] to yield 103.1 mg of lV-hydroxy-4- (4-(2-methoxyethyl]phenoxy]-/V-methylbenzamide (74%].

MS: m/z [M+H] ⁺ , calc for [Ci ₇ H ₂ oN0 ₄ ] ⁺ = 302.14; found 302.17 ⁱ H-NMR, [300 MHz, CDCI3] d 10.00 (s, 1H], 7.73 - 7.61 (m, 2H], 7.37 - 7.20 (m, 2H], 7.07 - 6.82 [m, 4H], 3.55 (t ,J = 6.8 Hz, 2H], 3.26 (s, 3H], 3.25 (s, 3H], 2.82 (t = 6.8 Hz, 2H]

¹³ C-NMR, (75 MHz, CDC13] d 168.6, 159.2, 154.3, 135.6, 131.2, 130.9, 129.5, 119.9, 117.1, 73.2, 58.3, 37.9, 35.1.

XPW-0832 N'-cyano-6-(4-cyclohexylphenoxy]nicotinimidamide

To 6-(4-cyclohexylphenoxy]nicotinonitrile (41 mg, 0.15 mmol, 1 equiv], dissolved in THF/MeOH (1:1, 1.5 mL, 0.1 M], at 0 °C under argon and stirring, was added NaH (6.6 mg, 0.17 mmol, 1.1 equiv, 60% in oil]. After 4 h, the ice bath was removed and cyanamide (9.5 mg, 0.23 mmol, 1.5 equiv] was added and the mixture stirred for a further 16 h. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt/MeOH] to yield 32 mg of N'-cyano-6-(4-cyclohexylphenoxy]nicotinimidamide (67%].

MS: m/z [M+H] ⁺ , calc for [C ₂₀ H ₂₂ N ₃ O] ⁺ = 320.18; found 320.27

^! H-NMR (300 MHz, DMSO-d ₆ ) d 7.79 (d,/ = 8.9 Hz, 2H], 7.25 - 7.17 (m, 2H], 7.07 - 6.94 (m, 4H], 3.83 (s, 2H), 2.63 - 2.41 (m, 1H], 1.94 - 1.55 (m, 5H], 1.48 - 1.16 (m, 5H]. ¹³ C-NMR (75 MHz, DMSO-d ₆ ] d 152.9, 144.9, 129.3, 129.3, 128.4, 124.4, 120.1, 117.4, 116.4, 113.3, 77.5, 44.0, 34.6, 26.9, 26.1.

XPW-0902:N-(l-(4-(4-((3r,5r,7r]-adamantan-l-yl]phenoxy]ph enyl]-2,2,2-trifluoroethy l]-2-methylpropane-2-sulfinamide

(3r,5r,7r]-l-(4-(4-bromophenoxy]phenyl]adamantane (100 mg, 0.26 mmol, 1 equiv] was dissolved in dry THF (1.3 mL, 0.2 M] under argon and stirring and the resulting solution was cooled to -78 °C with a dry ice/acetone bath. ⁿ BuLi (0.11 mL, 0.26 mmol, 1.0 equiv, 2.3 M in pentane] was then added dropwise and the mixture left to stir at that temperature for 30 min then at -50 °C for another 30 min. The mixture was then cooled back down to -78 °C. A solution of 2-methyl-N-(2,2,2-trifluoroethylidene]propane-2- sulfinamide (79 mg, 0.39 mmol, 1.5 equiv] in THF (0.39 mL, 1 M] was added dropwise and the reaction was stirred 1 hour before allowed to return to room temperature slowly overnight. The reaction was then partitioned between AcOEt and NH ₄ CI aq sat., the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S0 ₄ , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O ₂ , gradient petroleum ether/AcOEt] to yield 81 mg of N-(l-(4-(4-((3r,5r,7r]-adamantan-l- yl]phenoxy]phenyl]-2,2,2-trifluoroethyl]-2-methylpropane-2-s ulfinamide (62%].

MS: m/z [M+H] ⁺ , calc for [C ₂ sH ₃₅ F ₃ N0 ₂ S] ⁺ = 506.23; found 506.70

NMR (400 MHz, CDC1 ₃ ] d 7.38 - 7.32 (m, 4H], 7.03 - 6.95 (m, 4H], 4.83 (qd = 7.1, 3.5 Hz, 1H], 3.88 (d J = 3.5 Hz, 1H], 2.10 (p = 3.5 Hz, 3H], 1.91 (dj = 2.9 Hz, 6H], 1.83 - 1.68 (m, 6H], 1.23 (s, 9H]

¹³ C NMR (101 MHz, CDCI ₃ ] d 159.29, 153.59, 147.36, 130.78, 126.31, 125.24, 124.53 (qj = 281.3 Hz], 119.39, 117.93, 59.87 (q,/ = 30.4 Hz], 56.31, 43.33, 36.76, 35.91, 28.95, 22.41.

