NOVEL AROMATIC MOLECULES

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:

embedded image

- R¹=C₁-C₁₂preferably C₄-C₁₂alkyl, C₂-C₁₂preferably C₄-C₁₂alkenyl, C₂-C₁₂preferably C₄-C₁₂alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, —OC₁—C₁₂preferably —OC₃—C₁₂alkyl, —OC₂—C₁₂preferably —OC₃—C₁₂alkenyl, —OC₂—C₁₂preferably —OC₃—C₁₂alkynyl, —OC₃—C₈cycloalkyl, —OC₅—C₈cycloalkenyl, —OC₅—C₁₂bicycloalkyl, —OC₇—C₁₂bicycloalkenyl, —OC₈—C₁₄tricycloalkyl, —SC₁—C₁₂preferably —SC₃—C₁₂alkyl, —SC₂—C₁₂preferably —SC₃—C₁₂alkenyl, —SC₂—C₁₂preferably —SC₃—C₁₂alkynyl, —SC₃—C₈cycloalkyl, —SC₅—C₈cycloalkenyl, —SC₅—C₁₂bicycloalkyl, —SC₇—C₁₂bicycloalkenyl, —SC₈—C₁₄tricycloalkyl, —NHR⁶or —NR⁶R⁷wherein R⁶and R⁷are independently from each other selected from: C₁-C₁preferably C₃-C₁₂alkyl, C₂-C₁₂preferably C₃-C₁₂alkenyl, C₂-C₁₂preferably C₃-C₁₂alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, or wherein R⁶can form a ring structure together with R⁷wherein 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 O, 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 O, S and N;
- wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R¹, R⁶and R⁷are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, ═O, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, linear or branched —OC₁—C₅alkyl such as —OCH₃, —OC₃—C₈cycloalkyl such as —O(cyclopropyl), linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₈cycloalkyl);
- wherein when an alkyl, alkenyl and alkynyl residue contained in the definitions of R¹, R⁶and R⁷is substituted with one or more substituents being ═O, such substitution with ═O cannot result in one of the groups selected from C═O, S═O and N═O 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 R¹, R⁶and R⁷are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, ═O, linear or branched C₁-C₅alkyl such as —CH₃, linear or branched —OC₁—C₅alkyl such as —OCH₃, linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₅cycloalkyl);
- wherein all alkyl, alkenyl and alkynyl residues contained in the definitions of R¹, R⁶and R⁷can contain one or more heteroatoms independently selected from O, 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 O, S and N, and wherein such replacement additionally cannot result in one of the groups selected from C═O, S═O and N═O directly bound to an aromatic ring;
- wherein all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R¹, R⁶and R⁷can contain one or more heteroatoms independently selected from O, 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 O, S and N;
- wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R¹, R⁶and R⁷can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
- wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;
- and wherein R¹is 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, —CF₃, —CF₂CF₃, —(CF₂)₂CF₃, —CH(CF₃)₂, —CH₂SCH₃, —CH₂CH₂SCH₃, —CH₂SCH₂CH₃, —CH₂CH₂SCH₂CH₃, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, propoxymethyl, dimethyl-aminomethyl, dimethyl-aminoethyl, diethyl-aminomethyl, ethyl-methyl-aminomethyl, cyclopropyl, methyl-cyclopropyl, ethyl-cyclopropyl, trifluoromethyl-cyclopropyl, perfluoroethyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 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, —O(adamantyl), oxa-azabicyclononyl, N-methyloxa-azabicyclononyl, oxa-azabicycloheptyl, N-methyloxa-azabicycloheptyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, N,N-dimethyldiazabicyclooctyl, diazabicycloheptyl, N-methyldiazabicycloheptyl, N,N-dimethyldiazabicycloheptyl; 4-oxocyclohexyl; 3-oxocyclopentyl; 2-oxocyclobutyl, 4-oxobicyclo[4.1.0]heptan-1-yl
- and wherein R¹is even more preferably selected from C₄-C₁₂alkyl, C₄-C₁₂alkenyl, C₄-C₁₂alkynyl, cyclic, bicyclic and tricyclic residues, wherein the alkyl, alkenyl and alkynyl residues are preferably branched, including:

embedded image

R²-R⁵are independently from each other selected from —H, —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);

- wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R²-R⁵are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, —NHCH₃, —N(CH₃)₂;
- wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R²-R⁵can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, and wherein such a replacement cannot result in one of the groups selected from C═O and S═O directly bound to an aromatic ring;
- wherein R²-R³each are preferably —H, R⁴is preferably —H or —F, and R⁵is preferably —H, —F, —Cl, —Br, —CH₃, —CF₃, —CH═CH₂, —C≡CH, —CH₂OH, —CH₂NHCH₃, —OH, —OCH₃, —OCF₃, cyclopropyl, oxiranyl, —CH₂—N-morpholinyl, —C(CH₃)₃, —CH₂OCH₃, —NO₂, —CN, —NH₂, —N(CH₃)₂, —OCH(CH₃)₂, —CH₂NH₂, —CH₂N(CH₃)₂;
- wherein the six-membered aromatic ring, to which substituents R¹to R⁵are bound as defined in general formula (I), is preferably selected from:

embedded image

- X¹-X⁴are independently from each other selected from N, CR⁸, CR⁹, CR¹⁰, CR¹¹;
- R⁸-R¹¹are independently from each other selected from —H, —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
- wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R⁸-R¹¹are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, —NHCH₃, —N(CH₃)₂;
- wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R⁸-R¹¹can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom, and wherein such a replacement cannot result in one of the groups selected from C═O and S═O directly bound to an aromatic ring;
- wherein R⁸-R¹¹are preferably selected from —H, —F, —Cl, —Br, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃, cyclopropyl, oxiranyl, —C(CH₃)₃, —N(CH₃)₂, —NH₂, —CN, —CH₂OCH₃, —OCH(CH₃)₂, —CH₂NH₂, —CH₂N(CH₃)₂, —CH₂OH, —NO₂, —CH₂—N-morpholinyl;
- and wherein the six-membered aromatic ring containing X¹-X⁴as defined in general formula (I) is preferably selected from:

embedded image

- wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R²-R⁵and R⁸-R¹¹can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
- Y=—H, —OH, linear or branched —OC₁—C₆alkyl, linear or branched —OC₂—C₆alkenyl, linear or branched —OC₂—C₆alkynyl, —OC₃—C₆cycloalkyl, —SH, linear or branched —SC₁—C₆alkyl, linear or branched —SC₂—C₆alkenyl, linear or branched —SC₂—C₆alkynyl, —SC₃—C₆cycloalkyl, aromatic and heteroaromatic residues preferably six-membered aromatic cycles and five- to six-membered heteroaromatic cycles;
- wherein all aromatic and heteroaromatic residues contained in the definition of Y are linked through an —O—, or an —S—, or an —O—CH₂—, or an —O—CH₂—CH₂—, or an —S—CH₂—, or an —S—CH₂—CH₂—, or an —O—CH₂—O—, or an —S—CH₂—O—, or an —O—CH₂—NH—, or an —S—CH₂—NH— linker to the carbon atom to which Y is bound; wherein the said linkers are connected by their heteroatoms to the carbon atom to which Y is bound;
- wherein the said linkers 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, ═O, linear or branched C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, cyclopropyl, linear or branched —OC₁—C₃alkyl such as —OCH₃, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
- wherein all 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-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, cyclopropyl, linear or branched —OC₁—C₃alkyl such as —OCH₃, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
- wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definition of Y are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, ═O, linear or branched C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, cyclopropyl, linear or branched —OC₁—C₃alkyl such as —OCH₃, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
- wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and heteroaromatic residues 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 the said linkers contained in the definition of Y can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
- wherein Y is preferably —H, —OH, —OCH₃, —OCH₂CH₃, —O(cyclopropyl), —OC₆H₅, —OCH₂C₆H₅, —SH, —SCH₃, —SCH₂CH₃, —S(cyclopropyl), —SCH₂C₆H₅, —OS(O)C(CH₃)₃, —OS(O)₂CH₃, —OS(O)₂CF₃, —OS(O)C₆H₄CH₃;
- Z¹and Z²are selected from the following groups:

embedded image

- wherein Z¹is —H, and wherein Z²is —OH, linear or branched —OC₁—C₆alkyl, linear or branched —OC₂—C₆alkenyl, linear or branched —OC₂—C₆alkynyl, —OC₃—C₆cycloalkyl, —SH, linear or branched —SC₁—C₆alkyl, linear or branched —SC₂—C₆alkenyl, linear or branched —SC₂—C₆alkynyl, —SC₃—C₆cycloalkyl, aromatic and heteroaromatic residues preferably five- to six-membered aromatic cycles and five- to six-membered heteroaromatic cycles, —OS(O)R¹²and —OS(O)₂R¹²wherein R¹²is selected from linear or branched C₁-C₆alkyl, linear or branched C₂-C₆alkenyl, linear or branched C₂-C₆alkynyl, C₃-C₆cycloalkyl, C₅-C₆cycloalkenyl, —CF₃, and —C₆H₄CH₃(general formula Ia);
- wherein all aromatic and heteroaromatic residues contained in the definition of Z²are linked through an —O—, or an —S—, or an —O—CH₂—, or an —O—CH₂—CH₂—, or an —S—CH₂—, or an —S—CH₂—CH₂—, or an —O—CH₂—O—, or an —S—CH₂—O—, or an —O—CH₂—NH—, or an —S—CH₂—NH— linker to the carbon atom to which Z²is bound; wherein the said linkers are connected by their heteroatoms to the carbon atom to which Y is bound;
- wherein the said linkers contained in the definition of Z²are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, ═O, linear or branched C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, cyclopropyl, linear or branched —OC₁—C₃alkyl such as —OCH₃, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
- wherein all aromatic and heteroaromatic residues contained in the definition of Z²are 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-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, cyclopropyl, linear or branched —OC₁—C₃alkyl such as —OCH₃, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
- wherein all alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl residues contained in the definition of Z²are linear or branched, and are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, ═O, linear or branched C₁-C₃alkyl, C₂-C₃alkenyl, C₂-C₃alkynyl, cyclopropyl, linear or branched —OC₁—C₃alkyl such as —OCH₃, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
- wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and heteroaromatic residues contained in the definition of Z²can 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 the said linkers contained in the definition of Z²can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
- wherein Z²is preferably —OH, —OCH₃, —OCH₂CH₃, —O(cyclopropyl), —OC₆H₅, —OCH₂C₆H₅and —SCH₂CH₃;
- or wherein Z¹and Z²are together ═O or ═S, (general formula Ib);
- wherein Z¹and Z²are together preferably ═O
- or wherein Z¹and Z²form 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 O, S and N in replacement of a carbon atom; wherein all rings are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, ═O, —CH₃and —CF₃, tert-butyloxycarbonyl, and —CH₂C₆H₅;
- wherein Z¹and Z²form together preferably a cyclic residue including the carbon atom to which they are bound if Y is different from —H; 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 O, S and N in replacement of a carbon atom; wherein all rings are unsubstituted or substituted with one or more substituents independently selected from: —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, ═O, —CH₃, tert-butyloxycarbonyl, —CF₃and —CH₂C₆H₅;
- and wherein Z¹and Z²form 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, thietanyl, thiazolidinyl, methylthiazolidinyl, thiazolidine-dionyl, methylthiazolidine-dionyl, oxazolidinyl, methyloxazolidinyl, oxazolidine-dionyl, methyloxazolidine-dionyl and wherein this cyclic residue is optionally substituted preferably with —F, —OH, —OCH₃, —NH₂, —NHCH₃, —N(CH₃)₂, ═O, —CH₃, tert-butyloxycarbonyl, —CF₃and —CH₂C₆H₅:

embedded image

- wherein all cyclic residues contained in the definitions of Z¹and Z²can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated.

Following preferred definitions of R¹-R¹², X¹-X⁴, Z¹, Z²and 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) R¹preferably contains four or more preferably six or more and even more preferably seven or more carbon atoms;
- 2) R¹is preferably selected from branched alkyl, alkenyl and alkynyl residues; 3) R¹is preferably selected from cyclic, bicyclic and tricyclic structures, wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;
- 4) R¹preferably contains no heteroatom;
- 5) R¹is preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and most preferably adamantyl, e.g. 1-adamantyl and 2-adamantyl;
- 6) R¹preferably 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 R¹;
- 7) R¹is preferably selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, azaadamantyl and —O(adamantyl);
- 8) preferably two, or more preferably three of the substituents independently selected from R²-R⁵are —H, i.e. preferably two and more preferably one of the substituents independently selected from R²-R⁵are different from —H;
- 9) in the case that two of the substituents independently selected from R²-R⁵are 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 —NO₂and more preferably different from each other;
- 10) the composition of ring atoms as defined by X¹-X⁴is preferably selected from the cases that all of X¹-X⁴are independently selected from CR⁸, CR⁹, CR¹⁰, CR¹¹, or that one of X¹-X⁴is N and the other three are independently selected from CR⁸, CR⁹, CR¹⁰, CR¹¹, or that two of X¹-X⁴are N and the other two are independently selected from CR⁸, CR⁹, CR¹⁰, CR¹¹; i.e. the aromatic or hetoromatic ring is selected from benzene, pyridine, pyrimidine, pyridazine and pyrazine;
- 11) preferably two, or more preferably three of the substituents independently selected from R⁸-R¹¹are —H, i.e. preferably two and more preferably one of the substituents independently selected from R⁸-R¹¹are different from —H;
- 12) in the case that two of the substituents independently selected from R⁸-R¹¹are 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 —NO₂and more preferably different from each other;
- 13) Y is preferably selected from —OH, —OCH₃and —OCH₂CH₃.

A preferred aspect of the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R¹is selected from residues as contained in the general definition of R¹, which contain four or more preferably six or more and even more preferably seven or more carbon atoms,

- and wherein R¹contains no heteroatom,
- and wherein R¹is even more preferably selected from cyclic, bicyclic and tricyclic structures
- and wherein R¹is even more preferably selected from cyclohexyl, norbornyl, bicyclooctyl, bicyclononyl, methylbicyclononyl, tricyclodecyl and adamantyl,
- and wherein R¹is most preferably adamantyl,
- and R²-R⁵, R⁸-R¹², X¹-X⁴, Z¹, Z²and 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 R¹is selected from residues as contained in the general definition of R¹, which contain four or more preferably six or more and even more preferably seven or more carbon atoms,