¹⁹ F NMR (376 MHz, CDCI ₃ ] d -74.56 (d J = 7.2 Hz]

XPW-30S2 3-(6-(4-((adamantan-l-yl]phenoxy]pyridin-3-yl]oxetan-3-amine

To a solution of N-(3-(4-(4-((3r,5r,7r]-adamantan-l-yl]phenoxy]phenyl]oxetan- 3-yl]-2- methylpropane-2-sulfinamide (31 mg, 0.065 mmol, 1 equiv] in THF (0.32 mL, 0.2 M] was added HC1 (0.8 mL, 0.5 M in MeOH, 6 equiv] and the reaction was left to stir till completion. The reaction was then partitioned between AcOEt and NaHC0 ₃ aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over NazSC , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiOz, gradient DCM/MeOH] to yield 17.4 mg of 3-(6-(4-((adamantan-l-yl]phenoxy]pyridin-3-yl]oxetan-3-amine [71%].

MS: m/z [M+H] ⁺ , calc for [Cz^zgNzOz]* = 377.22; found 377.34

^! H-NMR, [300 MHz, DMSO-d ₆ ] d 8.33 (dd,/ = 2.6, 0.7 Hz, 1H], 8.02 (dd = 8.6, 2.6 Hz,

1H], 7.50 - 7.36 (m, 2H], 7.14 - 6.96 (m, 3H], 4.70 (d,/ = 6.3 Hz, 2H], 4.64 (d J = 6.3 Hz, 2H], 2.65 [brs, 2H], 2.18 - 1.99 (m, 3H], 1.96 - 1.83 (m, 6H], 1.75 (s, 6H]

¹³ C-NMR, [75 MHz, DMS0-d6] d 162.6, 152.3, 147.4, 144.9, 138.0, 136.4, 126.4, 121.0, 111.3, 85.7, 57.6, 43.2, 36.6, 35.9, 28.8.

XPW-4642 N-(l-(4-(4-((3r,5r,7r]-adamantan-l-yl]phenoxy]phenyl)-

2,2,2-trifluoroethyl]-N,2-dimethylpropane-2-sulfinamide

To a solution of N-(l-(4-(4-((3r,5r,7r]-adamantan-l-yl]phenoxy]phenyl]-2,2,2- trifluoroethyl]-2-methylpropane-2-sulfinamide (360 mg, 0.71 mmol, 1 equiv] in THF (7.2 mL, 0.1 M] was added CS2CO3 (464 mg, 1.42 mmol, 2 equiv]. After 30 min, iodomethane (0.089 mL, 1.42 mmol, 2 equiv] was added. The mixture then heated for a further 16 h at 50 °C. The reaction was then partitioned between AcOEt and water. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over NazSC , filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiOz, gradient petroleum ether/AcOEt] to yield 300 mg of N-(l-(4-(4-((3r,5r,7r]-adamantan-l- yl]phenoxy]phenyl]-2,2,2-trifluoroethyl]-N,2-dimethylpropane -2-sulfinamide (81%].

MS: m/z [M+H] ⁺ , calc for [Cz9H37F3NOzS] ⁺ = 520.25; found 520.69

NMR (400 MHz, CDCI ₃ ] d 7.42 (d,/ = 8.6 Hz, 2H], 7.37 - 7.32 (m, 2H], 7.02 - 6.96 (m, 4H], 4.92 (q = 8.6 Hz, 1H], 2.71 (s, 3H], 2.11 (s, 3H], 1.91 (d = 2.9 Hz, 6H], 1.85 - 1.71 (m, 6H], 1.20 (s, 9H]

¹⁹ F NMR (376 MHz, CDCI ₃ ) d -67.23 (d = 8.2 Hz]

XPW-0028: l-(4-(4-((3r,5r,7r]-adamantan-l-yl]phenoxy]phenyl]-2,2,2-tri fluoro-

N-methylethan- 1-amine hydrochloride

To N-(l-(4-(4-((3r,5r,7r]-adamantan-l-yl]phenoxy]phenyl]-2,2,2- trifluoroethyl]-N,2- dimethylpropane-2-sulfinamide (300 mg, 0.58 mmol, 1 equiv], dissolved in THF (5.8 mL, 0.1 M] was added HC1 (2.3 mL, 1.15 mmol, 0.5 M in MeOH, 2 equiv] and the reaction was left to stir till completion. Then either the reaction was evaporated to dryness to yield 255 mg of l-(4-(4-((3r,5r,7r)-adamantan-l-yl)phenoxy)phenyl)-2,2,2-tri fluoro-N- methylethan-1 -amine as HC1 salt (Quantitative).

MS: m/z [M+H] ⁺ , calc for [C25H29F ₃ NO] ⁺ = 416.22; found 416.69

NMR (400 MHz, CDC1 ₃ ) d 11.04 (brs, 2H), 7.62 (d = 8.5 Hz, 2H), 7.43 - 7.33 (m, 2H), 7.08 (d J = 8.4 Hz, 2H), 7.05 - 6.96 (m, 2H), 4.71 - 4.36 (m, 1H), 2.69 (s, 3H), 2.14 (s, 3H), 1.94 (d = 2.9 Hz, 6H), 1.88 - 1.73 (m, 6H).