- and wherein R¹contains one or more preferably one to two heteroatoms independently selected from O, S and N in replacement of a carbon atom contained in R¹,
- and wherein R¹is even more preferably selected from cyclic, bicyclic and tricyclic structures, or wherein R¹is selected from residues containing cyclic, bicyclic and tricyclic structures,
- and wherein R¹is even more preferably selected from tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicycloheptyl, N-methylazabicycloheptyl, oxa-azabicycloheptyl, N-methyldiazabicycloheptyl, azabicyclooctyl, diazabicyclooctyl, N-methyldiazabicyclooctyl, oxa-azabicyclooctyl, azabicyclononyl, aza-adamantyl and —O(adamantyl),
- and wherein R¹is most preferably tetrahydropyranyl, N-methylpiperidinyl, morpholinyl, 4-oxocyclohexyl, azabicyclooctyl, aza-adamantyl and —O(adamantyl), and R²-R¹², X¹-X⁴, Z¹, Z²and 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.1 If Z¹and Z²are defined as in general formula (I) including their substitutions and preferred definitions, with the proviso that Z¹and Z²are different from being together ═O or ═S,
  - then R¹-R¹², X¹-X⁴, and Y are defined as in general formula (I) including their substitutions and preferred definitions.
- S.2 If Y is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that Y is different from —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then R¹-R¹², X¹-X⁴, Z¹and Z²are defined as in general formula (I) including their substitutions and preferred definitions.
- S.3 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then R¹=C₁-C₁₂preferably C₁-C₆alkyl, C₂-C₁₂preferably C₂-C₆alkenyl, C₂-C₁₂preferably C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, —OC₁—C₁₂preferably —OC₁—C₆alkyl, —OC₂—C₁₂preferably —OC₂—C₆alkenyl, —OC₂—C₁₂preferably —OC₂—C₆alkynyl, —OC₃—C₈cycloalkyl, —OC₅—C₈cycloalkenyl, —OC₅—C₁₂bicycloalkyl, —OC₇—C₁₂bicycloalkenyl, —OC₈—C₁₄tricycloalkyl, —SC₁—C₁₂preferably —SC₁—C₆alkyl, —SC₂—C₁₂preferably —SC₂—C₆alkenyl, —SC₂-C₁₂preferably —SC₂—C₆alkynyl, —SC₃—C₈cycloalkyl, —SC₅—C₈cycloalkenyl, —SC₅—C₁₂bicycloalkyl, —SC₇—C₁₂bicycloalkenyl, —SC₈—C₁₄tricycloalkyl, —NHR⁶or —NR⁶R⁷wherein R⁶and R⁷are independently from each other selected from: C₁-C₁₂preferably C₁-C₆alkyl, C₂-C₁₂preferably C₂-C₆alkenyl, C₂-C₁₂preferably C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, or wherein R⁶can form a ring structure together with R⁷wherein 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 O, S and N in replacement of a carbon atom contained in the ring structure;
  - wherein all C₁-C₁₂alkyl, C₂-C₅alkenyl, C₂-C₅alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, 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, —NH₂, —NO₂, ═O, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl including norbornyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl including adamantyl, linear or branched —OC₁—C₅alkyl such as —OCH₃, —OC₃—C₈cycloalkyl such as —O(cyclopropyl), linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₈cycloalkyl); and wherein all said C₁-C₁₂alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, 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 C₉-C₁₂alkenyl, C₉-C₁₂alkynyl, —OC₁—C₁₂alkyl, —OC₂—C₁₂alkenyl, —OC₂—C₁₂alkynyl, —SC₁—C₁₂alkyl, —SC₂—C₁₂alkenyl, —SC₂—C₁₂alkynyl, and all residues contained in the definition of R⁶and R⁷are 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, —NH₂, —NO₂, ═O, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, linear or branched —OC₁—C₅alkyl such as —OCH₃, —OC₃—C₈cycloalkyl such as —O(cyclopropyl), linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₈cycloalkyl);
  - wherein all —OC₃—C₈cycloalkyl, —OC₅—C₈cycloalkenyl, —SC₃—C₈cycloalkyl, —SC₅—C₈cycloalkenyl residues, and all cycloalkyl and cycloalkenyl residues contained in the definition of R⁶and R⁷and 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 R¹, R⁶and R⁷, 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, —NH₂, —NO₂, ═O, linear or branched C₁-C₅alkyl such as —CH₃, linear or branched —OC₁—C₅alkyl such as —OCH₃, linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₈cycloalkyl);
  - wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R⁶and R⁷can 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 R¹can 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 —N₃if not explicitly contained in the definition of R¹;
  - wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R¹, R⁶and R⁷can be partially or fully halogenated, particularly fluorinated, more particularly perfluorinated;
  - wherein bicyclic and tricyclic residues include fused, bridged and spiro systems;
  - and then R²-R⁵, R⁸-R¹¹, and X¹-X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.4 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then R²is selected from —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, and C₃-C₄cycloalkyl residues are substituted with one or more substituents independently selected from —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein the C₅-C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R²can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and R³-R⁵are independently from each other selected from —H, —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R³-R⁵are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, —NHCH₃, —N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definitions of R³-R⁵can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹, R⁶-R¹¹, and X¹-X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.5 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X¹is CR⁸
  - and R⁸is selected from —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, and C₃-C₄cycloalkyl residues are substituted with one or more substituents independently selected from —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein the C₅-C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹, and X²-X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.6 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X²is CR⁸
  - and R⁸is selected from —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, and C₃-C₄cycloalkyl residues are substituted with one or more substituents independently selected from —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein the C₅-C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹, X¹, X³and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.7 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X³is CR⁸
  - and R⁸is selected from —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, and C₃-C₄cycloalkyl residues are substituted with one or more substituents independently selected from —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein the C₅-C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹, X¹, X²and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.8 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X⁴is CR⁸
  - and R⁸is selected from —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, and C₃-C₄cycloalkyl residues are substituted with one or more substituents independently selected from —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein the C₅-C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH, —OCH₃, —OCF₃, —NH₂, —NHCH₃and —N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹and X¹-X³are defined as in general formula (I) including their substitutions and preferred definitions.
- S.9 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X¹, X²and X³are each N
  - and then R¹-R¹¹, and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.10 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X¹, X²and X⁴are each N
  - and then R¹-R¹¹, and X³are defined as in general formula (I) including their substitutions and preferred definitions.
- S.11 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X¹, X³and X⁴are each N
  - and then R¹-R¹¹, and X²are defined as in general formula (I) including their substitutions and preferred definitions.
- S.12 If Z¹and Z²are together ═O or ═S, and Y is —OH, or linear unsubstituted or branched unsubstituted —OC₁—C₆alkyl,
  - then X², X³and X⁴are each N
  - and then R¹-R¹¹, and X¹are defined as in general formula (I) including their substitutions and preferred definitions.
- S.13 If R¹is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R¹contains 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,
  - then R²-R¹², X¹-X⁴, Y, Z¹and Z²are defined as in general formula (I) including their substitutions and preferred definitions.
- S.14 If Z¹and Z²are defined as in general formula (I) including their substitutions and preferred definitions, with the proviso that Z¹and Z²are different from being together ═O,
  - then R¹-R¹², X¹-X⁴, and Y are defined as in general formula (I) including their substitutions and preferred definitions.
- S.15 If Y is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that Y is different from —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then R¹-R¹², X¹-X⁴, Z¹and Z²are defined as in general formula (I) including their substitutions and preferred definitions.
- S.16 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then R¹=C₁-C₁₂preferably C₁-C₆alkyl, C₂-C₁₂preferably C₂-C₆alkenyl, C₂-C₁₂preferably C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, —OC₁—C₁₂preferably —OC₁—C₆alkyl, —OC₂—C₁₂preferably —OC₂—C₆alkenyl, —OC₂—C₁₂preferably —OC₂—C₆alkynyl, —OC₃—C₈cycloalkyl, —OC₅—C₈cycloalkenyl, —OC₅—C₁₂bicycloalkyl, —OC₇—C₁₂bicycloalkenyl, —OC₈—C₁₄tricycloalkyl, —SC₁—C₁₂preferably —SC₁—C₆alkyl, —SC₂—C₁₂preferably —SC₂—C₆alkenyl, —SC₂—C₁₂preferably —SC₂—C₆alkynyl, —SC₃—C₈cycloalkyl, —SC₅—C₈cycloalkenyl, —SC₅—C₁₂bicycloalkyl, —SC₇—C₁₂bicycloalkenyl, —SC₈—C₁₄tricycloalkyl, —NHR⁶or —NR⁶R⁷wherein R⁶and R⁷are independently from each other selected from: C₁-C₁₂preferably C₁-C₆alkyl, C₂-C₁₂preferably C₂-C₆alkenyl, C₂-C₁₂preferably C₂-C₆alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, or wherein R⁶can form a ring structure together with R⁷wherein 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 O, S and N in replacement of a carbon atom contained in the ring structure;
  - wherein all C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl and C₈-C₁₄tricycloalkyl residues are linear or branched, and are substituted with one or more substituents, here referred to as side-substituents, independently selected from: —OH, —NH₂, —NO₂, ═O, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, linear or branched —OC₄—C₅alkyl, —OC₃—C₈cycloalkyl such as —O(cyclopropyl), linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₈cycloalkyl); and wherein all said C₁-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl and C₈-C₁₄tricycloalkyl residues can optionally contain in addition one or more substituents independently selected from —F, —Cl, —Br, —I, —CN, —NCO, —NCS;
  - and all —OC₁—C₁₂alkyl, —OC₂—C₁₂alkenyl, —OC₂—C₁₂alkynyl, —SC₁—C₁₂alkyl, —SC₂—C₁₂alkenyl, —SC₂—C₁₂alkynyl, and all alkyl, alkenyl and alkynyl residues contained in the definition of R⁶and R⁷are 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, —NH₂, —NO₂, ═O, C₃-C₈cycloalkyl, C₅-C₈cycloalkenyl, C₅-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, linear or branched —OC₁—C₅alkyl such as —OCH₃, —OC₃—C₈cycloalkyl such as —O(cyclopropyl), linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₈cycloalkyl);
  - wherein all —OC₃—C₈cycloalkyl, —OC₅—C₈cycloalkenyl, —OC₅—C₁₂bicycloalkyl, —OC₇—C₁₂bicycloalkenyl, —OC₈—C₁₄tricycloalkyl, —SC₃—C₈cycloalkyl, —SC₅—C₈cycloalkenyl, —SC₅—C₁₂bicycloalkyl, —SC₇—C₁₂bicycloalkenyl, —SC₈—C₁₄tricycloalkyl, residues, and all cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definition of R⁶and R⁷and 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, —NH₂, —NO₂, ═O, linear or branched C₁-C₅alkyl such as —CH₃, linear or branched —OC₁—C₅alkyl such as —OCH₃, linear or branched —NH(C₁-C₅alkyl), linear or branched —N(C₁-C₅alkyl)(C₁-C₅alkyl), —NH(C₃-C₈cycloalkyl) such as —NH(cyclopropyl), —N(C₃-C₈cycloalkyl)(C₃-C₈cycloalkyl), linear or branched —N(C₁-C₅alkyl)(C₃-C₈cycloalkyl);
  - wherein all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, bicycloalkenyl and tricycloalkyl residues contained in the definitions of R⁶and R⁷can 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 R¹can 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—C₃alkyl if not explicitly contained in the definition of R¹;
  - wherein bicyclic and tricyclic residues include fused, bridged and spiro systems; and then R²-R⁵, R⁸-R¹¹and X¹-X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.17 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then R²is selected from —F, —Cl, —Br, —I, —CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R²are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, —NHCH₃, —N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R²can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹, R³-R¹¹and X¹-X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.18 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X¹is CR⁸
  - and R⁸is selected from —Cl, —Br, —I, CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, NHCH₃, N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹and X²—X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.19 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X²is CR⁸
  - and R⁸is selected from —Cl, —Br, —I, CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, NHCH₃, N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹, X¹, X³and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.20 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X³is CR⁸
  - and R⁸is selected from —F, —Cl, —Br, —I, CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, NHCH₃, N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹, X¹, X²and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.21 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X⁴is CR⁸
  - and R⁸is selected from —F, —Cl, —Br, —I, CN, —NCO, —NCS, —OH, —NH₂, —NO₂, linear or branched C₁-C₄alkyl, linear or branched C₂-C₄alkenyl, linear or branched C₂-C₄alkynyl, C₃-C₆cycloalkyl, —CH₂(C₃-C₆cycloalkyl), linear or branched —OC₁—C₃alkyl, —O(cyclopropyl), linear or branched —NH(C₁-C₃alkyl), linear or branched —N(C₁-C₃alkyl)(C₁-C₃alkyl), —NH(cyclopropyl), —N(cyclopropyl)₂, linear or branched —N(C₁-C₃alkyl)(cyclopropyl);
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CH₃, —CF₃, —OH and —OCH₃, —OCF₃, —NH₂, NHCH₃, N(CH₃)₂;
  - wherein all alkyl, alkenyl, alkynyl and cycloalkyl residues contained in the definition of R⁸can contain one or more heteroatoms independently selected from O, S and N in replacement of a carbon atom;
  - and then R¹-R⁷, R⁹-R¹¹and X¹-X³are defined as in general formula (I) including their substitutions and preferred definitions.
- S.22 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X³is N
  - and then R¹-R¹¹, X¹, X²and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.23 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X⁴is N
  - and then R¹-R¹¹and X¹-X³are defined as in general formula (I) including their substitutions and preferred definitions.
- S.24 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X¹and X²are each N
  - and then R¹-R¹¹, X³and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.25 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X¹and X³are each N
  - and then R¹-R¹¹, X²and X⁴are defined as in general formula (I) including their substitutions and preferred definitions.
- S.26 If Z¹and Z²are together ═O or ═S, and Y is —OH, or —OC₁—C₆alkyl, or —OC₃—C₆cycloalkyl,
  - wherein all said —OC₁—C₆alkyl residues are linear or branched, and unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I and —OC₁—C₃alkyl,
  - and wherein all said —OC₃—C₆cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl and cycloalkyl residues can optionally be halogenated or perhalogenated,
  - then X¹and X⁴are each N
  - and then R¹-R¹¹, X²and X³are defined as in general formula (I) including their substitutions and preferred definitions.
- S.27 If R¹is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R¹is different from C₃-C₈cycloalkyl,
  - wherein the said C₃-C₈cycloalkyl residues are unsubstituted or substituted with one or more substituents independently selected from —F, —Cl, —Br, —I, —CN, —NCO, —NCS, C₁-C₃alkyl and —OC₁—C₃alkyl,
  - wherein the said C₃-C₈cycloalkyl residues can optionally be perhalogenated
  - and wherein the said C₃-C₈cycloalkyl 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-C₁₂alkyl, C₂-C₁₂alkenyl, C₂-C₁₂alkynyl, C₃-C₈cycloalkyl or C₅-C₈cycloalkenyl,
  - 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—C₃alkyl,
  - 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-C₃alkyl and —OC₁—C₃alkyl,
  - and wherein all said alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl residues can optionally be perhalogenated,
  - then R²-R¹², X¹-X⁴, Y, Z¹and Z²are 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 R¹is adamantyl,

- and wherein Z¹and Z²are defined as in general formula (I), including general formula (Ta), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions, with the proviso that in the case of general formula (Ib) Z¹and Z²are together different from ═O,
- and wherein R¹²is defined as in general formula (Ta), including the substitutions and preferred definitions,
- and wherein R²-R⁵, R⁸-R¹¹, X¹-X⁴and Y are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (I-1):

embedded image

- and wherein the compounds of structure (I-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 XPA-0014, XPA-0140, XPA-0154, XPA-0168, XPA-0182, XPA-0196, XPA-0210, XPA-0238, XPA-0518, XPA-0644, XPA-0658, XPA-0672, XPA-1278, XPA-1280, XPA-1308, XPA-1311, XPA-1312, XPA-1316, XPA-1318, XPA-1326, XPA-1327, XPA-1328, XPA-1329, XPA-1330, XPA-1331, XPA-1333, XPA-1336 and XPA-1338.

In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R¹is adamantyl, and wherein X²is CR⁸, and R⁸is —Br,

- and wherein Z¹and Z²are defined as in general formula (I), including general formula (Ta), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions,
- and wherein R¹²is defined as in general formula (Ta), including the substitutions and preferred definitions,
- and wherein R²-R⁵, R⁹-R¹¹, X¹, X³, X⁴and Y are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (I-2):

embedded image

- and wherein the compounds of structure (I-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 XPA-1299, XPA-1300, XPA-1320, XPA-1321, XPA-1326 and XPA-1327.

In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, wherein R¹is adamantyl,

- and wherein R⁵is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that R⁵is different from —H,
- and wherein Z¹and Z²are defined as in general formula (I), including general formula (Ta), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions,
- and wherein R¹²is defined as in general formula (Ta), including the substitutions and preferred definitions,
- and wherein R²-R⁴, R⁸-R¹¹, X¹-X⁴and Y are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (I-3):

embedded image

- and wherein the compounds of structure (I-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 XPA-1270, XPA-1272, XPA-1274, XPA-1276, XPA-1278, XPA-1280, XPA-1284 and XPA-1286.

In a further certain embodiment, the present invention relates to compounds of general formula (I) and salts and solvates thereof, and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, and wherein R¹is selected from unsubstituted or substituted C₆-C₈cycloalkyl, C₆-C₈cycloalkenyl, C₆-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, wherein optionally any carbon atom contained in R¹can be independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),

- and wherein Z¹and Z²are defined as in general formula (I), including general formula (Ta), general formula (Ib) and general formula (Ic), including the substitutions and preferred definitions, wherein in the case of general formula (Ib) Z¹and Z²are together different from ═O,
- 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 R¹²is defined as in general formula (Ta), including the substitutions and preferred definitions,
- and wherein R²-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (I-4):

embedded image

- and wherein the compounds of structure (I-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 XPA-0006, XPA-0007, XPA-0008, XPA-0009, XPA-0014, XPA-0132, XPA-0140, XPA-0146, XPA-0154, XPA-0160, XPA-0168, XPA-0174, XPA-0182, XPA-0188, XPA-0196, XPA-0210, XPA-0230, XPA-0238, XPA-0510, XPA-0518, XPA-0644, XPA-0658, XPA-0672, XPA-1266, XPA-1277, XPA-1278, XPA-1279, XPA-1280, XPA-1281, XPA-1282, XPA-1293, XPA-1296, XPA-1297, XPA-1308, XPA-1309, XPA-1310, XPA-1311, XPA-1312, XPA-1313, XPA-1315, XPA-1316, XPA-1317, XPA-1318, XPA-1325, XPA-1326, XPA-1327, XPA-1328, XPA-1329, XPA-1330, XPA-1331, XPA-1333, XPA-1336, XPA-1338 and XPA-1884.

In a further certain embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Y and Z¹are each —H, and wherein X¹is CR¹¹, and X²is CR⁸, and X³is CR⁹, and X⁴is CR¹⁰,

- and wherein R¹is selected from unsubstituted or substituted C₆-C₈cycloalkyl, C₆-C₈cycloalkenyl, C₆-C₁₂bicycloalkyl, C₇-C₁₂bicycloalkenyl, C₈-C₁₄tricycloalkyl, wherein optionally any carbon atom in R¹can be independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),
- and wherein R⁵is defined as in general formula (I) including the substitutions and preferred definitions, wherein R⁵is in ortho-position relative to the ether bond, with the proviso that R⁵is different from —H,
- and wherein R¹²is defined as in general formula (Ia), including the substitutions and preferred definitions,
- and R²-R⁴, R⁶-R¹¹and Z²are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ia-1):

embedded image

- and wherein the compounds of structure (Ia-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, and cancer of the neuroendocrine system.

Examples are compounds XPA-1277, XPA-1278, XPA-1279, XPA-1280, XPA-1293, XPA-1296 and XPA-1297.

In a further certain embodiment, the present invention relates to compounds of general formula (Ia) and salts and solvates thereof, wherein Y and Z¹are each —H, and wherein X¹is N, and X²is CR⁸, and X³is CR⁹, and X⁴is CR¹⁰,

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), optionally with the proviso that R¹including any substituent contains no heteroatom or one or two heteroatoms independently selected from O, S, N,
- and wherein Z²and R¹²are defined as in general formula (Ia), including the substitutions and preferred definitions,
- and wherein R²-R¹⁰are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ia-2):

embedded image

- and wherein the compounds of structure (Ia-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, and cancer of the neuroendocrine system.

Examples are compounds XPA-0510, XPA-0518, XPA-1281, XPA-1327, XPA-1333, XPA-1338, and XPA-1884.

In a further certain embodiment, the present invention relates to compounds of general formula (Tb) and salts and solvates thereof, wherein Z¹and Z²are together ═O and Y is —OH, and wherein R², R³and R⁴are each —H,

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹contains five or more, preferably six or more carbon atoms, and R¹including any substituent contains no atom different from C and H,
- and wherein R⁵is defined as in general formula (I) including the substitutions and preferred definitions, wherein R⁵is in ortho-position relative to the ether bond, with the proviso that R⁵is different from —H,
- and R⁸-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-1):

embedded image

- and wherein the compounds of structure (Tb-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, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas and cancer of the tongue.

Examples are compounds XPA-1273, XPA-1274, XPA-1275, XPA-1276 and XPA-1292.

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹contains nine or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),
- and wherein R⁵is defined as in general formula (I) including the substitutions and preferred definitions, wherein R⁵is in ortho-position relative to the ether bond, with the proviso that R⁵is different from —H,
- and R⁶-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-2):

embedded image

- 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, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas and cancer of the tongue.

Examples are compounds XPA-1274 and XPA-1276.

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹is selected from cyclic, bicyclic and tricyclic structures, and wherein R¹contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),
- and wherein R⁵is defined as in general formula (I) including the substitutions and preferred definitions, and wherein R⁵is in ortho-position relative to the ether bond, with the proviso that R⁵is different from —H,
- and R⁶-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-3):

embedded image

- and wherein the compounds of structure (Ib-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, hyperproliferative disorders and cancer including cancer of the haematopoietic and haematologic system such as leukemias and lymphomas and cancer of the tongue.

Examples are compounds XPA-1273, XPA-1274, XPA-1275, XPA-1276 and XPA-1292.

In a further certain embodiment, the present invention relates to compounds of general formula (Tb) and salts and solvates thereof, wherein Z¹and Z²are together ═O, and wherein X⁴is N, and wherein Y is defined as in general formula (I) including the substitutions and preferred definitions, wherein Y is different from —H,

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹is selected from cyclic, bicyclic and tricyclic structures or contains a cyclic, bicyclic or tricyclic structure, optionally with the proviso that R¹contains five 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 R²-R¹¹and X¹-X³are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-4):

embedded image

- 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 XPA-1302, XPA-1303, XPA-1304, XPA-1305, XPA-1306, XPA-1322, XPA-1323 and XPA-1324.

In a further certain embodiment, the present invention relates to compounds of general formula (Tb) and salts and solvates thereof, wherein Z¹and Z²are together ═O, and wherein X²is CR⁹and X³is CR¹⁰, and R⁹and R¹⁰are each —H, and wherein X⁴is CR⁸, and R⁸is defined as in general formula (I) including the substitutions and preferred definitions, wherein R⁸is different from —H,

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), and wherein R¹including any substituent contains no heteroatom or one, two or three heteroatoms independently selected from O, S, N,
- and wherein Y is defined as in general formula (I) including the substitutions and preferred definitions, with the proviso that Y is different from —H,
- and wherein R²-R⁷, R¹¹and X¹are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-5):

embedded image

- 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 tongue, and breast.

Examples are compounds XPA-1334 and XPA-1335.

- and wherein Y is defined as in general formula (I) including the substitutions and preferred definitions, wherein Y is different from —H,
- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), with the proviso that R¹including any substituent contains no heteroatom or one, two, three or four heteroatoms independently selected from O, S, N,
- and R²-R⁷, R⁹-R¹¹, X¹, X³and X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-6):

embedded image

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, cancer of the skin, tongue and breast.

Examples are compounds XPA-1299, XPA-1300, XPA-1320 and XPA-1321.

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I),
- and R²-R⁷, R⁹-R¹¹, X¹, X³, X⁴and Y are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-7):

embedded image

- 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, cancer of the skin, tongue and breast.

Examples are compounds XPA-1299, XPA-1300, XPA-1301, XPA-1320, XPA-1321 and XPA-1344.

In a further certain embodiment, the present invention relates to compounds of general formula (Tb) and salts and solvates thereof, wherein Z¹and Z²are together ═O, and wherein Y is —H,

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹contains six or more carbon atoms, which are optionally independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), and wherein R¹is selected from cyclic, bicyclic and tricyclic structures, optionally with the proviso that R¹is different from unsubstituted cyclohexyl,
- and R²-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-8):

embedded image

- and wherein the compounds of structure (Ib-8) 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, tongue, lung, stomach, breast and cancer of the neuroendocrine system.

Examples are compounds XPA-0020, XPA-0028, XPA-0280, XPA-0511, XPA-0512, XPA-0524, XPA-0532, XPA-1283, XPA-1284, XPA-1285, XPA-1286, XPA-1298, XPA-1337 and XPA-1339.

In a further certain embodiment, the present invention relates to compounds of general formula (Tb) and salts and solvates thereof, wherein Z¹and Z²are together ═O, and wherein Y is —H,

- and wherein R⁵is defined as in general formula (I) including the substitutions and preferred definitions, wherein R⁵is in ortho-position relative to the ether bond, and wherein R⁵is different from —H,
- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹is selected from cyclic, bicyclic and tricyclic structures or contains a cyclic, bicyclic or tricyclic structure, optionally with the proviso that R¹including any substituent contains no heteroatom or one, two, three or four heteroatoms independently selected from O, S, N,
- and R²-R⁴, R⁶-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-9):

embedded image

- and wherein the compounds of structure (Ib-9) 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, tongue, lung, stomach, breast and cancer of the neuroendocrine system.

Examples are compounds XPA-1283, XPA-1284, XPA-1285, XPA-1286 and XPA-1298.

In a further certain embodiment, the present invention relates to compounds of general formula (Tb) and salts and solvates thereof, wherein Z¹and Z²are together ═O,

- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, wherein R¹is unsubstituted or substituted cyclohexyl, and wherein any ring carbon atom can optionally be independently replaced by a heteroatom selected from O, S and N as defined in general formula (I), and wherein R¹including any substituent contains one or more heteroatoms independently selected from O, S, N,
- and wherein Y is defined as in general formula (I) including the substitutions and preferred definitions, wherein Y is different from —H, optionally with the additional proviso that Y is different from —OCH₃,
- and R²-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ib-10):

embedded image

- and wherein the compounds of structure (Ib-10) 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, stomach and breast.

Examples are compounds XPA-0035, XPA-0036, XPA-0037, XPA-0063, XPA-0064, XPA-0065, XPA-0079, XPA-0541, XPA-0569, XPA-1267 and XPA-1268.

In a further certain embodiment, the present invention relates to compounds of general formula (Ic) and salts and solvates thereof, wherein Z¹and Z²form together a cyclic residue including the carbon atom to which they are bound, and wherein Z¹and Z²are defined as in general formula (Ic) including the substitutions and preferred definitions, wherein the cyclic residue is a four-membered ring, and wherein the said cyclic residue preferably contains one heteroatom selected from O, S and N in replacement of a carbon atom, and/or wherein the said cyclic residue is preferably substituted as defined in general formula (I), optionally with the proviso that the cyclic residue is not perhalogenated,

- and wherein Y is defined as in general formula (I) including the substitutions and preferred definitions, wherein Y is different from —H,
- and R¹-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ic-1):

embedded image

- 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 XPA-0132, XPA-0140, XPA-0146, XPA-0154, XPA-0160, XPA-0168, XPA-0174, XPA-0182, XPA-0188, XPA-0196, XPA-0210, XPA-0230, XPA-0238, XPA-0644, XPA-0658, XPA-0672, XPA-1308, XPA-1309, XPA-1310, XPA-1311, XPA-1312, XPA-1313, XPA-1315, XPA-1316, XPA-1317, XPA-1318 and XPA-1331.