XPW-0182:

N-(l-(4-(4-((3r,5r,7r)-adamantan-l-yl)phenoxy)phenyl)-2,2,2- trifluoroethyl)-N-methyl hydroxylamine

To l-(4-(4-((3r,5r,7r)-adamantan-l-yl)phenoxy)phenyl)-2,2,2-tri fluoro-

N-methylethan- 1-amine hydrochloride [50 mg, 0.12 mmol, 1 equiv) in DCM (1.2 mL, 0.1 M) was added mCPBA (35 mg, 0.144 mmol, 70%, 1.2 equiv) and the mixture was stirred at room temperature for 30 min. The reaction mixture was then partitioned between AcOEt and aq. sat. NaHC03, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient petroleum ether/AcOEt) to yield 44.5 mg of N-(l-(4-(4-((3r,5r,7r)- adamantan-l-yl)phenoxy)phenyl)-2,2,2-trifluoroethyl)-N-methy lhydroxylamine (86%). ⁱ H NMR (400 MHz, CDC1 ₃ ) d 7.41 - 7.33 (m, 4H), 7.05 - 6.96 (m, 4H), 4.32 (q ,J = 7.6 Hz, 1H), 2.87 (s, 3H), 2.16 - 2.07 (m, 3H), 1.92 (d,/ = 2.9 Hz, 6H), 1.85 - 1.67 (m, 6H).

¹⁹ F NMR (376 MHz, CDC1 ₃ ) d -67.82 (d J = 7.5 Hz).

«C NMR (101 MHz, CDCI ₃ ) d 159.24, 153.61, 147.38, 131.35, 126.33, 124.40, 124.18 (q = 282.5 Hz), 119.37, 117.73, 74.70 (q,/ = 29.0 Hz), 50.31, 43.34, 36.76, 35.92, 28.96.

XPW-0042: l-(4-(4-((3r,5r,7r)-adamantan-l-yl)phenoxy)phenyl)-2,2,2-tri fluoro-N,N- dimethylethan-1 -amine

To l-(4-(4-((3r,5r,7r)-adamantan-l-yl)phenoxy)phenyl)-2,2,2-tri fluoro-

N-methylethan- 1-amine hydrochloride (20 mg, 0.05 mmol, 1 equiv) in acetonitrile (0.25 mL, 0.2 M) was added formaldehyde (0.025 mL, 0.29 mmol, 6 equiv, 37% w/w in water) followed by NaBHsCN (6.1 mg, 0.10 mmol, 2 equiv). The reaction mixture was stirred till completion before being partitioned between AcOEt and aq. sat. NaHC03, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (S1O2, gradient DCM/MeOH) to yield 15 mg of l-(4-(4-((3r,5r,7r)-adamantan-l-yl)phenoxy)phenyl)-2,2,2-tri fluoro-N,N- dimethylethan-1 -amine (75%).

MS: m/z [M+H] ⁺ , calc for [C ₂ 6H3iF3NO] ⁺ = 430.27; found 430.71

NMR (400 MHz, CDC1 ₃ ) d 7.39 - 7.28 (m, 4H), 7.04 - 6.93 (m, 4H), 3.95 (q,/ = 8.7 Hz, 1H), 2.36 (s, 6H), 2.10 (s, 3H), 1.91 (d,/ = 2.9 Hz, 6H), 1.85 - 1.69 (m, 6H).

¹⁹ F NMR (376 MHz, CDCI3) d -67.30.

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

To a stirred solution under argon of 4-(4-cyclohexylphenoxy)benzaldehyde (50 mg, 0.18 mmol, 1 equiv) in toluene (0.9 mL, 0.2 M) was added dimethylamine (0.18 mL, 0.36 mmol, 2 equiv) followed by TMSCN (0.05 mL, 0.36 mmol, 2 equiv) and the reaction was stirred for 16 h. The reaction was then partitioned between AcOEt and NaHCC aq sat. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na ₂ S04, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (Si0 ₂ , gradient petroleum ether/AcOEt) to yield 29 mg of 2-(4-(4-cyclohexylphenoxy)phenyl)- 2-(dimethylamino)acetonitrile (48%).

MS: m/z [M+H] ⁺ , calc for [C ₂₂ H ₂₇ N ₂ 0] ⁺ = 335.21; found 335.31

^! H-NMR, (300 MHz, CDC1 ₃ ) d 7.46 - 7.32 (m, 2H), 7.16 - 7.07 (m, 2H), 6.99 - 6.82 (m,

4H), 4.75 (s, 1H), 2.43 (ddt = 11.7, 8.2, 5.0 Hz, 1H), 2.27 (s, 6H), 1.87 - 1.61 (m, 5H),

1.42 - 1.24 (m, 5H).

«C NMR (75 MHz, CDC1 ₃ ) d 158.5, 154.2, 143.8, 129.3, 128.1, 119.3, 118.3, 115.0, 62.5, 43.9, 41.7, 34.6, 26.9, 26.1.