- and wherein Y is defined as in general formula (I) including the substitutions and preferred definitions, wherein Y is different from —H, optionally with the additional proviso that Y is different from —OH and —OCH₃,
- and R¹-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ic-2):

embedded image

- and wherein the compounds of structure (Ic-2) 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, cervix, ovaries, and cancer of the neuroendocrine system.

- and wherein Y is —OH,
- and wherein R¹is defined as in general formula (I) including the substitutions and preferred definitions, optionally with the proviso that R¹contains two or more carbon atoms,
- and R²-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ic-3):

embedded image

- 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 XPA-0132, XPA-0140, XPA-0174, XPA-0182, XPA-0644, XPA-1308, XPA-1309, XPA-1312 and XPA-1313.

- and wherein Y is —OCH₃,
- and R¹-R¹¹and X¹-X⁴are defined as in general formula (I) including the substitutions and preferred definitions,
- and wherein the compounds share the following structure (Ic-4):

embedded image

- 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 XPA-0146, XPA-0154, XPA-0188, XPA-0196, XPA-0230, XPA-0238, XPA-0658, XPA-1310, XPA-1311, XPA-1315 and XPA-1316.

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

CAS

139-63-9

534-50-9

637-13-8

1814-47-7

2215-79-4

2288-40-6

2350-43-8

2416-40-2

2506-19-6

3072-49-9

3287-73-8

3287-74-9

3287-75-0

5280-88-6

5741-65-1

5741-66-2

5741-67-3

7344-22-1

7572-63-6

7572-65-8

7572-66-9

7572-67-0

7595-16-6

7595-17-7

7619-92-3

7708-35-2

7708-36-3

7708-38-5

7718-92-5

10436-58-5

13072-81-6

13753-60-1

14416-04-7

14416-25-2

14970-31-1

15962-63-7

17096-62-7

18133-76-1

18835-38-6

18835-39-7

18838-58-9

19103-38-9

19443-91-5

20105-31-1

20546-12-7

22071-36-9

23501-44-2

23501-46-4

23501-48-6

23501-49-7

23501-50-0

23582-77-6

24702-01-0

24982-69-2

30425-06-0

30920-59-3

31582-77-1

37768-13-1

40843-23-0

40843-63-8

41540-10-7

50772-75-3

51489-45-3

51489-46-4

51489-48-6

51489-49-7

51489-55-5

51489-56-6

51489-58-8

51489-59-9

51885-75-7

55047-07-9

57422-20-5

57422-25-0

61343-86-0

62050-97-9

62584-49-0

62584-52-5

64762-84-1

64762-85-2

64762-86-3

64762-87-4

64771-90-0

64771-91-1

64961-93-9

65538-20-7

65538-21-8

65781-88-6

67941-79-1

68548-71-0

68548-81-2

68548-87-8

68795-70-0

70115-13-8

70151-68-7

71108-60-6

71860-72-5

78303-12-5

78303-13-6

78303-15-8

78725-47-0

78725-49-2

80199-53-7

80199-54-8

83642-13-1

83642-16-4

84492-16-0

84492-18-2

84859-64-3

90035-20-4

90549-22-7

90570-89-1

92060-22-5

92554-36-4

92851-87-1

94757-14-9

94762-26-2

95524-26-8

96681-14-0

96681-19-5

97116-05-7

100537-24-4

100541-47-7

100717-19-9

100725-28-8

100866-75-9

100873-30-1

100874-06-4

100874-18-8

100961-27-1

100965-66-0

101096-21-3

101168-14-3

101284-59-7

101350-17-8

101350-18-9

101571-62-4

102224-78-2

102374-76-5

102767-18-0

102767-21-5

102873-38-1

104009-17-8

106473-15-8

106653-40-1

107455-96-9

108934-20-9

109600-68-2

109733-99-5

110789-83-8

114878-38-5

115414-87-4

115773-15-4

117088-67-2

117113-93-6

117114-43-9

117114-59-7

117114-60-0

117114-76-8

117114-77-9

117114-78-0

117114-84-8

117114-93-9

117114-97-3

117115-01-2

117115-09-0

117115-13-6

117115-15-8

117115-20-5

117115-22-7

118308-53-5

118308-54-6

118308-61-5

121244-66-4

121244-67-5

121244-68-6

124353-72-6

124746-95-8

124746-96-9

125587-34-0

128079-86-7

128079-91-4

128079-92-5

128158-28-1

128268-33-7

130936-31-1

131798-17-9

132129-98-7

132529-78-3

133256-12-9

134484-09-6

134484-16-5

135199-52-9

135533-55-0

135533-57-2

136805-22-6

137736-08-4

140841-13-0

143030-87-9

146057-99-0

146719-18-8

146719-19-9

146719-20-2

152609-23-9

152609-25-1

153308-13-5

157126-43-7

157126-44-8

157126-45-9

158018-75-8

158769-47-2

158769-48-3

158769-49-4

158769-50-7

158769-51-8

158769-52-9

158769-53-0

158769-54-1

158769-60-9

158769-68-7

158770-91-3

158770-92-4

158770-93-5

158770-94-6

158770-95-7

158770-96-8

158771-24-5

158771-25-6

158771-36-9

158771-38-1

165118-97-8

169244-02-4

169244-03-5

169245-34-5

169245-35-6

169245-40-3

178044-23-0

179056-16-7

180636-78-6

180636-79-7

181231-61-8

185614-05-5

196604-16-7

204592-28-9

204592-31-4

204592-34-7

208171-61-3

219692-13-4

219692-19-0

250129-95-4

264927-56-2

282100-39-4

282100-47-4

282100-51-0

282100-66-7

282100-73-6

322472-29-7

322472-30-0

322472-32-2

322472-33-3

322472-40-2

322472-41-3

322472-43-5

322472-44-6

322472-48-0

322472-49-1

322472-51-5

322472-52-6

322472-54-8

322472-55-9

329063-84-5

332010-61-4

338960-65-9

341510-25-6

341510-27-8

367912-11-6

367953-29-5

367953-34-2

367953-39-7

367953-40-0

391927-56-3

391927-70-1

408341-46-8

428467-15-6

448956-60-3

448957-06-0

459125-44-1

503617-35-4

515813-60-2

515813-61-3

521289-55-4

529507-54-8

592508-69-5

592508-70-8

592508-76-4

606933-00-0

676501-50-1

676501-52-3

676501-53-4

680579-64-0

688318-27-6

688318-39-0

688318-48-1

688318-60-7

698356-65-9

698356-74-0

698356-82-0

724760-25-2

726151-45-7

750641-06-6

763932-52-1

802915-08-8

808168-39-0

808168-42-5

816450-55-2

847951-19-3

848773-54-6

850084-03-6

851431-78-2

851431-85-1

851431-86-2

851431-88-4

851431-91-9

851431-92-0

851431-93-1

851431-96-4

852631-21-1

852949-05-4

855264-88-9

857015-72-6

857397-05-8

857397-07-0

857825-76-4

857838-96-1

857951-02-1

859034-08-5

860523-83-7

860562-95-4

860679-73-8

860695-23-4

872187-37-6

872187-39-8

872976-92-6

872976-93-7

872977-19-0

875699-96-0

875699-97-1

875700-37-1

875700-45-1

875700-46-2

875702-23-1

875702-24-2

875706-31-3

875706-32-4

875707-69-0

875707-70-3

875707-71-4

875848-97-8

882976-32-1

883236-85-9

893723-95-0

897036-69-0

897036-70-3

897036-71-4

897036-72-5

903566-55-2

903566-56-3

904671-70-1

904671-72-3

904671-74-5

909789-16-8

909901-03-7

912755-79-4

915155-96-3

915407-05-5

915953-46-7

916075-75-7

918157-14-9

918157-21-8

918157-22-9

918157-23-0

918337-11-8

921609-83-8

926295-88-7

926305-00-2

926305-03-5

926305-05-7

926642-16-2

926642-25-3

931420-98-3

933786-79-9

934765-31-8

934765-37-4

934765-38-5

934765-51-2

934765-52-3

935252-64-5

946851-85-0

946884-24-8

958652-33-0

1000558-35-9

1009101-92-1

1009102-09-3

1009102-10-6

1020934-55-7

1021233-54-4

1030379-82-8

1030379-95-3

1033777-82-0

1033777-83-1

1038966-29-8

1039898-13-9

1054553-99-9

1054554-00-5

1054554-01-6

1054554-02-7

1054554-03-8

1054554-04-9

1054554-05-0

1054554-06-1

1054554-07-2

1054554-08-3

1054554-09-4

1055361-67-5

1055361-72-2

1055361-73-3

1055361-74-4

1055361-85-7

1061685-77-5

1061686-42-7

1061686-75-6

1061687-73-7

1061687-75-9

1061687-76-0

1061687-78-2

1061689-55-1

1061689-59-5

1071161-52-8

1081545-99-4

1094166-66-1

1094166-78-5

1094166-84-3

1094166-95-6

1098622-86-6

1126633-00-8

1130877-74-5

1150100-30-3

1150100-68-7

1150100-71-2

1150100-95-0

1150103-12-0

1150103-15-3

1150103-16-4

1150103-18-6

1150103-19-7

1150103-24-4

1150187-90-8

1155197-52-6

1155391-95-9

1155391-97-1

1160430-68-1

1160430-79-4

1160430-81-8

1161086-36-7

1161086-82-3

1161086-91-4

1161086-94-7

1188327-63-0

1188327-68-5

1188327-72-1

1188476-56-3

1190360-96-3

1191038-86-4

1192310-84-1

1194817-15-6

1195191-30-0

1195200-95-3

1195632-25-7

1195670-81-5

1198164-69-0

1198164-70-3

1198165-49-9

1198166-54-9

1198166-63-0

1198168-18-1

1198168-51-2

1216165-79-5

1217505-86-6

1225032-58-5

1225032-59-6

1225032-61-0

1225032-63-2

1225032-64-3

1231952-22-9

1233540-72-1

1233540-86-7

1236349-47-5

1236349-49-7

1237606-12-0

1237606-15-3

1237606-16-4

1237606-18-6

1237606-19-7

1237606-23-3

1237606-25-5

1237606-26-6

1237606-28-8

1237606-29-9

1237606-33-5

1237606-35-7

1237606-36-8

1237606-38-0

1237606-39-1

1237606-59-5

1237606-61-9

1237606-64-2

1237606-65-3

1237606-66-4

1237606-69-7

1237606-71-1

1237606-72-2

1237606-74-4

1237606-75-5

1237606-94-8

1237606-95-9

1237608-34-2

1237608-37-5

1237608-38-6

1237608-40-0

1237608-41-1

1237608-45-5

1237608-47-7

1237608-48-8

1237608-50-2

1237608-51-3

1237608-55-7

1237608-57-9

1237608-58-0

1237608-60-4

1237608-61-5

1237608-81-9

1237608-83-1

1237608-86-4

1237608-87-5

1237608-88-6

1237608-91-1

1237608-93-3

1237608-94-4

1237608-96-6

1237608-97-7

1237609-16-3

1237609-17-4

1237610-57-9

1237610-60-4

1237610-61-5

1237610-63-7

1237610-64-8

1237610-68-2

1237610-70-6

1237610-71-7

1237610-73-9

1237610-74-0

1237610-78-4

1237610-80-8

1237610-81-9

1237610-83-1

1237610-84-2

1237611-04-9

1237611-06-1

1237611-09-4

1237611-10-7

1237611-11-8

1237611-14-1

1237611-16-3

1237611-17-4

1237611-19-6

1237611-20-9

1237611-39-0

1237611-40-3

1237612-78-0

1237612-81-5

1237612-82-6

1237612-84-8

1237612-85-9

1237612-89-3

1237612-91-7

1237612-92-8

1237612-94-0

1237612-95-1

1237612-99-5

1237613-01-2

1237613-02-3

1237613-04-5

1237613-05-6

1237613-25-0

1237613-27-2

1237613-30-7

1237613-31-8

1237613-32-9

1237613-35-2

1237613-37-4

1237613-38-5

1237613-40-9

1237613-41-0

1237613-60-3

1237613-61-4

1237615-10-9

1237615-13-2

1237615-14-3

1237615-16-5

1237615-17-6

1237615-21-2

1237615-23-4

1237615-24-5

1237615-26-7

1237615-27-8

1237615-31-4

1237615-33-6

1237615-34-7

1237615-36-9

1237615-37-0

1237615-57-4

1237615-59-6

1237615-62-1

1237615-63-2

1237615-64-3

1237615-67-6

1237615-69-8

1237615-70-1

1237615-72-3

1237615-73-4

1237615-92-7

1237615-93-8

1237617-33-2

1237617-36-5

1237617-37-6

1237617-39-8

1237617-40-1

1237617-44-5

1237617-46-7

1237617-47-8

1237617-49-0

1237617-50-3

1237617-54-7

1237617-56-9

1237617-57-0

1237617-59-2

1237617-60-5

1237617-80-9

1237617-82-1

1237617-85-4

1237617-86-5

1237617-87-6

1237617-90-1

1237617-92-3

1237617-93-4

1237617-95-6

1237617-96-7

1237618-15-3

1237618-16-4

1237619-55-4

1237619-58-7

1237619-59-8

1237619-61-2

1237619-62-3

1237619-66-7

1237619-68-9

1237619-69-0

1237619-71-4

1237619-72-5

1237619-76-9

1237619-78-1

1237619-79-2

1237619-81-6

1237619-82-7

1237620-02-8

1237620-04-0

1237620-07-3

1237620-08-4

1237620-09-5

1237620-12-0

1237620-14-2

1237620-15-3

1237620-17-5

1237620-18-6

1237620-37-9

1237620-38-0

1237621-81-6

1237621-84-9

1237621-85-0

1237621-87-2

1237621-88-3

1237621-92-9

1237621-94-1

1237621-95-2

1237621-97-4

1237621-98-5

1237622-02-4

1237622-04-6

1237622-05-7

1237622-07-9

1237622-08-0

1237622-28-4

1237622-30-8

1237622-33-1

1237622-34-2

1237622-35-3

1237622-38-6

1237622-40-0

1237622-41-1

1237622-43-3

1237622-44-4

1237622-63-7

1237622-64-8

1237688-59-3

1237688-62-8

1237688-63-9

1237688-65-1

1237688-66-2

1237688-70-8

1237688-72-0

1237688-73-1

1237688-75-3

1237688-76-4

1237688-80-0

1237688-82-2

1237688-83-3

1237688-85-5

1237688-86-6

1237689-06-3

1237689-08-5

1237689-11-0

1237689-12-1

1237689-13-2

1237689-16-5

1237689-18-7

1237689-19-8

1237689-21-2

1237689-22-3

1237689-41-6

1237689-42-7

1237690-83-3

1237690-86-6

1237690-87-7

1237690-89-9

1237690-90-2

1237690-94-6

1237690-96-8

1237690-97-9

1237690-99-1

1237691-00-7

1237691-04-1

1237691-06-3

1237691-07-4

1237691-09-6

1237691-10-9

1237691-30-3

1237691-32-5

1237691-35-8

1237691-36-9

1237691-37-0

1237691-40-5

1237691-42-7

1237691-43-8

1237691-45-0

1237691-46-1

1237691-65-4

1237691-66-5

1237693-12-7

1237693-15-0

1237693-16-1

1237693-18-3

1237693-19-4

1237693-23-0

1237693-25-2

1237693-26-3

1237693-28-5

1237693-29-6

1237693-33-2

1237693-35-4

1237693-36-5

1237693-38-7

1237693-39-8

1237693-59-2

1237693-61-6

1237693-64-9

1237693-65-0

1237693-66-1

1237693-69-4

1237693-71-8

1237693-72-9

1237693-74-1

1237693-75-2

1237693-94-5

1237693-95-6

1237695-40-7

1237695-43-0

1237695-44-1

1237695-46-3

1237695-47-4

1237695-51-0

1237695-53-2

1237695-54-3

1237695-56-5

1237695-58-7

1237695-66-7

1237695-70-3

1237695-72-5

1237695-76-9

1237695-77-0

1237696-01-3

1237696-03-5

1237696-06-8

1237696-07-9

1237696-08-0

1237696-11-5

1237696-13-7

1237696-14-8

1237696-16-0

1237696-17-1

1237696-36-4

1237696-37-5

1237697-83-4

1237697-86-7

1237697-87-8

1237697-89-0

1237697-90-3

1237697-94-7

1237697-96-9

1237697-97-0

1237697-99-2

1237698-00-8

1237698-04-2

1237698-06-4

1237698-07-5

1237698-09-7

1237698-10-0

1237698-30-4

1237698-32-6

1237698-35-9

1237698-36-0

1237698-37-1

1237698-40-6

1237698-42-8

1237698-43-9

1237698-45-1

1237698-46-2

1237698-65-5

1237698-66-6

1237700-03-6

1237700-05-8

1237700-06-9

1237700-08-1

1237700-09-2

1237700-12-7

1237700-15-0

1237700-16-1

1237700-18-3

1237700-22-9

1237700-24-1

1237700-25-2

1237700-27-4

1237700-44-5

1237700-46-7

1237700-49-0

1237700-50-3

1237700-51-4

1237700-54-7

1237700-56-9

1237700-57-0

1237700-59-2

1237700-60-5

1237700-79-6

1237700-80-9

1237702-14-5

1237702-17-8

1237702-18-9

1237702-20-3

1237702-21-4

1237702-25-8

1237702-27-0

1237702-28-1

1237702-30-5

1237702-31-6

1237702-35-0

1237702-37-2

1237702-38-3

1237702-40-7

1237702-41-8

1237702-61-2

1237702-63-4

1237702-66-7

1237702-67-8

1237702-68-9

1237702-71-4

1237702-73-6

1237702-74-7

1237702-76-9

1237702-77-0

1237702-96-3

1237702-97-4

1237704-37-8

1237704-40-3

1237704-41-4

1237704-43-6

1237704-44-7

1237704-48-1

1237704-50-5

1237704-51-6

1237704-53-8

1237704-54-9

1237704-58-3

1237704-60-7

1237704-61-8

1237704-63-0

1237704-64-1

1237704-84-5

1237704-86-7

1237704-89-0

1237704-90-3

1237704-91-4

1237704-94-7

1237704-96-9

1237704-97-0

1237704-99-2

1237705-00-8

1237705-20-2

1237705-21-3

1238110-97-8

1239518-83-2

1239521-18-6

1239620-71-3

1240114-79-7

1240117-21-8

1240613-87-9

1242172-59-3

1262328-74-4

1293368-01-0

1312596-78-3

1316759-32-6

1316759-34-8

1316759-36-0

1316759-38-2

1316759-40-6

1316759-43-9

1316759-45-1

1316759-47-3

1326216-70-9

1338916-32-7

1339805-31-0

1344734-55-9

1346148-63-7

1354961-37-7

1355070-20-0

1355070-22-2

1355071-15-6

1355071-18-9

1355071-33-8

1355071-36-1

1355071-40-7

1355071-42-9

1355071-44-1

1355071-48-5

1355071-50-9

1355071-53-2

1355071-55-4

1355071-58-7

1355071-63-4

1355071-66-7

1357346-75-8

1361451-37-7

1361968-40-2

1369257-64-6

1369257-65-7

1380430-22-7

1381805-28-2

1392279-49-0

1398091-01-4

1398091-06-9

1403316-37-9

1407493-68-8

1408173-78-3

1420363-28-5

1420365-61-2

1420365-65-6

1420366-53-5

1420369-27-2

1421433-93-3

1421434-06-1

1421434-10-7

1421434-36-7

1421434-62-9

1421434-63-0

1421434-68-5

1421434-69-6

1422261-85-5

1426224-07-8

1438425-40-1

1441954-06-8

1448759-01-0

1455432-80-0

1467695-23-3

1467697-98-8

1483811-30-8

1491329-66-8

1499185-20-4

1505224-22-5

1521289-35-9

1528349-36-1

1531626-31-9

1531626-34-2

1531626-56-8

1531626-59-1

1531626-62-6

1531626-65-9

1531626-68-2

1531626-74-0

1531626-93-3

1531627-15-2

1531627-17-4

1531627-21-0

1553268-30-6

1554127-50-2

1554132-62-5

1554133-77-5

1554134-23-4

1554154-94-7

1554156-42-1

1554159-62-4

1554164-24-7

1554382-13-6

1554382-79-4

1554384-10-9

1554385-91-9

1554386-44-5

1554388-71-4

1558001-53-8

1609019-17-1

1609019-19-3

1609019-21-7

1609019-22-8

1609019-23-9

1609019-24-0

1609019-25-1

1609019-26-2

1609019-27-3

1609019-28-4

1609019-29-5

1609019-41-1

1609019-42-2

1609019-43-3

1609019-45-5

1609019-47-7

1609019-48-8

1616458-13-9

1616592-16-5

1620680-48-9

1620680-49-0

1629326-33-5

1629350-80-6

1629459-49-9

1629485-99-9

1629632-02-5

1643132-46-0

1643132-92-6

1646816-78-5

1646816-86-5

1646816-88-7

1681054-64-7

1686102-88-4

1788036-31-6

1788036-47-4

1799518-98-1

1799519-00-8

1817658-18-6

1817658-19-7

1818866-22-6

1818866-28-2

1818866-29-3

1818866-32-8

1818866-33-9

1818870-30-2

1824042-44-5

1824042-46-7

1824042-49-0

1824042-53-6

1824042-54-7

1840958-09-9

1840958-14-6

1840958-15-7

1840958-18-0

1840958-19-1

1840958-20-4

1851361-16-4

1865785-32-5

1873325-41-7

1875080-94-6

1875080-95-7

1875080-96-8

1875080-98-0

1878180-12-1

1878180-14-3

1878180-16-5

1884560-40-0

1902928-14-6

1902928-16-8

1902928-25-9

1902928-31-7

1902928-33-9

1902928-49-7

1908452-86-7

1908452-88-9

1908452-89-0

1908452-90-3

1908452-92-5

1908452-94-7

1908452-97-0

1908452-98-1

1908452-99-2

1908453-02-0

1908453-05-3

1908453-84-8

1973409-98-1

1973409-99-2

1974285-92-1

2017556-57-7

2017556-58-8

2017556-59-9

2017556-72-6

2017556-73-7

2017556-74-8

2019212-09-8

2029044-28-6

2043951-55-7

2081130-42-7

2088051-80-1

2088051-81-2

2089059-98-1

2089290-68-4

2098376-10-2

2098671-39-5

2098671-40-8

2098671-41-9

2133291-91-3

2166377-88-2

2180956-84-5

2197983-82-5

2201104-40-5

2201104-41-6

2205862-78-6

2222531-08-8

2222532-04-7

2234239-43-9

2234239-47-3

2243103-86-6

2243103-96-8

2243258-35-5

2243258-36-6

2252484-90-3

2252489-06-6

2284445-56-1

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

CAS

2260-08-4

52606-55-0

72133-26-7

72133-36-9

72133-40-5

72133-57-4

72133-59-6

72133-61-0

73441-69-7

73441-81-3

107947-02-4

183269-42-3

183269-51-4

192768-22-2

213692-22-9

219765-88-5

364323-06-8

364323-07-9

364323-08-0

364323-09-1

364323-10-4

364323-11-5

364323-12-6

364323-13-7

364323-62-6

397871-91-9

397871-92-0

402912-59-8

473255-43-5

620628-09-3

620628-10-6

676501-11-4

676642-20-9

717821-91-5

720695-22-7

755017-94-8

761455-51-0

851461-59-1

857167-45-4

859505-52-5

866949-35-1

866949-38-4

866949-39-5

866949-40-8

866949-97-5

866949-98-6

866950-11-0

866950-12-1

897035-90-4

913090-08-1

931421-04-4

931421-08-8

1033777-52-4

1033777-54-6

1055424-58-2

1056951-64-4

1056952-71-6

1056952-72-7

1061378-00-4

1061686-44-9

1061686-45-0

1204513-18-7

1240613-66-4

1262328-59-5

1355063-66-9

1355064-15-1

1355064-56-0

1355064-57-1

1355064-70-8

1355064-71-9

1355064-73-1

1355064-74-2

1355064-76-4

1355064-77-5

1355065-31-4

1355318-52-3

1381792-28-4

1403681-85-5

1427279-41-1

1427279-41-1

1453851-81-4

1558081-43-8

1802916-06-8

1818842-81-7

1984790-55-7

1987879-22-0

2170885-80-8

2196258-67-8

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

CAS
Reference
CAS
Reference
CAS
Reference

21120-65-0
WO2003073999
420122-09-4
WO2002034726 A2
1316759-21-3
10.1016/j.bmcl.2011.11.034

21120-72-9
PCT/EP2018/054686
420122-10-7
WO2002034726 A2
1316759-24-6
10.1016/j.bmcl.2011.11.034

33927-09-2
1. WO9920263 A1
420122-15-2
WO2002034726 A2
1357175-98-4
10.1016/j.bmcl.2011.11.034

33927-30-9
10.1016/j.bmcl.2006.12.048
461021-18-1
WO2002074770 A1
1357175-99-5
10.1016/j.bmcl.2011.11.034

34043-77-1
WO9920263 A1
461021-88-5
WO2002074770 A1
1417988-54-5
WO2013004190 A1

50793-28-7
10.1016/j.bmcl.2006.12.048
461022-02-6
WO2002074770 A1
1417988-55-6
WO 2013004190 A1

51362-47-1
PCT/EP2018/054686
461441-44-1
WO2002074770 A1
1417988-66-9
WO2013004190 A1

61343-83-7
JP56012310
461442-03-5
WO2002074770 A1
1417989-82-2
WO2013004190 A1

69240-57-9
WO9842328 A1
461442-52-4
WO2002074770 A1
1417989-83-3
WO 2013004190 A1

78161-82-7
PCT/EP2018/054686
461442-59-1
WO2002074770 A1
1417989-94-6
WO2013004190 A1

94709-08-7
WO9842328 A1
491861-74-6
WO2003007955 A2
1431503-10-4
WO 2013059648 A1

101169-11-3
PCT/EP2018/054686
503617-61-6
PCT/EP2018/054686
1431503-11-5
WO 2013059648 A1

145224-76-6
10.1016/s0031-9422(00)97570-8
676455-11-1
WO2004026873 A1
1431504-43-6
WO 2013059648 A1

158769-86-9
WO2017158190 A1
862088-75-3
PCT/EP2018/054686
1431504-44-7
WO 2013059648 A1

158769-99-4
WO9324442 A1
862088-98-0
PCT/EP2018/054686
1431504-45-8
WO 2013059648 A1

158770-01-5
WO9324442 A1
866152-40-1
PCT/EP2018/054686
1480752-41-7
PCT/EP2018/054686

158770-02-6
WO9324442 A1
873927-78-7
US 20060014812 A1
1506498-75-4
PCT/EP2018/054686

158770-03-7
WO9324442 A1
873927-81-2
US 20060014812 A1
1550449-98-3
PCT/EP2018/054686

158770-04-8
WO9324442 A1
892217-09-3
WO2009051801 A2
1550451-20-1
PCT/EP2018/054686

158770-05-9
WO9324442 A1
900015-10-3
WO2017158190 A1
1550461-90-9
PCT/EP2018/054686

158770-06-0
WO9324442 A1
915017-69-5
PCT/EP2018/054686
1623468-51-8
Anticancer Research (2014),

34(4), 1801-1810

158770-07-1
WO9324442 A1
915155-97-4
WO2006125208 A1
1627709-06-1
Anticancer Research (2014),

34(4), 1801-1810

158770-08-2
WO9324442 A1
918157-19-4
US20080200521 A1
1627709-79-8
Anticancer Research (2014),

34(4), 1801-1810

158770-55-9
WO 9324442 A1
925005-92-1
WO2017158190 A1
1627709-86-7
Anticancer Research (2014),

34(4), 1801-1810

158770-58-2
WO 9324442 A1
933786-93-7
WO2007039171 A1
1627709-96-9
Anticancer Research (2014),

34(4), 1801-1810

158770-60-6
WO 9324442 A1
934690-57-0
10.1016/j.bmcl.2006.12.048
1627710-75-1
Anticancer Research (2014),

34(4), 1801-1810

158770-68-4
WO 9324442 A1
934690-58-1
10.1016/j.bmcl.2006.12.048
1628281-17-3
Anticancer Research (2014),

34(4), 1801-1810

176694-37-4
EP700899 A1
934690-60-5
10.1016/j.bmcl.2006.12.048
1875080-72-0
10.1002/cmdc.201500461

179018-67-8
WO9610999 A2
934690-62-7
10.1016/j.bmcl.2006.12.048
1875080-73-1
10.1002/cmdc.201500461

188609-20-3
WO9707769 A2
934690-63-8
10.1016/j.bmcl.2006.12.048
1875080-74-2
10.1002/cmdc.201500461

188609-21-4
WO9707769 A2
934690-64-9
10.1016/j.bmcl.2006.12.048
1875080-76-4
10.1002/cmdc.201500461

188609-22-5
WO9707769 A2
934690-65-0
10.1016/j.bmcl.2006.12.048
1917642-56-8
PCT/EP2018/054686

189156-55-6
WO9920263 A1
934690-70-7
10.1016/j.bmcl.2006.12.048
1944481-23-5
PCT/EP2018/054686

189156-57-8
WO9920263 A1
934690-74-1
10.1016/j.bmcl.2006.12.048
2089290-66-2
PCT/EP2018/054686

189156-58-9
WO9920263 A1
934690-75-2
10.1016/j.bmcl.2006.12.048
2133382-71-3
WO2017158190 A1

189156-59-0
WO9920263 A1
934690-76-3
10.1016/j.bmcl.2006.12.048
2133382-74-6
WO2017158190 A1

189156-66-9
WO9920263 A1
934690-77-4
10.1016/j.bmcl.2006.12.048
2133382-76-8
WO2017158190 A1

189156-67-0
WO9920263
934690-78-5
10.1016/j.bmcl.2006.12.048
2133382-78-0
WO2017158190 A1

189156-68-1
WO9920263
938301-04-3
PCT/EP2018/054686
2133382-81-5
WO2017158190 A1

189156-69-2
WO9920263
938356-51-5
WO2017158190 A1
2133382-86-0
WO2017158190 A1

189156-70-5
WO9920263
954564-77-3
PCT/EP2018/054686
2133382-89-3
WO2017158190 A1

213684-07-2
WO9842328 A1
960133-36-2
US20070292883
2133382-92-8
WO2017158190 A1

213684-08-3
WO9842328 A1
1036524-79-4
PCT/EP2018/054686
2133382-94-0
WO2017158190 A1

213684-09-4
WO9842328 A1
1036598-46-5
PCT/EP2018/054686
2133382-97-3
WO2017158190 A1

257605-04-2
WO2000005198 A1
1039970-54-1
WO2017158190 A1
2133382-99-5
WO2017158190 A1

262287-91-2
WO 2000017162 A1
1040017-39-7
WO2017158190 A1
2243095-72-7
PCT/EP2018/054686

270260-24-7
JP2000143650 A
1041517-52-5
PCT/EP2018/054686
2243096-02-6
PCT/EP2018/054686

270260-26-9
JP2000143650 A
1041551-78-3
WO2017158190 A1
2243099-18-3
PCT/EP2018/054686

303146-33-0
US 20090163545 A1
1049144-30-0
PCT/EP2018/054686
2243099-43-4
PCT/EP2018/054686

342912-00-9
WO2001040227 A1
1099155-64-2
WO2017158190 A1
2243098-92-0
PCT/EP2018/054686

342912-94-1
WO2001040227 A1
1128268-16-5
PCT/EP2018/054686
2243102-88-5
PCT/EP2018/054686

342914-22-1
WO2001040227 A1
1216118-86-3
WO2017158190 A1
2247265-52-5
CN108309959 A

343274-25-9
WO2001040227 A1
1268609-70-6
PCT/EP2018/054686

343276-73-3
WO2001040227 A1
1411168-7788
PCT/EP2018/054686

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 keratinocytes and cells and malignant cells selected from cutaneous T-cell lymphoma and acute promyelocytic leukemia. Thus, these compounds as well as salts and solvates thereof are particularly suitable for the treatment of hyperproliferative skin diseases as defined herein, as well as for the treatment of diseases of the haematopoietic system including the haematologic system and immune system-related disorders, such as cutaneous T-cell lymphoma and acute promyelocytic leukemia, as defined herein.

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, gastric cancer, breast cancer and ovarian cancer, epidermoid skin cancer such as non-melanoma skin cancer, cancer of the oral cavity, cancer of the tongue, lung cancer, acute myeloid leukemia and hyperproliferative muscle diseases 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 skin diseases as defined herein (A), cutaneous T-cell lymphoma (B), acute promyelocytic leukemia (C), T-cell leukemia (D), B-cell leukemia (E), gastric cancer (F), breast cancer (G), ovarian cancer (H), epidermoid skin cancer (I), cancer of the tongue (J), lung cancer (K), acute myeloid leukemia (L), cancer of oral cavity (M) and hyperproliferative muscle diseases (N).

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

TABLE 4

Compound No.
Medical use

XPA-0033
B C

XPA-0042
B

XPA-0044
C

XPA-0070
A

XPA-0282
A

XPA-0310
A

XPA-0313
C

XPA-0547
C

XPA-0565
C

XPA-0574
A

XPA-0814
C

XPA-0817
C

XPA-1009
B C

XPA-1011
C

XPA-1013
C

XPA-1014
A

XPA-1017
C

XPA-1018
C

XPA-1019
C

XPA-1020
C

XPA-1021
C

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

TABLE 5

Compound No.
Medical use

XPA-0029
A

XPA-0030
A

XPA-0033
A

XPA-0034
A E

XPA-0039
A

XPA-0040
A

XPA-0042
A C J N

XPA-0043
A

XPA-0044
A E J N

XPA-0047
A D E F G I J K

XPA-0048
A D E G I

XPA-0053
A D G

XPA-0054
A D E G I

XPA-0056
A D G I

XPA-0057
A

XPA-0058
A

XPA-0061
D E G I J

XPA-0062
A G

XPA-0067
A D E G I

XPA-0068
A D G J

XPA-0070
D E G L

XPA-0285
A

XPA-0294
A B

XPA-0299
A I E

XPA-0300
A E I

XPA-0308
D E G

XPA-0309
A

XPA-0310
C N

XPA-0313
A D E I N

XPA-0314
A I

XPA-0322
A D

XPA-0533
A

XPA-0534
A

XPA-0537
A

XPA-0544
A

XPA-0546
J N

XPA-0547
A

XPA-0551
A

XPA-0558
A J

XPA-0560
A J

XPA-0561
E

XPA-0562
A D K N

XPA-0565
D E G I J K M

XPA-0566
A

XPA-0571
A D E G I J

XPA-0572
A D E G I J N

XPA-0574
D E G J L

XPA-0786
K H

XPA-0789
A K

XPA-0803
A D I J

XPA-0804
A B

XPA-0814
A E G I

XPA-0817
A D E G I K N

XPA-0818
A D G

XPA-0826
A E G

XPA-1009
A

XPA-1011
A

XPA-1012
A

XPA-1013
A

XPA-1015
E G I J K N

XPA-1016
A

XPA-1017
A I

XPA-1018
A B E H I

XPA-1019
A B H

XPA-1020
A I

XPA-1021
A E

XPA-1034
G

XPA-1035
D E G I J

XPA-1246
A I N

XPA-1247
A D H I

XPA-1248
A I

XPA-1249
A E

XPA-1250
A D I N

XPA-1251
A D I J

XPA-1252
A I

XPA-1253
A I K

XPA-1254
A K

XPA-1255
A K

XPA-1256
A H K

XPA-1257
A H

XPA-1258
A D E

XPA-1259
A

XPA-1261
A H

XPA-1262
A C D E G I J K N

XPA-1263
A C D E F G I N

XPA-1264
G I

XPA-1265
A G I J

XPA-1340
A E

XPA-1341
A E

XPA-1342
G

XPA-1343
D E G I

XPA-1345
A I E K

XPA-1346
A

XPA-1347
A

XPA-1826
A

XPA-1827
A

XPA-1830
A N

XPA-1831
A

XPA-1832
A C

XPA-1855
A

XPA-1856
A

XPA-1857
A B

XPA-1885
A

XPA-1886
A

XPA-1887
A

XPA-1890
A

XPA-1891
A

XPA-1892
A

XPA-1893
A

XPA-1894
A

Specific examples of compounds falling under the scope of formula (I) are shown in Table 6 to Table 29. Intermediates are denoted as “XPA-I”.

TABLE 6

B

A
embedded image

XPA-0001
XPA-1348
XPA-1362

embedded image

XPA-0002
XPA-1349
XPA-1363

embedded image

XPA-0003
XPA-1350
XPA-1364

embedded image

XPA-0004
XPA-1351
XPA-1365

embedded image

XPA-0005
XPA-1352
XPA-1366

embedded image

XPA-0006
XPA-1353
XPA-1266

embedded image

XPA-0007
XPA-1354
XPA-1367

embedded image

XPA-0008
XPA-1355
XPA-1368

embedded image

XPA-0009
XPA-1356
XPA-1369

embedded image

XPA-0010
XPA-1357
XPA-1370

embedded image

XPA-0011
XPA-1358
XPA-1371

embedded image

XPA-0012
XPA-1359
XPA-1372

embedded image

XPA-0013
XPA-1360
XPA-1373

embedded image

XPA-0014
XPA-1361
XPA-1374

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

TABLE 7

B

A

embedded image

XPA-0015
XPA-0029
XPA-0043
XPA-0057
XPA-0071

embedded image

XPA-0016
XPA-0030
XPA-0044
XPA-0058
XPA-0072

embedded image

XPA-0017
XPA-0031
XPA-0045
XPA-0059
XPA-0073

embedded image

XPA-0018
XPA-0032
XPA-0046
XPA-0060
XPA-0074

embedded image

XPA-0019
XPA-0033
XPA-0047
XPA-0061
XPA-0075

embedded image

XPA-0020
XPA-0034
XPA-0048
XPA-0062
XPA-0076

embedded image

XPA-0021
XPA-0035
XPA-0049
XPA-0063
XPA-0077

embedded image

XPA-0022
XPA-0036
XPA-0050
XPA-0064
XPA-0078

embedded image

XPA-0023
XPA-0037
XPA-0051
XPA-0065
XPA-0079

embedded image

XPA-0024
XPA-0038
XPA-0052
XPA-0066
XPA-0080

embedded image

XPA-0025
XPA-0039
XPA-0053
XPA-0067
XPA-0081

embedded image

XPA-0026
XPA-0040
XPA-0054
XPA-0068
XPA-0082

embedded image

XPA-0027
XPA-0041
XPA-0055
XPA-0069
XPA-0083

embedded image

XPA-0028
XPA-0042
XPA-0056
XPA-0070
XPA-0084

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

TABLE 8

B

A
embedded image

XPA-0085
XPA-0099
XPA-0113
XPA-0127
XPA-0141
XPA-0155

embedded image

XPA-0086
XPA-0100
XPA-0114
XPA-0128
XPA-0142
XPA-0156

embedded image

XPA-0087
XPA-0101
XPA-0115
XPA-0129
XPA-0143
XPA-0157

embedded image

XPA-0088
XPA-0102
XPA-0116
XPA-0130
XPA-0144
XPA-0158

embedded image

XPA-0089
XPA-0103
XPA-0117
XPA-0131
XPA-0145
XPA-0159

embedded image

XPA-0090
XPA-0104
XPA-0118
XPA-0132
XPA-0146
XPA-0160

embedded image

XPA-0091
XPA-0105
XPA-0119
XPA-0133
XPA-0147
XPA-0161

embedded image

XPA-0092
XPA-0106
XPA-0120
XPA-0134
XPA-0148
XPA-0162

embedded image

XPA-0093
XPA-0107
XPA-0121
XPA-0135
XPA-0149
XPA-0163

embedded image

XPA-0094
XPA-0108
XPA-0122
XPA-0136
XPA-0150
XPA-0164

embedded image

XPA-0095
XPA-0109
XPA-0123
XPA-0137
XPA-0151
XPA-0165

embedded image

XPA-0096
XPA-0110
XPA-0124
XPA-0138
XPA-0152
XPA-0166

embedded image

XPA-0097
XPA-0111
XPA-0125
XPA-0139
XPA-0153
XPA-0167

embedded image

XPA-0098
XPA-0112
XPA-0126
XPA-0140
XPA-0154
XPA-0168

B

A
embedded image

XPA-0169
XPA-0183
XPA-0197
XPA-0211
XPA-0225
XPA-1375

embedded image

XPA-0170
XPA-0184
XPA-0198
XPA-0212
XPA-0226
XPA-1376

embedded image

XPA-0171
XPA-0185
XPA-0199
XPA-0213
XPA-0227
XPA-1377

embedded image

XPA-0172
XPA-0186
XPA-0200
XPA-0214
XPA-0228
XPA-1378

embedded image

XPA-0173
XPA-0187
XPA-0201
XPA-0215
XPA-0229
XPA-1379

embedded image

XPA-0174
XPA-0188
XPA-0202
XPA-0216
XPA-0230
XPA-1380

embedded image

XPA-0175
XPA-0189
XPA-0203
XPA-0217
XPA-0231
XPA-1381

embedded image

XPA-0176
XPA-0190
XPA-0204
XPA-0218
XPA-0232
XPA-1382

embedded image

XPA-0177
XPA-0191
XPA-0205
XPA-0219
XPA-0233
XPA-1383

embedded image

XPA-0178
XPA-0192
XPA-0206
XPA-0220
XPA-0234
XPA-1384

embedded image

XPA-0179
XPA-0193
XPA-0207
XPA-0221
XPA-0235
XPA-1385

embedded image

XPA-0180
XPA-0194
XPA-0208
XPA-0222
XPA-0236
XPA-1386

embedded image

XPA-0181
XPA-1095
XPA-0209
XPA-0223
XPA-0237
XPA-1387

embedded image

XPA-0182
XPA-0196
XPA-0210
XPA-0224
XPA-0238
XPA-1331

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

TABLE 9

B

A

embedded image

XPA-0239
XPA-1022
XPA-1036
XPA-1050
XPA-1064

embedded image

XPA-0240
XPA-1023
XPA-1037
XPA-1051
XPA-1065

embedded image

XPA-0241
XPA-1024
XPA-1038
XPA-1052
XPA-1066

embedded image

XPA-0242
XPA-1025
XPA-1039
XPA-1053
XPA-1067

embedded image

XPA-0243
XPA-1026
XPA-1040
XPA-1054
XPA-1068

embedded image

XPA-0244
XPA-1027
XPA-1041
XPA-1055
XPA-1069

embedded image

XPA-0245
XPA-1028
XPA-1042
XPA-1056
XPA-1070

embedded image

XPA-0246
XPA-1029
XPA-1043
XPA-1057
XPA-1071

embedded image

XPA-0247
XPA-1030
XPA-1044
XPA-1058
XPA-1072

embedded image

XPA-0248
XPA-1031
XPA-1045
XPA-1059
XPA-1073

embedded image

XPA-0249
XPA-1032
XPA-1046
XPA-1060
XPA-0174

embedded image

XPA-0250
XPA-1033
XPA-1047
XPA-1061
XPA-1075

embedded image

XPA-0251
XPA-1034
XPA-1048
XPA-1062
XPA-1076

embedded image

XPA-0252
XPA-1035
XPA-1049
XPA-1063
XPA-1077

B

A

embedded image

XPA-1388
XPA-1400
XPA-1412
XPA-1425
XPA-1438

embedded image

XPA-1389
XPA-1401
XPA-1413
XPA-1426
XPA-1439

embedded image

XPA-1390
XPA-1402
XPA-1414
XPA-1427
XPA-1440

embedded image

XPA-1391
XPA-1403
XPA-1415
XPA-1428
XPA-1441

embedded image

XPA-1392
XPA-1404
XPA-1416
XPA-1429
XPA-1442

embedded image

XPA-1309
XPA-1310
XPA-1313
XPA-1314
XPA-1315

embedded image

XPA-1393
XPA-1405
XPA-1417
XPA-1430
XPA-1443

embedded image

XPA-1394
XPA-1406
XPA-1418
XPA-1431
XPA-1444

embedded image

XPA-1395
XPA-1407
XPA-1419
XPA-1432
XPA-1445

embedded image

XPA-1396
XPA-1408
XPA-1420
XPA-1433
XPA-1446

embedded image

XPA-1397
XPA-1409
XPA-1421
XPA-1434
XPA-1447

embedded image

XPA-1398
XPA-1410
XPA-1422
XPA-1435
XPA-1448

embedded image

XPA-1399
XPA-1411
XPA-1423
XPA-1436
XPA-1449

embedded image

XPA-1308
XPA-1311
XPA-1424
XPA-1437
XPA-1316

B

A

embedded image

XPA-1450

XPA-1451

XPA-1452

XPA-1453

XPA-1454

XPA-1317

XPA-1455

XPA-1456

XPA-1457

XPA-1458

XPA-1459

XPA-1460

XPA-1461

XPA-1318

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

TABLE 10

B

A
embedded image

XPA-0253
XPA-1462
XPA-1476

embedded image

XPA-0254
XPA-1463
XPA-1477

embedded image

XPA-0255
XPA-1464
XPA-1478

embedded image

XPA-0256
XPA-1465
XPA-1479

embedded image

XPA-0257
XPA-1466
XPA-1480

embedded image

XPA-0258
XPA-1467
XPA-1481

embedded image

XPA-0259
XPA-1468
XPA-1482

embedded image

XPA-0260
XPA-1469
XPA-1483

embedded image

XPA-0261
XPA-1470
XPA-1484

embedded image

XPA-0262
XPA-1471
XPA-1485

embedded image

XPA-0263
XPA-1472
XPA-1486

embedded image

XPA-0264
XPA-1473
XPA-1487

embedded image

XPA-0265
XPA-1474
XPA-1488

embedded image

XPA-0266
XPA-1475
XPA-1489

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

TABLE 11

B

A

embedded image

XPA-0267
XPA-0281
XPA-0295
XPA-0309
XPA-0323

embedded image

XPA-0268
XPA-0282
XPA-0296
XPA-0310
XPA-0324

embedded image

XPA-0269
XPA-0283
XPA-0297
XPA-0311
XPA-0325

embedded image

XPA-0270
XPA-0284
XPA-0298
XPA-0312
XPA-0326

embedded image

XPA-0271
XPA-0285
XPA-0299
XPA-0313
XPA-0327

embedded image

XPA-0272
XPA-0286
XPA-0300
XPA-0314
XPA-0328

embedded image

XPA-0273
XPA-0287
XPA-0301
XPA-0315
XPA-0329

embedded image

XPA-0274
XPA-0288
XPA-0302
XPA-0316
XPA-0330

embedded image

XPA-0275
XPA-0289
XPA-0303
XPA-0317
XPA-0331

embedded image

XPA-0276
XPA-0290
XPA-0304
XPA-0318
XPA-0332

embedded image

XPA-0277
XPA-0291
XPA-0305
XPA-0319
XPA-0333

embedded image

XPA-0278
XPA-0292
XPA-0306
XPA-0320
XPA-0334

embedded image

XPA-0279
XPA-0293
XPA-0307
XPA-0321
XPA-0335

embedded image

XPA-0280
XPA-0294
XPA-0308
XPA-0322
XPA-0336

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

TABLE 12

B

A
embedded image

XPA-0337
XPA-0351
XPA-0365
XPA-0379
XPA-0393
XPA-0407

embedded image

XPA-0338
XPA-0352
XPA-0366
XPA-0380
XPA-0394
XPA-0408

embedded image

XPA-0339
XPA-0353
XPA-0367
XPA-0381
XPA-0395
XPA-0409

embedded image

XPA-0340
XPA-0354
XPA-0368
XPA-0382
XPA-0396
XPA-0410

embedded image

XPA-0341
XPA-0355
XPA-0369
XPA-0383
XPA-0397
XPA-0411

embedded image

XPA-0342
XPA-0356
XPA-0370
XPA-0384
XPA-0398
XPA-0412

embedded image

XPA-0343
XPA-0357
XPA-0371
XPA-0385
XPA-0399
XPA-0413

embedded image

XPA-0344
XPA-0358
XPA-0372
XPA-0386
XPA-0400
XPA-0414

embedded image

XPA-0345
XPA-0359
XPA-0373
XPA-0387
XPA-0401
XPA-0415

embedded image

XPA-0346
XPA-0360
XPA-0374
XPA-0388
XPA-0402
XPA-0416

embedded image

XPA-0347
XPA-0361
XPA-0375
XPA-0389
XPA-0403
XPA-0417

embedded image

XPA-0348
XPA-0362
XPA-0376
XPA-0390
XPA-0404
XPA-0418

embedded image

XPA-0349
XPA-0363
XPA-0377
XPA-0391
XPA-0405
XPA-0419

embedded image

XPA-0350
XPA-0364
XPA-0378
XPA-0392
XPA-0406
XPA-0420

B

A
embedded image

XPA-0421
XPA-0435
XPA-0449
XPA-0463
XPA-0477
XPA-1490

embedded image

XPA-0422
XPA-0436
XPA-0450
XPA-0464
XPA-0478
XPA-1491

embedded image

XPA-0423
XPA-0437
XPA-0451
XPA-0465
XPA-0479
XPA-1492

embedded image

XPA-0424
XPA-0438
XPA-0452
XPA-0466
XPA-0480
XPA-1493

embedded image

XPA-0425
XPA-0439
XPA-0453
XPA-0467
XPA-0481
XPA-1494

embedded image

XPA-0426
XPA-0440
XPA-0454
XPA-0468
XPA-0482
XPA-1495

embedded image

XPA-0427
XPA-0441
XPA-0455
XPA-0469
XPA-0483
XPA-1496

embedded image

XPA-0428
XPA-0442
XPA-0456
XPA-0470
XPA-0484
XPA-1497

embedded image

XPA-0429
XPA-0443
XPA-0457
XPA-0471
XPA-0485
XPA-1498

embedded image

XPA-0430
XPA-0444
XPA-0458
XPA-0472
XPA-0486
XPA-1499

embedded image

XPA-0431
XPA-0445
XPA-0459
XPA-0473
XPA-0487
XPA-1500

embedded image

XPA-0432
XPA-0446
XPA-0460
XPA-0474
XPA-0488
XPA-1501

embedded image

XPA-0433
XPA-0447
XPA-0461
XPA-0475
XPA-0489
XPA-1502

embedded image

XPA-0434
XPA-0448
XPA-0462
XPA-0476
XPA-0490
XPA-1503

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

TABLE 13

B

A

embedded image

XPA-0491
XPA-1078
XPA-1092
XPA-1106

embedded image

XPA-0492
XPA-1079
XPA-1093
XPA-1107

embedded image

XPA-0493
XPA-1080
XPA-1094
XPA-1108

embedded image

XPA-0494
XPA-1081
XPA-1095
XPA-1109

embedded image

XPA-0495
XPA-1082
XPA-1096
XPA-1110

embedded image

XPA-0496
XPA-1083
XPA-1097
XPA-1111

embedded image

XPA-0497
XPA-1084
XPA-1098
XPA-1112

embedded image

XPA-0498
XPA-1085
XPA-1099
XPA-1113

embedded image

XPA-0499
XPA-1086
XPA-1100
XPA-1114

embedded image

XPA-0500
XPA-1087
XPA-1101
XPA-1115

embedded image

XPA-0501
XPA-1088
XPA-1102
XPA-1116

embedded image

XPA-0502
XPA-1089
XPA-1103
XPA-1117

embedded image

XPA-0503
XPA-1090
XPA-1104
XPA-1118

embedded image

XPA-0504
XPA-1091
XPA-1105
XPA-1119

B

A
embedded image

XPA-1120
XPA-1504
XPA-1518
XPA-1532
XPA-1546

embedded image

XPA-1121
XPA-1505
XPA-1519
XPA-1533
XPA-1547

embedded image

XPA-1122
XPA-1506
XPA-1520
XPA-1534
XPA-1548

embedded image

XPA-1123
XPA-1507
XPA-1521
XPA-1535
XPA-1549

embedded image

XPA-1124
XPA-1508
XPA-1522
XPA-1536
XPA-1550

embedded image

XPA-1125
XPA-1509
XPA-1523
XPA-1537
XPA-1551

embedded image

XPA-1126
XPA-1510
XPA-1524
XPA-1538
XPA-1552

embedded image

XPA-1127
XPA-1511
XPA-1525
XPA-1539
XPA-1553

embedded image

XPA-1128
XPA-1512
XPA-1526
XPA-1540
XPA-1554

embedded image

XPA-1129
XPA-1513
XPA-1527
XPA-1541
XPA-1555

embedded image

XPA-1130
XPA-1514
XPA-1528
XPA-1542
XPA-1556

embedded image

XPA-1131
XPA-1515
XPA-1529
XPA-1543
XPA-1557

embedded image

XPA-1132
XPA-1516
XPA-1530
XPA-1544
XPA-1558

embedded image

XPA-1133
XPA-1517
XPA-1531
XPA-1545
XPA-1559

B

A

embedded image

XPA-1560
XPA-1574

embedded image

XPA-1561
XPA-1575

embedded image

XPA-1562
XPA-1576

embedded image

XPA-1563
XPA-1577

embedded image

XPA-1564
XPA-1578

embedded image

XPA-1565
XPA-1579

embedded image

XPA-1566
XPA-1580

embedded image

XPA-1567
XPA-1581

embedded image

XPA-1568
XPA-1582

embedded image

XPA-1569
XPA-1583

embedded image

XPA-1570
XPA-1584

embedded image

XPA-1571
XPA-1585

embedded image

XPA-1572
XPA-1586

embedded image

XPA-1573
XPA-1587

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

TABLE 14

B

A
embedded image

XPA-0505
XPA-1588
XPA-1601

embedded image

XPA-0506
XPA-1589
XPA-1602

embedded image

XPA-0507
XPA-1590
XPA-1603

embedded image

XPA-0508
XPA-1591
XPA-1604

embedded image

XPA-0509
XPA-1592
XPA-1605

embedded image

XPA-0510
XPA-1593
XPA-1606

embedded image

XPA-0511
XPA-1594
XPA-1607

embedded image

XPA-0512
XPA-1595
XPA-1608

embedded image

XPA-0513
XPA-1281
XPA-1282

embedded image

XPA-0514
XPA-1596
XPA-1609

embedded image

XPA-0515
XPA-1597
XPA-1610

embedded image

XPA-0516
XPA-1598
XPA-1611

embedded image

XPA-0517
XPA-1599
XPA-1612

embedded image

XPA-0518
XPA-1600
XPA-1613

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

TABLE 15

B

A

embedded image

XPA-0519
XPA-0533
XPA-0547
XPA-0561
XPA-0575

embedded image

XPA-0520
XPA-0534
XPA-0548
XPA-0562
XPA-0576

embedded image

XPA-0521
XPA-0535
XPA-0549
XPA-0563
XPA-0577

embedded image

XPA-0522
XPA-0536
XPA-0550
XPA-0564
XPA-0578

embedded image

XPA-0523
XPA-0537
XPA-0551
XPA-0565
XPA-0579

embedded image

XPA-0524
XPA-0538
XPA-0552
XPA-0566
XPA-0580

embedded image

XPA-0525
XPA-0539
XPA-0553
XPA-0567
XPA-0581

embedded image

XPA-0526
XPA-0540
XPA-0554
XPA-0568
XPA-0582

embedded image

XPA-0527
XPA-0541
XPA-0555
XPA-0569
XPA-0583

embedded image

XPA-0528
XPA-0542
XPA-0556
XPA-0570
XPA-0584

embedded image

XPA-0529
XPA-0543
XPA-0557
XPA-0571
XPA-0585

embedded image

XPA-0530
XPA-0544
XPA-0558
XPA-0572
XPA-0586

embedded image

XPA-0531
XPA-0545
XPA-0559
XPA-0573
XPA-0587

embedded image

XPA-0532
XPA-0546
XPA-0560
XPA-0574
XPA-0588

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

TABLE 16

B

A

embedded image

XPA-0589
XPA-0603
XPA-0617
XPA-0631
XPA-0645
XPA-0659
XPA-0673
XPA-0687
XPA-0701
XPA-0715
XPA-0729
XPA-1614

embedded image

XPA-0590
XPA-0604
XPA-0618
XPA-0632
XPA-0646
XPA-0660
XPA-0674
XPA-0688
XPA-0702
XPA-0716
XPA-0730
XPA-1615

embedded image

XPA-0591
XPA-0605
XPA-0619
XPA-0633
XPA-0647
XPA-0661
XPA-0675
XPA-0689
XPA-0703
XPA-0717
XPA-0731
XPA-1616

embedded image

XPA-0592
XPA-0606
XPA-0620
XPA-0634
XPA-0648
XPA-0662
XPA-0676
XPA-0690
XPA-0704
XPA-0718
XPA-0732
XPA-1617

embedded image

XPA-0593
XPA-0607
XPA-0621
XPA-0635
XPA-0649
XPA-0663
XPA-0677
XPA-0691
XPA-0705
XPA-0719
XPA-0733
XPA-1618

embedded image

XPA-0594
XPA-0608
XPA-0622
XPA-0636
XPA-0650
XPA-0664
XPA-0678
XPA-0692
XPA-0706
XPA-0720
XPA-0734
XPA-1619

embedded image

XPA-0595
XPA-0609
XPA-0623
XPA-0637
XPA-0651
XPA-0665
XPA-0679
XPA-0693
XPA-0707
XPA-0721
XPA-0735
XPA-1620

embedded image

XPA-0596
XPA-0610
XPA-0624
XPA-0638
XPA-0652
XPA-0666
XPA-0680
XPA-0694
XPA-0708
XPA-0722
XPA-0736
XPA-1621

embedded image

XPA-0597
XPA-0611
XPA-0625
XPA-0639
XPA-0653
XPA-0667
XPA-0681
XPA-0695
XPA-0709
XPA-0723
XPA-0737
XPA-1622

embedded image

XPA-0598
XPA-0612
XPA-0626
XPA-0640
XPA-0654
XPA-0668
XPA-0682
XPA-0696
XPA-0710
XPA-0724
XPA-0738
XPA-1623

embedded image

XPA-0599
XPA-0613
XPA-0627
XPA-0641
XPA-0655
XPA-0669
XPA-0683
XPA-0697
XPA-0711
XPA-0725
XPA-0739
XPA-1624

embedded image

XPA-0600
XPA-0614
XPA-0628
XPA-0642
XPA-0656
XPA-0670
XPA-0684
XPA-0698
XPA-0712
XPA-0726
XPA-0740
XPA-1625

embedded image

XPA-0601
XPA-0615
XPA-0629
XPA-0643
XPA-0657
XPA-0671
XPA-0685
XPA-0699
XPA-0713
XPA-0727
XPA-0741
XPA-1626

embedded image

XPA-0602
XPA-0616
XPA-0630
XPA-0644
XPA-0658
XPA-0672
XPA-0686
XPA-0700
XPA-0714
XPA-0728
XPA-0742
XPA-1627

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

TABLE 17

B

A

embedded image

XPA-0743
XPA-1134
XPA-1148
XPA-1162
XPA-1176
XPA-1628
XPA-1642
XPA-1656
XPA-1670
XPA-1684
XPA-1698

embedded image

XPA-0744
XPA-1135
XPA-1149
XPA-1163
XPA-1177
XPA-1629
XPA-1643
XPA-1657
XPA-1671
XPA-1685
XPA-1699

embedded image

XPA-0745
XPA-1136
XPA-1150
XPA-1164
XPA-1178
XPA-1630
XPA-1644
XPA-1658
XPA-1672
XPA-1686
XPA-1700

embedded image

XPA-0746
XPA-1137
XPA-1151
XPA-1165
XPA-1179
XPA-1631
XPA-1645
XPA-1659
XPA-1673
XPA-1687
XPA-1701

embedded image

XPA-0747
XPA-1138
XPA-1152
XPA-1166
XPA-1180
XPA-1632
XPA-1646
XPA-1660
XPA-1674
XPA-1688
XPA-1702

embedded image

XPA-0748
XPA-1139
XPA-1153
XPA-1167
XPA-1181
XPA-1633
XPA-1647
XPA-1661
XPA-1675
XPA-1689
XPA-1703

embedded image

XPA-0749
XPA-1140
XPA-1154
XPA-1168
XPA-1182
XPA-1634
XPA-1648
XPA-1662
XPA-1676
XPA-1690
XPA-1704

embedded image

XPA-0750
XPA-1141
XPA-1155
XPA-1169
XPA-1183
XPA-1635
XPA-1649
XPA-1663
XPA-1677
XPA-1691
XPA-1705

embedded image

XPA-0751
XPA-1142
XPA-1156
XPA-1170
XPA-1184
XPA-1636
XPA-1650
XPA-1664
XPA-1678
XPA-1692
XPA-1706

embedded image

XPA-0752
XPA-1143
XPA-1157
XPA-1171
XPA-1185
XPA-1637
XPA-1651
XPA-1665
XPA-1679
XPA-1693
XPA-1707

embedded image

XPA-0753
XPA-1144
XPA-1158
XPA-1172
XPA-1186
XPA-1638
XPA-1652
XPA-1666
XPA-1680
XPA-1694
XPA-1708

embedded image

XPA-0754
XPA-1145
XPA-1159
XPA-1173
XPA-1187
XPA-1639
XPA-1653
XPA-1667
XPA-1681
XPA-1695
XPA-1709

embedded image

XPA-0755
XPA-1146
XPA-1160
XPA-1174
XPA-1188
XPA-1640
XPA-1654
XPA-1668
XPA-1682
XPA-1696
XPA-1710

embedded image

XPA-0756
XPA-1147
XPA-1161
XPA-1175
XPA-1189
XPA-1641
XPA-1655
XPA-1669
XPA-1683
XPA-1697
XPA-1711

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

TABLE 18

B

A

embedded image

XPA-0757
XPA-1698
XPA-1712

embedded image

XPA-0758
XPA-1699
XPA-1713

embedded image

XPA-0759
XPA-1700
XPA-1714

embedded image

XPA-0760
XPA-1701
XPA-1715

embedded image

XPA-0761
XPA-1702
XPA-1716

embedded image

XPA-0762
XPA-1703
XPA-1717

embedded image

XPA-0763
XPA-1704
XPA-1718

embedded image

XPA-0764
XPA-1705
XPA-1719

embedded image

XPA-0765
XPA-1706
XPA-1720

embedded image

XPA-0766
XPA-1707
XPA-1721

embedded image

XPA-0767
XPA-1708
XPA-1722

embedded image

XPA-0768
XPA-1709
XPA-1723

embedded image

XPA-0769
XPA-1710
XPA-1724

embedded image

XPA-0770
XPA-1711
XPA-1725

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

TABLE 19

B

A

embedded image

XPA-0771
XPA-0785
XPA-0799
XPA-0813
XPA-0827

embedded image

XPA-0772
XPA-0786
XPA-0800
XPA-0814
XPA-0828

embedded image

XPA-0773
XPA-0787
XPA-0801
XPA-0815
XPA-0829

embedded image

XPA-0774
XPA-0788
XPA-0802
XPA-0816
XPA-0830

embedded image

XPA-0775
XPA-0789
XPA-0803
XPA-0817
XPA-0831

embedded image

XPA-0776
XPA-0790
XPA-0804
XPA-0818
XPA-0832

embedded image

XPA-0777
XPA-0791
XPA-0805
XPA-0819
XPA-0833

embedded image

XPA-0778
XPA-0792
XPA-0806
XPA-0820
XPA-0834

embedded image

XPA-0779
XPA-0793
XPA-0807
XPA-0821
XPA-0835

embedded image

XPA-0780
XPA-0794
XPA-0808
XPA-0822
XPA-0836

embedded image

XPA-0781
XPA-0795
XPA-0809
XPA-0823
XPA-0837

embedded image

XPA-0782
XPA-0796
XPA-0810
XPA-0824
XPA-0838

embedded image

XPA-0783
XPA-0797
XPA-0811
XPA-0825
XPA-0839

embedded image

XPA-0784
XPA-0798
XPA-0812
XPA-0826
XPA-0840

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

TABLE 20

B

A

embedded image

XPA-0841
XPA-0855
XPA-0869
XPA-0883
XPA-0897
XPA-0911
XPA-0925
XPA-0939
XPA-0953
XPA-0967
XPA-0981
XPA-1726

embedded image

XPA-0842
XPA-0856
XPA-0870
XPA-0884
XPA-0898
XPA-0912
XPA-0926
XPA-0940
XPA-0954
XPA-0968
XPA-0982
XPA-1727

embedded image

XPA-0843
XPA-0857
XPA-0871
XPA-0885
XPA-0899
XPA-0913
XPA-0927
XPA-0941
XPA-0955
XPA-0969
XPA-0983
XPA-1728

embedded image

XPA-0844
XPA-0858
XPA-0872
XPA-0886
XPA-0900
XPA-0914
XPA-0928
XPA-0942
XPA-0956
XPA-0970
XPA-0984
XPA-1729

embedded image

XPA-0845
XPA-0859
XPA-0873
XPA-0887
XPA-0901
XPA-0915
XPA-0929
XPA-0943
XPA-0957
XPA-0971
XPA-0985
XPA-1730

embedded image

XPA-0846
XPA-0860
XPA-0874
XPA-0888
XPA-0902
XPA-0916
XPA-0930
XPA-0944
XPA-0958
XPA-0972
XPA-0986
XPA-1731

embedded image

XPA-0847
XPA-0861
XPA-0875
XPA-0889
XPA-0903
XPA-0917
XPA-0931
XPA-0945
XPA-0959
XPA-0973
XPA-0987
XPA-1732

embedded image

XPA-0848
XPA-0862
XPA-0876
XPA-0890
XPA-0904
XPA-0918
XPA-0932
XPA-0946
XPA-0960
XPA-0974
XPA-0988
XPA-1733

embedded image

XPA-0849
XPA-0863
XPA-0877
XPA-0891
XPA-0905
XPA-0919
XPA-0933
XPA-0947
XPA-0961
XPA-0975
XPA-0989
XPA-1734

embedded image

XPA-0850
XPA-0864
XPA-0878
XPA-0892
XPA-0906
XPA-0920
XPA-0934
XPA-0948
XPA-0962
XPA-0976
XPA-0990
XPA-1735

embedded image

XPA-0851
XPA-0865
XPA-0879
XPA-0893
XPA-0907
XPA-0921
XPA-0935
XPA-0949
XPA-0963
XPA-0977
XPA-0991
XPA-1736

embedded image

XPA-0852
XPA-0866
XPA-0880
XPA-0894
XPA-0908
XPA-0922
XPA-0936
XPA-0950
XPA-0964
XPA-0978
XPA-0992
XPA-1737

embedded image

XPA-0853
XPA-0867
XPA-0881
XPA-0895
XPA-0909
XPA-0923
XPA-0937
XPA-0951
XPA-0965
XPA-0979
XPA-0993
XPA-1738

embedded image

XPA-0854
XPA-0868
XPA-0882
XPA-0896
XPA-0910
XPA-0924
XPA-0938
XPA-0952
XPA-0966
XPA-0980
XPA-0994
XPA-1739

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

TABLE 21

B

A

embedded image

XPA-0995
XPA-1190
XPA-1204
XPA-1218
XPA-1232
XPA-1740
XPA-1754
XPA-1768
XPA-1782
XPA-1796
XPA-1810

embedded image

XPA-0996
XPA-1191
XPA-1205
XPA-1219
XPA-1233
XPA-1741
XPA-1755
XPA-1769
XPA-1783
XPA-1797
XPA-1811

embedded image

XPA-0997
XPA-1192
XPA-1206
XPA-1220
XPA-1234
XPA-1742
XPA-1756
XPA-1770
XPA-1784
XPA-1798
XPA-1812

embedded image

XPA-0998
XPA-1193
XPA-1207
XPA-1221
XPA-1235
XPA-1743
XPA-1757
XPA-1771
XPA-1785
XPA-1799
XPA-1813

embedded image

XPA-0999
XPA-1194
XPA-1208
XPA-1222
XPA-1236
XPA-1744
XPA-1758
XPA-1772
XPA-1786
XPA-1800
XPA-1814

embedded image

XPA-1000
XPA-1195
XPA-1209
XPA-1223
XPA-1237
XPA-1745
XPA-1759
XPA-1773
XPA-1787
XPA-1801
XPA-1815

embedded image

XPA-1001
XPA-1196
XPA-1210
XPA-1224
XPA-1238
XPA-1746
XPA-1760
XPA-1774
XPA-1788
XPA-1802
XPA-1816

embedded image

XPA-1002
XPA-1197
XPA-1211
XPA-1225
XPA-1239
XPA-1747
XPA-1761
XPA-1775
XPA-1789
XPA-1803
XPA-1817

embedded image

XPA-1003
XPA-1198
XPA-1212
XPA-1226
XPA-1240
XPA-1748
XPA-1762
XPA-1776
XPA-1790
XPA-1804
XPA-1818

embedded image

XPA-1004
XPA-1199
XPA-1213
XPA-1227
XPA-1241
XPA-1749
XPA-1763
XPA-1777
XPA-1791
XPA-1805
XPA-1819

embedded image

XPA-1005
XPA-1200
XPA-1214
XPA-1228
XPA-1242
XPA-1750
XPA-1764
XPA-1778
XPA-1792
XPA-1806
XPA-1820

embedded image

XPA-1006
XPA-1201
XPA-1215
XPA-1229
XPA-1243
XPA-1751
XPA-1765
XPA-1779
XPA-1793
XPA-1807
XPA-1821

embedded image

XPA-1007
XPA-1202
XPA-1216
XPA-1230
XPA-1244
XPA-1752
XPA-1766
XPA-1780
XPA-1794
XPA-1808
XPA-1822

embedded image

XPA-1008
XPA-1203
XPA-1217
XPA-1231
XPA-1245
XPA-1753
XPA-1767
XPA-1781
XPA-1795
XPA-1809
XPA-1823

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

TABLE 22

B

A

embedded image

XPA-1887
XPA-1888
XPA-1889

embedded image

XPA-1016
XPA-1343
XPA-1835

embedded image

XPA-1249
XPA-1246
XPA-1345

embedded image

XPA-1824
XPA-1247
XPA-1836

embedded image

XPA-1825
XPA-1830
XPA-1251

embedded image

XPA-1826
XPA-1831
XPA-1258

embedded image

XPA-1827
XPA-1832
XPA-1260

embedded image

XPA-1855
XPA-1856
XPA-1857

embedded image

XPA-1828
XPA-1833
XPA-1837
XPA-I-0017

embedded image

XPA-1268
XPA-1267
XPA-1838

embedded image

XPA-1289
XPA-1288
XPA-1839

embedded image

XPA-1829
XPA-1834
XPA-1840

The above table constitutes an individualized description of the specifically indicated compound therein as well as its salts and solvates, and the intermediate as well as its salts and solvates used for the synthesis of the specifically indicated compound. 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 23

B

A

embedded image

XPA-1012
XPA-I-0005
XPA-1347
XPA-I-0008
XPA-1018

XPA-1252
XPA-1255

embedded image

XPA-1011
XPA-I-0004
XPA-I-0009
XPA-1342
XPA-1019

embedded image

XPA-1892
XPA-1248
XPA-I-0011
XPA-I-0013
XPA-1020

embedded image

XPA-1013
XPA-1341
XPA-1890
XPA-1885
XPA-1257

XPA-1017
XPA-1254

embedded image

XPA-1891
XPA-1886
XPA-I-0014
XPA-I-0015
XPA-1021

embedded image

XPA-1010
XPA-I-0003
XPA-1014
XPA-1015

XPA-1250

XPA-1893

embedded image

XPA-1009
XPA-1340
XPA-1259
XPA-1346
XPA-1261

XPA-1253
XPA-1256

embedded image

XPA-1034
XPA-1035
XPA-1265

XPA-I-0001

The above table constitutes an individualized description of each of the specifically indicated compounds therein as well as their salts and solvates, and intermediates as well as their salts and solvates used for the synthesis of the specifically indicated compounds. 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 24

B

A

embedded image

XPA-1262
XPA-1841
XPA-1842
XPA-1843
XPA-1263
XPA-1894
XPA-1264
XPA-1848
XPA-1849
XPA-1850
XPA-1851

embedded image

XPA-1269
XPA-1273
XPA-1277
XPA-1283
XPA-1844
XPA-1895
XPA-1846
XPA-1271
XPA-1275
XPA-1279
XPA-1285

embedded image

XPA-1270
XPA-1274
XPA-1278
XPA-1284
XPA-1845
XPA-1896
XPA-1847
XPA-1272
XPA-1276
XPA-1280
XPA-1286

The above table constitutes an individualized description of the specifically indicated compound therein as well as its salts and solvates.

TABLE 25

B

A

embedded image

XPA-I-0019
XPA-1287
XPA-1290
XPA-1294

embedded image

XPA-1852
XPA-1853
XPA-1854

TABLE 26

B

A

embedded image

XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-1865
XPA-
XPA-

1897
1898
1858
1859
1860
1861
1862
1863
1864

1866
1867

embedded image

XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-
XPA-1336
XPA-
XPA-

1302
1303
1304
1322

1305
1323
1329
1337

1307
1332

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

TABLE 27

B

A

embedded image

XPA-1291
XPA-1292
XPA-1294
XPA-1293
XPA-1296
XPA-1297
XPA-1298
XPA-1306
XPA-1324
XPA-1330

embedded image

XPA-1868
XPA-1869
XPA-1870
XPA-1871
XPA-1872
XPA-1873
XPA-1874
XPA-1875
XPA-1876
XPA-1877

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

TABLE 28

B

A

embedded image

XPA-1878
XPA-1879
XPA-1880
XPA-1881
XPA-1882

embedded image

XPA-1334
XPA-1335
XPA-1333
XPA-1338
XPA-1339

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

TABLE 29

B

A

embedded image

XPA-1301
XPA-1319
XPA-1325
XPA-1344
XPA-1883
XPA-1884

embedded image

XPA-1299
XPA-1320
XPA-1326
XPA-1300
XPA-1321
XPA-1327

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

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.

Further Definitions

The term “C₁-C₁₂alkyl” 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 “C₂-C₁₂alkenyl” 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 “C₂-C₁₂alkynyl” 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 “C₃-C₈cycloalkyl” 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 “C₅-C₈cycloalkenyl” comprises the corresponding unsaturated non-aromatic and non-heteroaromatic hydrocarbon groups containing five to eight carbon atoms, of which at least one is sp³-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-C₁₂bicycloalkyl” 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 “C₇-C₁₂bicycloalkenyl” 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 “C₈-C₁₄tricycloalkyl” 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 R¹mean that such cyclic, bicyclic or tricyclic residue is directly linked by a chemical bond to the aromatic ring to which R¹is bound, and wherein the terms “cyclic”, “bicyclic”, “tricyclic”, “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl”, “bicycloalkenyl” and “tricycloalkyl” for a substituent of R¹mean 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 R¹; e.g. “R¹is cyclohexyl” means that the cyclohexyl residue is linked to the aromatic ring to which R¹is bound; and “R¹is methyl and R¹is substituted with cyclohexyl” means that the resulting —CH₂(cyclohexyl) residue is linked to the aromatic ring to which R¹is bound.

In case a carbon atom is replaced by a heteroatom selected from O, N, or S, the number of substituents on the respective heteroatom is adapted according to its valency, e.g. a —CR₂— group may be replaced by a —NR—, —NR₂⁺—, —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 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 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^thed., 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 31H-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 (Ia), (Tb) 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 C₂-C₁₂. The cells were treated with compounds at indicated final concentrations (diluted from the 1000× 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 30 to Table 62 and by their sum formula in Table 63.

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^thedition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauβ′ 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% CO₂.

A compound is considered as a growth inhibitor of HL-60 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation 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 (Ta), (Tb) 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 30 and Table 31. The entries of Table 30 and Table 31 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 30

Proliferation assay with HL-60 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0006

3
XPA-1289

4
XPA-1325

0.7 < AVE_w≤ 0.8
5
XPA-0020

6
XPA-0064

7
XPA-0188

8
XPA-0840

9
XPA-1274

10
XPA-1296

11
XPA-1307

0.6 < AVE_w≤ 0.7
12
XPA-0160

13
XPA-1276

14
XPA-1277

15
XPA-1279

16
XPA-1283

17
XPA-1288

18
XPA-1308

19
XPA-1334

0.4 < AVE_w≤ 0.6
20
XPA-0007

21
XPA-0028

22
XPA-0132

23
XPA-0174

24
XPA-0672

25
XPA-1298

26
XPA-1310

27
XPA-1311

28
XPA-1322

29
XPA-1333

0.4 ± 0.1
30
RES
Control at 20 μM

0.2 < AVE_w≤ 0.4
31
XPA-0146

32
XPA-0154

33
XPA-0644

34
XPA-0658

35
XPA-1285

36
XPA-1293

37
XPA-1302

38
XPA-1306

39
XPA-1323

40
XPA-1331

0.2 ± 0.1
41
RES
Control at 40 μM

0.1 ± 0.1
42
MTREX
Control at 20 μM

0.0 < AVE_w≤ 0.2
43
XPA-0140

44
XPA-0182

45
XPA-0230

46
XPA-0238

47
XPA-0280

48
XPA-1278

49
XPA-1280

50
XPA-1284

51
XPA-1286

52
XPA-1299
Measured at 10 μM

53
XPA-1300
Measured at 10 μM

54
XPA-1309

55
XPA-1312

56
XPA-1313

57
XPA-1315

58
XPA-1316

59
XPA-1317

60
XPA-1318

61
XPA-1324

62
XPA-1326

63
XPA-1337

64
XPA-1338

65
XPA-1339

TABLE 31

Proliferation assay with HL-60 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.6 < AVE_w≤ 0.7
2
XPA-0070

0.4 ± 0.1
3
RES
Control at 20 μM

0.2 ± 0.1
4
RES
Control at 40 μM

0.2 < AVE_w≤ 0.4
5
XPA-0574

0.1 ± 0.1
6
MTREX
Control at 20 μM

The data in Table 30 relate to novel compounds, wherein the data in Table 31 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% CO₂.

A compound is considered as a growth inhibitor of NB-4 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation 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 (Ib) 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 32 and Table 33. The entries of Table 32 and Table 33 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 32

Proliferation assay with NB-4 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0020

3
XPA-0060

4
XPA-0146

5
XPA-0644

6
XPA-0672

7
XPA-1288

8
XPA-1289

9
XPA-1298

10
XPA-1310

11
XPA-1335

0.7 < AVE_w≤ 0.8
12
XPA-1321

0.6 < AVE_w≤ 0.7
13
XPA-0140

14
XPA-1293

15
XPA-1331

0.4 < AVE_w≤ 0.6
16
XPA-0028

17
XPA-0154

18
XPA-1274

19
XPA-1276

20
XPA-1280

21
XPA-1322

22
XPA-1333

0.2 < AVE_w≤ 0.4
23
XPA-0064

24
XPA-0658

25
XPA-1278

26
XPA-1284

27
XPA-1286

28
XPA-1323

0.1 ± 0.0
29
MTREX
Control at 20 μM

0.1 ± 0.0
30
RES
Control at 20 μM

0.0 < AVE_w≤ 0.2
31
XPA-0182

32
XPA-0230

33
XPA-0238

34
XPA-0280

35
XPA-1299
Measured at 10 μM

36
XPA-1300
Measured at 10 μM

37
XPA-1306

38
XPA-1309

39
XPA-1312

40
XPA-1313

41
XPA-1315

42
XPA-1316

43
XPA-1317

44
XPA-1318

45
XPA-1324

46
XPA-1326

47
XPA-1337

48
XPA-1338

49
XPA-1339

0.0 ± 0.0
50
RES
Control at 40 μM

TABLE 33

Proliferation assay with NB-4 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0033

3
XPA-0042

4
XPA-0044

5
XPA-0310

6
XPA-0547

7
XPA-0565

8
XPA-0814

9
XPA-1009

10
XPA-1011

11
XPA-1013

12
XPA-1017

13
XPA-1018

14
XPA-1019

15
XPA-1020

16
XPA-1021

17
XPA-1262

18
XPA-1263

19
XPA-1832

0.7 < AVE_w≤ 0.8
20
XPA-0313

21
XPA-0817

0.1 ± 0.0
22
MTREX
Control at 20 μM

0.1 ± 0.0
23
RES
Control at 20 μM

0.0 ± 0.0
24
RES
Control at 40 μM

The data in Table 32 relate to novel compounds, wherein the data in Table 33 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% CO₂.

A compound is considered as a growth inhibitor of HH cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after 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 (Ib) 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 34 and Table 35. The entries of Table 34 and Table 35 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 34

Proliferation assay with HH cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0512

0.7 < AVE_w≤ 0.8
3
XPA-0140

4
XPA-0182

5
XPA-1280

6
XPA-1322

7
XPA-1335

0.6 < AVE_w≤ 0.7
8
XPA-0060

9
XPA-1278

10
XPA-1284

11
XPA-1323

0.6 ± 0.1
12
RES
Control at 20 μM

0.4 < AVE_w≤ 0.6
13
XPA-0064

14
XPA-1286

15
XPA-1306

16
XPA-1309

17
XPA-1326

18
XPA-1339

0.4 ± 0.1
19
MTREX
Control at 20 μM

0.4 ± 0.1
20
RES
Control at 40 μM

0.2 < AVE_w≤ 0.4
21
XPA-1274

22
XPA-1276

23
XPA-1324

0.0 < AVE_w≤ 0.2
24
XPA-0230

25
XPA-0238

26
XPA-1312

27
XPA-1313

28
XPA-1315

29
XPA-1316

30
XPA-1317

31
XPA-1318

32
XPA-1338

TABLE 35

Proliferation assay with HH cells at 20 M

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0033

3
XPA-0042

4
XPA-0294

5
XPA-0804

6
XPA-1009

7
XPA-1018

8
XPA-1019

9
XPA-1857

0.6 ± 0.1
10
RES
Control at 20 μM

0.4 ± 0.1
11
MTREX
Control at 20 μM

0.4 ± 0.1
12
RES
Control at 40 μM

The data in Table 34 relate to novel compounds, wherein the data in Table 35 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 μM—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 (Ta), (Tb) 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 36 and Table 37. The entries of Table 36 and Table 37 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 36

Proliferation assay with RPMI-8402 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0008

3
XPA-0009

4
XPA-0063

5
XPA-0076

6
XPA-0196

7
XPA-0328

8
XPA-0505

9
XPA-0506

10
XPA-0510

11
XPA-0518

12
XPA-0532

13
XPA-0563

14
XPA-1269

15
XPA-1271

16
XPA-1272

17
XPA-1274

18
XPA-1287

19
XPA-1297

20
XPA-1303

21
XPA-1328

22
XPA-1329

23
XPA-1330

24
XPA-1336

0.7 < AVE_w≤ 0.8
25
XPA-0079

26
XPA-0511

27
XPA-0524

28
XPA-0580

29
XPA-0832

30
XPA-0840

31
XPA-1266

32
XPA-1267

33
XPA-1270

34
XPA-1282

35
XPA-1300
Measured at 10 μM

36
XPA-1320

37
XPA-1321

38
XPA-1332

39
XPA-1334

0.6 < AVE_w≤ 0.7
40
XPA-0006

41
XPA-0188

42
XPA-1276

43
XPA-1288

44
XPA-1307

45
XPA-1311

46
XPA-1325

0.6 ± 0.0
47
RES
Control at 20 μM

0.4 < AVE_w≤ 0.6
48
XPA-0007

49
XPA-0014

50
XPA-0020

51
XPA-0028

52
XPA-0060

53
XPA-0132

54
XPA-0160

55
XPA-0174

56
XPA-0280

57
XPA-0512

58
XPA-0644

59
XPA-0658

60
XPA-0672

61
XPA-1277

62
XPA-1279

63
XPA-1283

64
XPA-1285

65
XPA-1293

66
XPA-1298

67
XPA-1302

68
XPA-1308

69
XPA-1310

70
XPA-1333

0.2 < AVE_w≤ 0.4
71
XPA-0140

72
XPA-0146

73
XPA-0154

74
XPA-1278

75
XPA-1284

76
XPA-1286

77
XPA-1326

78
XPA-1331

79
XPA-1337

0.1 ± 0.0
80
MTREX
Control at 20 μM

0.1 ± 0.0
81
RES
Control at 40 μM

0.0 < AVE_w≤ 0.2
82
XPA-0064

83
XPA-0182

84
XPA-0230

85
XPA-0238

86
XPA-1280

87
XPA-1299
Measured at 10 μM

88
XPA-1306

89
XPA-1309

90
XPA-1312

91
XPA-1313

92
XPA-1315

93
XPA-1316

94
XPA-1317

95
XPA-1318

96
XPA-1322

97
XPA-1323

98
XPA-1324

99
XPA-1338

100
XPA-1339

TABLE 37

Proliferation assay with RPMI-8402 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0322

3
XPA-0562

4
XPA-0803

5
XPA-0818

6
XPA-1247

7
XPA-1251

8
XPA-1258

0.7 < AVE_w≤ 0.8
9
XPA-0048

10
XPA-0053

11
XPA-0054

12
XPA-0067

13
XPA-0068

14
XPA-0308

15
XPA-0313

16
XPA-0571

17
XPA-0817

18
XPA-1250

19
XPA-1343

0.6 < AVE_w≤ 0.7
20
XPA-0047

21
XPA-0056

22
XPA-0061

23
XPA-0070

24
XPA-0565

25
XPA-0572

26
XPA-1035

0.6 ± 0.0
27
RES
Control at 20 μM

0.4 < AVE_w≤ 0.6
28
XPA-0574

29
XPA-1262

30
XPA-1263

0.1 ± 0.0
31
MTREX
Control at 20 μM

0.1 ± 0.0
32
RES
Control at 40 μM

The data in Table 36 relate to novel compounds, wherein the data in Table 37 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 μM—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 (Ia), (Tb) 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 38 and Table 39. The entries of Table 38 and Table 39 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 38

Proliferation assay with TANQUE cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0014

3
XPA-0063

4
XPA-0160

5
XPA-0505

6
XPA-0510

7
XPA-0511

8
XPA-0518

9
XPA-0532

10
XPA-0580

11
XPA-0832

12
XPA-1282

13
XPA-1290

14
XPA-1303

15
XPA-1321

16
XPA-1328

0.7 < AVE_w≤ 0.8
17
XPA-0020

18
XPA-1267

19
XPA-1325

0.6 < AVE_w≤ 0.7
20
XPA-0007

0.4 < AVE_w≤ 0.6
21
XPA-0132

22
XPA-0672

23
XPA-1274

24
XPA-1276

25
XPA-1277

26
XPA-1279

27
XPA-1283

28
XPA-1293

29
XPA-1310

0.2 < AVE_w≤ 0.4
30
XPA-0154

31
XPA-0174

32
XPA-0644

33
XPA-0658

34
XPA-1285

35
XPA-1298

36
XPA-1322

37
XPA-1331

0.1 ± 0.0
38
MTREX
Control at 20 μM

0.1 ± 0.0
39
RES
Control at 20 μM

0.0 < AVE_w≤ 0.2
40
XPA-0028

41
XPA-0064

42
XPA-0140

43
XPA-0146

44
XPA-0182

45
XPA-0230

46
XPA-0238

47
XPA-0280

48
XPA-1278

49
XPA-1280

50
XPA-1284

51
XPA-1286

52
XPA-1302

53
XPA-1306

54
XPA-1309

55
XPA-1312

56
XPA-1313

57
XPA-1315

58
XPA-1316

59
XPA-1317

60
XPA-1318

61
XPA-1323

62
XPA-1324

63
XPA-1326

64
XPA-1337

65
XPA-1338

66
XPA-1339

0.0 ± 0.0
67
RES
Control at 40 μM

TABLE 39

Proliferation assay with TANQUE cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0034

3
XPA-0044

4
XPA-0048

5
XPA-0054

6
XPA-0067

7
XPA-0070

8
XPA-0300

9
XPA-0308

10
XPA-0561

11
XPA-0571

12
XPA-0814

13
XPA-0826

14
XPA-1018

15
XPA-1021

16
XPA-1035

17
XPA-1249

18
XPA-1258

19
XPA-1340

20
XPA-1341

21
XPA-1343

22
XPA-1345

0.7 < AVE_w≤ 0.8
23
XPA-0047

24
XPA-0299

25
XPA-0313

26
XPA-0565

27
XPA-0572

28
XPA-0574

29
XPA-0817

30
XPA-1015

0.6 < AVE_w≤ 0.7
31
XPA-1263

0.4 < AVE_w≤ 0.6
32
XPA-0061

0.2 < AVE_w≤ 0.4
33
XPA-1262

0.1 ± 0.0
34
MTREX
Control at 20 μM

0.1 ± 0.0
35
RES
Control at 20 μM

0.0 ± 0.0
36
RES
Control at 40 μM

The data in Table 38 relate to novel compounds, wherein the data in Table 39 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 μM—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 (Ia), (Ib) 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 40 and Table 41. The entries of Table 40 and Table 41 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 40

Proliferation assay with MDA-MB-231 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0020

3
XPA-0036
Used as HCl Salt

4
XPA-0063

5
XPA-0076

6
XPA-0328

7
XPA-0505

8
XPA-0511

9
XPA-0512

10
XPA-0519

11
XPA-0520

12
XPA-0524

13
XPA-0535

14
XPA-0563

15
XPA-1281

16
XPA-1296

17
XPA-1301

18
XPA-1310

19
XPA-1321

20
XPA-1330

21
XPA-1344

0.7 < AVE_w≤ 0.8
22
XPA-0008

23
XPA-0009

24
XPA-0028

25
XPA-0196

26
XPA-0336

27
XPA-0506

28
XPA-0510

29
XPA-0518

30
XPA-0532

31
XPA-0569

32
XPA-0580

33
XPA-1266

34
XPA-1267

35
XPA-1288

36
XPA-1290

37
XPA-1297

38
XPA-1307

39
XPA-1308

40
XPA-1325

41
XPA-1327

42
XPA-1328

43
XPA-1334

44
XPA-1337

0.6 < AVE_w≤ 0.7
45
XPA-0006

46
XPA-0079

47
XPA-0160

48
XPA-0188

49
XPA-0280

50
XPA-0832

51
XPA-0840

52
XPA-1283

0.6 ± 0.0
53
MTREX
Control at 20 μM

0.6 ± 0.0
54
RES
Control at 20 μM

0.4 < AVE_w≤ 0.6
55
XPA-0014

56
XPA-0060

57
XPA-0064

58
XPA-1282

59
XPA-1285

60
XPA-1326

61
XPA-1333

0.2 < AVE_w≤ 0.4
62
XPA-0007

63
XPA-0140

64
XPA-0154

65
XPA-0174

66
XPA-0644

67
XPA-1277

68
XPA-1279

69
XPA-1284

70
XPA-1286

71
XPA-1298

72
XPA-1306

73
XPA-1324

74
XPA-1331

75
XPA-1338

76
XPA-1339

0.0 < AVE_w≤ 0.2
77
XPA-0132

78
XPA-0146

79
XPA-0182

80
XPA-0230

81
XPA-0238

82
XPA-0658

83
XPA-0672

84
XPA-1278

85
XPA-1280

86
XPA-1293

87
XPA-1309

88
XPA-1312

89
XPA-1313

90
XPA-1315

91
XPA-1316

92
XPA-1317

93
XPA-1318

TABLE 41

Proliferation assay with MDA-MB-231 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0062

3
XPA-0814

4
XPA-0826

5
XPA-1034

6
XPA-1264

7
XPA-1265

8
XPA-1342

0.7 < AVE_w≤ 0.8
9
XPA-0047

10
XPA-0048

11
XPA-0053

12
XPA-0308

13
XPA-0817

14
XPA-0818

0.6 < AVE_w≤ 0.7
15
XPA-0056

16
XPA-0067

17
XPA-0068

18
XPA-0070

19
XPA-0571

20
XPA-1015

21
XPA-1035

22
XPA-1343

0.6 ± 0.0
23
MTREX
Control at 20 μM

0.6 ± 0.0
24
RES
Control at 20 μM

0.4 < AVE_w≤ 0.6
25
XPA-0054

26
XPA-0061

27
XPA-0565

28
XPA-0572

29
XPA-0574

30
XPA-1262

31
XPA-1263

The data in Table 40 relate to novel compounds, wherein the data in Table 41 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 1 mM sodium pyruvate (Fisherscientific, #11501871) at 37° C. and 5% CO₂.

A compound is considered as a growth inhibitor of FU-OV-1 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation 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 (Ib) and (Ic), respectively, 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 42 and Table 43. The entries of Table 42 and Table 43 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 42

Proliferation assay with FU-OV-1 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

1.0 ± 0.0
2
MTREX
Control at 20 μM

0.7 ± 0.0
3
RES
Control at 20 μM

0.6 < AVE_w≤ 0.7
4
XPA-1324

0.4 ± 0.0
5
RES
Control at 40 μM

0.0 < AVE_w≤ 0.2
6
XPA-0230

7
XPA-0238

8
XPA-1312

9
XPA-1313

10
XPA-1315

11
XPA-1316

12
XPA-1317

13
XPA-1318

TABLE 43

Proliferation assay with FU-OV-1 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1 ± 0.0
1
MTREX
Control at 20 μM

1.0 ± 0.0
2
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
3
XPA-0786

4
XPA-1018

5
XPA-1019

6
XPA-1247

7
XPA-1256

8
XPA-1257

9
XPA-1261

0.7 ± 0.0
10
RES
Control at 20 μM

0.4 ± 0.0
11
RES
Control at 40 μM

The data in Table 42 relate to novel compounds, wherein the data in Table 43 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% CO₂.

A compound is considered as a growth inhibitor of LOU-NH91 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation 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 (Ib) 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 44 and Table 45. The entries of Table 44 and Table 45 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 44

Proliferation assay with LOU-NH91 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.9 ± 0.1
2
RES
Control at 20 μM

0.8 < AVE_w≤ 0.9
3
XPA-0028

4
XPA-0132

5
XPA-0154

6
XPA-0174

7
XPA-0532

8
XPA-1277

9
XPA-1293

10
XPA-1298

11
XPA-1322

12
XPA-1323

13
XPA-1325

0.7 < AVE_w≤ 0.8
14
XPA-0644

15
XPA-0658

16
XPA-1279

17
XPA-1326

18
XPA-1331

0.7 ± 0.0
19
RES
Control at 40 μM

0.6 < AVE_w≤ 0.7
20
XPA-0140

21
XPA-0280

22
XPA-1286

23
XPA-1309

0.5 ± 0.1
24
MTREX
Control at 20 μM

0.4 < AVE_w≤ 0.6
25
XPA-1278

26
XPA-1280

27
XPA-1284

28
XPA-1338

29
XPA-1339

0.2 < AVE_w≤ 0.4
30
XPA-0182

31
XPA-1306

32
XPA-1324

0.0 < AVE_w≤ 0.2
33
XPA-0230

34
XPA-0238

35
XPA-1312

36
XPA-1313

37
XPA-1315

38
XPA-1316

39
XPA-1317

40
XPA-1318

TABLE 45

Proliferation assay with LOU-NH91 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.9 ± 0.1
2
RES
Control at 20 μM

0.8 < AVE_w≤ 0.9
3
XPA-0047

4
XPA-0565

5
XPA-0817

6
XPA-1254

7
XPA-1345

0.7 < AVE_w≤ 0.8
8
XPA-0562

9
XPA-0786

10
XPA-0789

11
XPA-1015

12
XPA-1253

13
XPA-1255

14
XPA-1256

0.7 ± 0.0
15
RES
Control at 40 μM

0.5 ± 0.1
16
MTREX
Control at 20 μM

0.2 < AVE_w≤ 0.4
17
XPA-1262

The data in Table 44 relate to novel compounds, wherein the data in Table 45 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% CO₂.

A compound is considered as a growth inhibitor of 23132/87 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation 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 (Ta), (Tb) 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 46 and Table 47. The entries of Table 46 and Table 47 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 46

Proliferation assay with 23132/87 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0132

3
XPA-0672

4
XPA-1302

0.7 < AVE_w≤ 0.8
5
XPA-0064

6
XPA-0140

7
XPA-0160

8
XPA-0174

9
XPA-1277

10
XPA-1284

11
XPA-1323

12
XPA-1325

0.6 < AVE_w≤ 0.7
13
XPA-0146

14
XPA-0154

15
XPA-1286

0.5 ± 0.1
16
RES
Control at 20 μM

0.3 ± 0.0
17
MTREX
Control at 20 μM

0.2 < AVE_w≤ 0.4
18
XPA-1278

19
XPA-1280

20
XPA-1306

0.2 ± 0.0
21
RES
Control at 40 μM

0.0 < AVE_w≤ 0.2
22
XPA-0182

23
XPA-0230

24
XPA-0238

25
XPA-1309

26
XPA-1312

27
XPA-1313

28
XPA-1315

29
XPA-1316

30
XPA-1317

31
XPA-1318

32
XPA-1324

33
XPA-1326

34
XPA-1338

35
XPA-1339

TABLE 47

Proliferation assay with 23132/87 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0047

3
XPA-1263

0.5 ± 0.1
4
RES
Control at 20 μM

0.3 ± 0.0
5
MTREX
Control at 20 μM

0.2 ± 0.0
6
RES
Control at 40 μM

The data in Table 46 relate to novel compounds, wherein the data in Table 47 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% CO₂.

A compound is considered as a growth inhibitor of CAL-27 cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation 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 (Ia) and (Tb), 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 48. The entries of Table 48 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 48

Proliferation assay with CAL-27 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 ± 0.1
2
RES
Control at 20 μM

0.7 < AVE_w≤ 0.8
3
XPA-0007

4
XPA-0644

5
XPA-1277

6
XPA-1298

0.6 < AVE_w≤ 0.7
7
XPA-0672

8
XPA-1279

9
XPA-1284

10
XPA-1324

11
XPA-1339

0.4 < AVE_w≤ 0.6
12
XPA-0060

13
XPA-0132

14
XPA-1286

15
XPA-1293

16
XPA-1306

17
XPA-1326

18
XPA-1338

0.4 ± 0.3
19
RES
Control at 40 μM

0.2 < AVE_w≤ 0.4
20
XPA-0140

21
XPA-0146

22
XPA-0154

23
XPA-0174

24
XPA-1278

25
XPA-1280

26
XPA-1309

0.1 ± 0.0
27
MTREX
Control at 20 μM

0.0 < AVE_w≤ 0.2
28
XPA-0064

29
XPA-0182

30
XPA-0230

31
XPA-0238

32
XPA-0658

33
XPA-1312

34
XPA-1313

35
XPA-1315

36
XPA-1316

37
XPA-1317

38
XPA-1318

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% CO₂.

A compound is considered as a growth inhibitor of BHY cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after addition of the corresponding combined standard deviation 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 (Ta), (Tb) 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 49 and Table 50. The entries of Table 49 and Table 50 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 49

Proliferation assay with BHY cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0006

3
XPA-0154

4
XPA-0644

5
XPA-1323

6
XPA-1326

0.7 < AVE_w≤ 0.8
7
XPA-0007

8
XPA-0060

9
XPA-0140

10
XPA-0146

11
XPA-1277

0.6 < AVE_w≤ 0.7
12
XPA-0174

13
XPA-1279

14
XPA-1293

15
XPA-1338

0.5 ± 0.1
16
RES
Control at 20 μM

0.4 < AVE_w≤ 0.6
17
XPA-0132

18
XPA-0658

19
XPA-1278

20
XPA-1280

21
XPA-1306

22
XPA-1324

0.3 ± 0.0
23
MTREX
Control at 20 μM

0.3 ± 0.0
24
RES
Control at 40 μM

0.2 < AVE_w≤ 0.4
25
XPA-1309

0.0 < AVE_w≤ 0.2
26
XPA-0064

27
XPA-0182

28
XPA-0230

29
XPA-0238

30
XPA-1312

31
XPA-1313

32
XPA-1315

33
XPA-1316

34
XPA-1317

35
XPA-1318

TABLE 50

Proliferation assay with BHY cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0565

0.5 ± 0.1
3
RES
Control at 20 μM

0.3 ± 0.0
4
MTREX
Control at 20 μM

0.3 ± 0.0
5
RES
Control at 40 μM

The data in Table 49 relate to novel compounds, wherein the data in Table 50 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 1 mM 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 μM—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 (Ib) 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 51 and Table 52. The entries of Table 51 and Table 52 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 51

Proliferation assay with SCC-25 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0020

3
XPA-0028

4
XPA-0520

5
XPA-0532

6
XPA-1269

7
XPA-1270

8
XPA-1271

9
XPA-1272

10
XPA-1274

11
XPA-1276

12
XPA-1302

13
XPA-1304

14
XPA-1307

15
XPA-1325

16
XPA-1329

17
XPA-1331

18
XPA-1332

19
XPA-1334

0.7 < AVE_w≤ 0.8
20
XPA-1284

21
XPA-1286

22
XPA-1335

23
XPA-1337

0.6 < AVE_w≤ 0.7
24
XPA-1322

0.5 ± 0.1
25
MTREX
Control at 20 μM

0.4 < AVE_w≤ 0.6
26
XPA-1323

27
XPA-1338

0.4 ± 0.1
28
RES
Control at 20 μM

0.2 < AVE_w≤ 0.4
29
XPA-0060

30
XPA-0140

31
XPA-1278

32
XPA-1280

33
XPA-1306

34
XPA-1309

35
XPA-1324

36
XPA-1339

0.1 ± 0.0
37
RES
Control at 40 μM

0.0 < AVE_w≤ 0.2
38
XPA-0064

39
XPA-0182

40
XPA-0230

41
XPA-0238

42
XPA-1312

43
XPA-1313

44
XPA-1315

45
XPA-1316

46
XPA-1317

47
XPA-1318

48
XPA-1326

TABLE 52

Proliferation assay with SCC-25 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0044

3
XPA-0047

4
XPA-0061

5
XPA-0068

6
XPA-0546

7
XPA-0558

8
XPA-0560

9
XPA-0571

10
XPA-0574

11
XPA-0803

12
XPA-1015

13
XPA-1251

14
XPA-1262

0.7 < AVE_w≤ 0.8
15
XPA-0042

16
XPA-0565

17
XPA-0572

18
XPA-1035

19
XPA-1265

0.5 ± 0.1
20
MTREX
Control at 20 μM

0.4 ± 0.1
21
RES
Control at 20 μM

0.1 ± 0.0
22
RES
Control at 40 μM

The data in Table 51 relate to novel compounds, wherein the data in Table 52 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 μM—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 (Ta) and (Tb), 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 53 and Table 54. The entries of Table 53 and Table 54 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 53

Proliferation assay with A-431 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0020

3
XPA-0028

4
XPA-0060

5
XPA-0174

6
XPA-0520

7
XPA-1277

8
XPA-1279

0.7 < AVE_w≤ 0.8
9
XPA-0006

10
XPA-0132

11
XPA-0524

12
XPA-1293

13
XPA-1298

14
XPA-1299
Measured at 10 μM

15
XPA-1331

0.6 < AVE_w≤ 0.7
16
XPA-1280

17
XPA-1310

0.6 ± 0.0
18
RES
Control at 20 μM

0.4 < AVE_w≤ 0.6
19
XPA-0140

20
XPA-0672

21
XPA-1278

22
XPA-1284

23
XPA-1286

24
XPA-1306

25
XPA-1338

0.2 < AVE_w≤ 0.4
26
XPA-0146

27
XPA-0658

28
XPA-1324

0.2 ± 0.1
29
MTREX
Control at 20 μM

0.2 ± 0.0
30
RES
Control at 40 μM

0.0 < AVE_w≤ 0.2
31
XPA-0064

32
XPA-0154

33
XPA-0182

34
XPA-0230

35
XPA-0238

36
XPA-1309

37
XPA-1312

38
XPA-1313

39
XPA-1315

40
XPA-1316

41
XPA-1317

42
XPA-1318

43
XPA-1339

TABLE 54

Proliferation assay with A-431 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0048

3
XPA-0054

4
XPA-0056

5
XPA-0067

6
XPA-0300

7
XPA-0314

8
XPA-0565

9
XPA-0814

10
XPA-0817

11
XPA-1017

12
XPA-1018

13
XPA-1020

14
XPA-1247

15
XPA-1248

16
XPA-1250

17
XPA-1251

18
XPA-1252

19
XPA-1253

20
XPA-1265

21
XPA-1343

22
XPA-1345

0.7 < AVE_w≤ 0.8
23
XPA-0047

24
XPA-0061

25
XPA-0299

26
XPA-0313

27
XPA-0571

28
XPA-0572

29
XPA-0803

30
XPA-1015

31
XPA-1035

32
XPA-1246

33
XPA-1262

34
XPA-1263

35
XPA-1264

0.6 ± 0.0
36
RES
Control at 20 μM

0.2 ± 0.1
37
MTREX
Control at 20 μM

0.2 ± 0.0
38
RES
Control at 40 μM

The data in Table 53 relate to novel compounds, wherein the data in Table 54 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 μM—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 (Ta) and (Tb), respectively, have been identified as growth inhibitors of HPEKp cells. The so far identified HPEKp growth inhibitors relate to the compounds listed in Table 55, Table 56 and Table 57. The entries of Table 55, Table 56 and Table 57 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 HPEKp cells at 10 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.9 ± 0.0
2
MTREX
Control at 20 μM

0.8 < AVE_w≤ 0.9
3
XPA-0001

4
XPA-0510

5
XPA-0511

6
XPA-0524

7
XPA-0580

8
XPA-0840

9
XPA-1267

10
XPA-1282

11
XPA-1305

0.7 < AVE_w≤ 0.8
12
XPA-0007

13
XPA-0519

14
XPA-1288

15
XPA-1295

16
XPA-1300
Measured at 10 μM

17
XPA-1304

18
XPA-1311

19
XPA-1328

20
XPA-1336

0.6 < AVE_w≤ 0.7
21
XPA-0076

22
XPA-0146

23
XPA-0188

24
XPA-0328

25
XPA-0505

26
XPA-0506

27
XPA-1293

28
XPA-1294

29
XPA-1301

0.4 < AVE_w≤ 0.6
30
XPA-0002

31
XPA-0006

32
XPA-0008

33
XPA-0020

34
XPA-0132

35
XPA-0210

36
XPA-0238

37
XPA-0520

38
XPA-0532

39
XPA-1269

40
XPA-1271

41
XPA-1277

42
XPA-1307

43
XPA-1308

44
XPA-1318

45
XPA-1332

46
XPA-1334

47
XPA-1337

0.2 < AVE_w≤ 0.4
48
XPA-0060

49
XPA-0336

50
XPA-1273

51
XPA-1275

52
XPA-1298

53
XPA-1299
Measured at 10 μM

54
XPA-1327

55
XPA-1335

0.2 ± 0.0
56
RES
Control at 20 μM

0.2 ± 0.0
57
RES
Control at 40 μM

0.0 < AVE_w≤ 0.2
58
XPA-0014

59
XPA-0028

60
XPA-0064

61
XPA-0140

62
XPA-0154

63
XPA-0168

64
XPA-0174

65
XPA-0182

66
XPA-0196

67
XPA-0230

68
XPA-0280

69
XPA-0512

70
XPA-0644

71
XPA-0658

72
XPA-0672

73
XPA-1270

74
XPA-1272

75
XPA-1274

76
XPA-1276

77
XPA-1278

78
XPA-1279

79
XPA-1280

80
XPA-1283

81
XPA-1284

82
XPA-1285

83
XPA-1286

84
XPA-1290

85
XPA-1302

86
XPA-1306

87
XPA-1309

88
XPA-1312

89
XPA-1313

90
XPA-1315

91
XPA-1316

92
XPA-1317

93
XPA-1320

94
XPA-1321

95
XPA-1322

96
XPA-1323

97
XPA-1324

98
XPA-1325

99
XPA-1326

100
XPA-1331

101
XPA-1333

102
XPA-1338

103
XPA-1339

TABLE 56

Proliferation assay with HPEKp cells at 10 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.9 ± 0.0
2
MTREX
Control 20 μM

0.8 < AVE_w≤ 0.9
3
XPA-0282

4
XPA-1014

0.6 < AVE_w≤ 0.7
5
XPA-0310

0.2 ± 0.0
6
RES
Control 20 μM

0.2 ± 0.0
7
RES
Control 40 μM

0.0 ≤ AVE_w≤ 0.2
8
XPA-0070

9
XPA-0574

TABLE 57

Proliferation assay with HPEKp cells at 10 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.9 ± 0.0
2
MTREX
Control at 20 AM

0.8 < AVE_w≤ 0.9
3
XPA-0029

4
XPA-0030

5
XPA-0033

6
XPA-0040

7
XPA-0057

8
XPA-0533

9
XPA-1017

10
XPA-1249

11
XPA-1252

12
XPA-1257

13
XPA-1826

14
XPA-1830

15
XPA-1832

16
XPA-1885

17
XPA-1891

18
XPA-1892

0.7 < AVE_w≤ 0.8
19
XPA-0062

20
XPA-0285

21
XPA-0299

22
XPA-0309

23
XPA-0547

24
XPA-0551

25
XPA-0562

26
XPA-0566

27
XPA-0814

28
XPA-1013

29
XPA-1020

30
XPA-1247

31
XPA-1248

32
XPA-1250

33
XPA-1253

34
XPA-1254

35
XPA-1258

36
XPA-1340

37
XPA-1346

38
XPA-1347

39
XPA-1827

40
XPA-1831

41
XPA-1856

42
XPA-1890

43
XPA-1893

0.6 < AVE_w≤ 0.7
44
XPA-0043

45
XPA-0314

46
XPA-0537

47
XPA-0560

48
XPA-0804

49
XPA-0817

50
XPA-0818

51
XPA-1011

52
XPA-1018

53
XPA-1246

54
XPA-1255

55
XPA-1256

56
XPA-1265

57
XPA-1341

58
XPA-1886

59
XPA-1887

0.4 < AVE_w≤ 0.6
60
XPA-0047

61
XPA-0048

62
XPA-0058

63
XPA-0068

64
XPA-0300

65
XPA-0313

66
XPA-0534

67
XPA-0544

68
XPA-0558

69
XPA-0789

70
XPA-0803

71
XPA-1009

72
XPA-1012

73
XPA-1019

74
XPA-1021

75
XPA-1251

76
XPA-1261

77
XPA-1263

78
XPA-1345

79
XPA-1857

80
XPA-1894

0.2 ± 0.0
81
RES
Control at 20 μM

0.2 ± 0.0
82
RES
Control at 40 μM

0.2 < AVE_w≤ 0.4
83
XPA-0044

84
XPA-0053

85
XPA-0054

86
XPA-0067

87
XPA-0294

88
XPA-0571

89
XPA-0572

90
XPA-1016

91
XPA-1259

92
XPA-1855

0.0 < AVE_w≤ 0.2
93
XPA-0034

94
XPA-0039

95
XPA-0042

96
XPA-0056

97
XPA-0322

98
XPA-0826

99
XPA-1262

The data in Table 55 relate to novel compounds, wherein the data in Table 56 and Table 57 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 μM—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 (Ia) and (Tb), respectively, have been identified as growth inhibitors of C2C12 cells. The so far identified C2C12 growth inhibitors relate to the compounds listed in Table 58 and Table 59. The entries of Table 58 and Table 59 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 58

Proliferation assay with C2C12 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 < AVE_w≤ 0.9
2
XPA-0032
Used as HCl Salt

3
XPA-0059

4
XPA-0506

5
XPA-0532

6
XPA-0563

7
XPA-0658

8
XPA-1277

9
XPA-1279

10
XPA-1320

11
XPA-1321

12
XPA-1329

13
XPA-1332

0.8 ± 0.0
14
RES
Control at 20 μM

0.7 < AVE_w≤ 0.8
15
XPA-0140

16
XPA-1280

17
XPA-1299
Measured at 10 μM

18
XPA-1302

19
XPA-1335

0.6 < AVE_w≤ 0.7
20
XPA-0028

21
XPA-1298

0.4 < AVE_w≤ 0.6
22
XPA-0060

23
XPA-0182

24
XPA-0280

25
XPA-0512

26
XPA-0672

27
XPA-1278

28
XPA-1293

0.2 < AVE_w≤ 0.4
29
XPA-1284

30
XPA-1286

31
XPA-1306

32
XPA-1309

33
XPA-1322

34
XPA-1323

35
XPA-1326

36
XPA-1338

0.2 ± 0.1
37
RES
Control at 40 μM

0.1 ± 0.0
38
MTREX
Control at 20 μM

0.0 < AVE_w≤ 0.2
39
XPA-0064

40
XPA-0230

41
XPA-0238

42
XPA-1312

43
XPA-1313

44
XPA-1315

45
XPA-1316

46
XPA-1317

47
XPA-1318

48
XPA-1324

49
XPA-1337

50
XPA-1339

TABLE 59

Proliferation assay with C2C12 cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.8 ± 0.0
2
RES
Control at 20 μM

0.8 < AVE_w≤ 0.9
3
XPA-0044

4
XPA-0310

5
XPA-0313

6
XPA-0546

7
XPA-0572

8
XPA-0817

9
XPA-1246

10
XPA-1250

11
XPA-1262

12
XPA-1830

0.7 < AVE_w≤ 0.8
13
XPA-0042

14
XPA-0562

15
XPA-1015

16
XPA-1263

0.2 ± 0.1
17
RES
Control at 40 μM

0.1 ± 0.0
18
MTREX
Control at 20 μM

The data in Table 58 relate to novel compounds, wherein the data in Table 59 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% CO₂.

A compound is considered as a growth inhibitor of TT cells, if—at a reference concentration of 20 μM—the weighted arithmetic mean of the normalized fluorescence intensity values after 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 (Ta), (Tb) 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 60. The entries of 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 60

Proliferation assay with TT cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

1.0 ± 0.0
2
MTREX
Control at 20 μM

0.9 ± 0.0
3
RES
Control at 20 μM

0.8 < AVE_w≤ 0.9
4
XPA-0006

5
XPA-1283

6
XPA-1298

7
XPA-1325

8
XPA-1333

0.7 < AVE_w≤ 0.8
9
XPA-0014

10
XPA-0132

11
XPA-0174

12
XPA-0280

13
XPA-1277

14
XPA-1279

15
XPA-1284

16
XPA-1285

17
XPA-1286

18
XPA-1293

19
XPA-1306

20
XPA-1324

21
XPA-1331

0.7 ± 0.0
22
RES
Control at 40 μM

0.6 < AVE_w≤ 0.7
23
XPA-0140

24
XPA-1309

25
XPA-1339

0.4 < AVE_w≤ 0.6
26
XPA-1278

0.2 < AVE_w≤ 0.4
27
XPA-1280

28
XPA-1326

0.0 < AVE_w≤ 0.2
29
XPA-0182

30
XPA-0230

31
XPA-0238

32
XPA-1312

33
XPA-1313

34
XPA-1315

35
XPA-1316

36
XPA-1317

37
XPA-1318

38
XPA-1338

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 μM—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 (Ic) have been identified as growth inhibitors of HeLa cells. The so far identified HeLa growth inhibitors relate to the compounds listed in Table 61. The entries of Table 61 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 HeLa cells at 20 μM

Activity Range
Entry
Compound No.
Specification

1.0 ± 0.0
1
DMSO
Baseline control

0.9 ± 0.0
2
RES
Control at 20 μM

0.4 ± 0.1
3
RES
Control at 40 μM

0.4 ± 0.0
4
MTREX
Control at 20 μM

0.0 < AVE_w≤ 0.2
5
XPA-0230

6
XPA-0238

7
XPA-1312

8
XPA-1313

9
XPA-1315

10
XPA-1316

11
XPA-1317

12
XPA-1318

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 Notch1 receptor (hNotch1ΔE) 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 μL Opti-MEM (Fisherscientific, #10149832) 40 μL of the hNotch1ΔE expression vector (100 ng/μL), 80 μL of the CSL luciferase reporter vector (40 ng/μL), 4 μL of the pRL-SV40-Renilla luciferase vector (10 ng/4 μL), and in the last step 18.1 μL 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 10,000 cells per well. The cells were then incubated with the test-compounds at a final concentration of 10 μM (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 μL 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 μL 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 μM.

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_wfor 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, Muhlig, Taschenbuch der Mathematik, 5^thedition 2001 (German), publisher: Verlag Harri Deutsch, Frankfurt am Main and Thun) and was combined with the Gauβ′ 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 (Ta) and (Tb), respectively, have been identified as enhancers of Notch signaling. The so far identified Notch enhancers relate to the compounds listed in Table 62. The entries of Table 62 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 62

Notch reporter assay

Activity Range
Entry
Compound No.
Specification

2.0 ≤ AVE_w
1
XPA-0020

2
XPA-0028

3
XPA-0031

4
XPA-0035

5
XPA-0037

6
XPA-0076

7
XPA-0511

8
XPA-0512

9
XPA-1274

10
XPA-1276

11
XPA-1335

1.9 ± 0.5
12
RES
Control at 10 μM

1.7 ≤ AVE_w< 2.0
13
XPA-0001

14
XPA-0002

15
XPA-0007

16
XPA-0008

17
XPA-0032
Used as HCl Salt

18
XPA-0063

19
XPA-0064

20
XPA-0065

21
XPA-0079

22
XPA-0563

23
XPA-0580

24
XPA-1273

25
XPA-1283

26
XPA-1284

27
XPA-1298

1.4 ≤ AVE_w< 1.7
28
XPA-0009

29
XPA-0059

30
XPA-0060

31
XPA-0280

32
XPA-0505

33
XPA-0506

34
XPA-0510

35
XPA-0519

36
XPA-1266

37
XPA-1269

38
XPA-1271

39
XPA-1281

40
XPA-1285

41
XPA-1286

42
XPA-1293

43
XPA-1294

1.3 ≤ AVE_w< 1.4
44
XPA-0006

45
XPA-1270

46
XPA-1291

47
XPA-1306

48
XPA-1323

49
XPA-1338

1.2 ≤ AVE_w< 1.3
50
XPA-0328

51
XPA-0524

52
XPA-1272

53
XPA-1277

54
XPA-1282

55
XPA-1287

56
XPA-1292

57
XPA-1320

58
XPA-1324

59
XPA-1333

60
XPA-1339

1.1 ≤ AVE_w< 1.2
61
XPA-0569

62
XPA-0541

1.0 ± 0.0
63
DMSO
Baseline control

0.1 ± 0.0
64
DAPT
Control at 10 μM

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.

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

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; and 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; and 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 Th1, Th2, Th17 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 hyperproliferative diseases, cancers or pre-cancerous 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.

The method of use of the present invention relates to the use in vivo, in vitro, and ex vivo, respectively.

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; and (3) slowing down disease progression. 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-β-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, AP1 signaling, JAK/STAT signaling, EGFR signaling, TGF-beta signaling, Notch signaling, Wnt signaling, Hedgehog signaling, hormone and nuclear receptor signaling, e.g. Erlotinib, Lapatinib, Dasatinib, Imatinib, Afatinib, Vemurafenib, Dabrafenib, Nilotinib, Cetuximab, Trametinib, Palbociclib, Cobimetinib, Cabozantinib, Pegaptanib, Crizotinib, Olaparib, Panitumumab, Cabozantinib, Ponatinib, Regorafenib, Entrectinib, Ranibizumab, Ibrutinib, Trastuzumab, Rituximab, Alemtuzumab, Gefitinib, Bevacizumab, Lenvatinib, Bosutinib, Axitinib, Pazopanib, Everolimus, Temsirolimus, Ruxolitinib, Tofacitinib, Sorafenib, Sunitinib, 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

Alk Alkyl

aq Aqueous

Bn Benzyl

BRSM Based on Recovered Starting Material (yield)

Bu Butyl

BOC tert-Butyloxycarbonyle

mCPBA meta-chloroperoxybenzoic acid

DCE 1,2-dichloroethane

DCM Dichloromethane

DIBAL-H Diisobutylaluminium hydride

DMF N,N-dimethylformamide

DMSO Dimethyl sulfoxide

equiv equivalent

ESI Electron Spray Ionization

Et Ethyl

LiHMDS Lithium bis(trimethylsilyl)amide

Me Methyl

NMR Nuclear Magnetic Resonance Spectroscopy

PE Petroleum Ether

PTSA p-Toluenesulfonic acid

sat Saturated

TBAF Tetrabutylammonium Fluoride

TFA Trifluoroacetic acid

THE Tetrahydrofuran

TLC Thin Layer Chromatography

TMS Trimethylsilyl

Ts p-Toluenesulfonyl

UV Ultraviolet

General Considerations

The compounds listed in Table 63 and Table 64 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 monitored 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 63 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 64). Chemical shifts (6) 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.: CHCl₃[¹H: 7.26 ppm, ¹³C: 77.2 ppm], DMSO [¹H: 2.50 ppm, ¹³C: 39.5 ppm]). Coupling constants (f) 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 the 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 N) mentioned herein as illustrated in Scheme 1.

embedded image

- A) To the corresponding mono or disubstituted 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 K₂CO₃(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 Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt, DCM/MeOH or petroleum ether/AcOEt/NEt₃) to yield the desired bi(hetero)aryl ether ethyl ester.
- B) The corresponding bi(hetero)aryl ether alkyl ester (1 equiv) was dissolved in dry THE (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 (SiO₂, 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 MnO₂(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 (SiO₂, 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 NaHCO₃and the phases separated. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to 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 HCl 1M and the phases separated. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired aldehyde.
- D) To the corresponding bi(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 HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified either by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) or by recrystallization (cyclohexane, AcOEt, EtOH or aq HCl) to yield the desired carboxylic acid.
- E) To the corresponding 4-substituted phenol (1 equiv) and 1,4-dibromoaryl (2.5 equiv), dissolved in DMF (0.2 M), was added Cs₂CO₃(2 equiv), CuI (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 2M. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired biaryl ether bromide.
- F) To the corresponding 4-substituted phenol (1.2-1.5 equiv) and 1,4-dibromo(hetero)aryl (1 equiv), dissolved in DMSO (0.5 M) under argon and stirring, was added K₂CO₃(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 Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired bi(hetero)aryl ether bromide.
- G) The corresponding bi(hetero)aryl ether bromide (1 equiv) was dissolved in dry THE (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 consumption of the starting material (monitored by TLC in pentane). The mixture was then cooled back down to −78° C., a solution in dry THE 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 NH₄Cl aq. sat, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt/NEt₃) or recrystallized in an appropriate solvent to yield the desired compound.
- H) Depending on the scale and substrate, either of these procedures were used.
  - To the corresponding bis(hetero)aryl ether carboxylic acid (1 equiv), suspended in stirred toluene (0.2 M), under argon, was added first SOCl₂(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. It was redissolved in the corresponding alcohol (0.2 M) or in a solution of the corresponding alcohol (1.5 equiv) in DCM (0.2 M). To this was added triethylamine (2.5 equiv) and the suspension was stirred for 16 hours. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired ester.
  - To the corresponding bis(hetero)aryl ether carboxylic acid (1 equiv), suspended in the corresponding alcohol (0.2 M) or in DCM (0.2 M) was added SOCl₂(2.5 equiv) followed by, if needed, then the corresponding alcohol (1.5 equiv) and the mixture stirred for 3 hours. The reaction was then partitioned between AcOEt and aq. sat. NaHCO₃. The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired ester.
- I) To the corresponding alcohol (1 equiv) in dry THE (0.2 M) was added NaH (1.2-2 equiv, 60% in oil) at 0° C. and the mixture stirred for 15-30 min at room temperature. The corresponding alkyl halide or acyl anhydride (1.5-2 equiv) was then added to the mixture, with KI (1.2-2 equiv) in the cases of alkyl bromides, and the whole was stirred at room temperature or 50° C. for the alkyl bromides for 16 h. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired ether or ester.
- J) To the corresponding aldehyde (1 equiv) in dry THE (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 until completion before being partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with aq. sat. NaHCO₃, Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired olefin.
- K) To the corresponding olefin (1 equiv) in DCM (0.2 M) at 0° C. was added NaHCO₃(2 equiv) and a solution of mCPBA (1.2 equiv) in DCM (1 M). The reaction was then allowed to return to room temperature slowly over 16 h. The mixture was then partitioned between AcOEt and aq. sat. NaHCO₃, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired compound.
- L) To DCM (0.2 M) at 0° C. was added dropwise ZnEt_z(2 equiv, 1.5 M in toluene). The reaction was then stirred for 30 min. CH₂I₂(4 equiv) was then added dropwise and the resulting mixture stirred for 30 more min. Next a solution of TFA (0.2 equiv) and 1,4-dioxane (1 equiv) in DCM (1 M) was added dropwise and the resulting mixture stirred for 30 more min. The corresponding olefin (1 equiv) in DCM (1 M) was then added and the resulting mixture stirred 16 h at room temperature. The reaction was then partitioned between DCM and aq. HCl 1 M, the aqueous layer was extracted twice more and the combined organic phases were then washed with NaHCO₃, Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield the desired compound.
- M) The corresponding BOC-protected amine (1 equiv) was dissolved in a mixture of 1,4-dioxane and aq 1 M HCl (0.2 M, 4:1 mixture). The reaction mixture was then stirred till completion at 80° C. It was then partitioned between AcOEt and aq. sat NaHCO₃, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum to yield the clean free amine.
- N) To the corresponding free amine (1 equiv) in acetonitrile (0.2 M) was added formaldehyde (6 equiv, 37% w/w in water) followed by NaBH₃CN (2 equiv). The reaction mixture was stirred till completion before being partitioned between AcOEt and aq. sat. NaHCO₃, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient DCM/MeOH/NEt₃) to yield the desired compound.

Analytical Data

The following compounds were synthetized according to the aforementioned protocols and characterized via mass spectrometry (Table 63) or NMR ( Table 64).

TABLE 63

Compound

m/z
Ion
m/z
Ion

No.
Formula
[ESI⁺]
[ESI⁺]
[ESI⁻]
[ESI⁻]
Procedure

XPA-0001
C₁₇H₂₀O₂
239.2
[M − OH]⁺

B

XPA-0002
C₁₇H₂₀O₂
239.2
[M − OH]⁺

B

XPA-0006
C₁₉H₂₂O₂
265.1
[M − OH]⁺

B

XPA-0007
C₁₈H₂₀O₃
267.1
[M − OH]⁺

B

XPA-0008
C₁₉H₂₃NO₂
298.2
[M + H]⁺

B

XPA-0009
C₁₇H₁₉NO₃
286.4
[M + H]⁺

B

XPA-0014
C₂₃H₂₆O₂
317.2
[M − OH]⁺

B

XPA-0015
C₁₇H₁₈O₂
255.1
[M + H]⁺

C

XPA-0016
C₁₇H₁₈O₂
255.1
[M + H]⁺

C

XPA-0020
C₁₉H₂₀O₂
281.2
[M + H]⁺

C

XPA-0028
C₂₃H₂₄O₂
333.3
[M + H]⁺

C

XPA-0029
C₁₇H₁₈O₃

269.18
[M − H]⁻
D

XPA-0030
C₁₇H₁₈O₃

269.18
[M − H]⁻
D

XPA-0031
C₁₆H₁₆O₄
273.1
[M + H]⁺
271.13
[M − H]⁻
D

XPA-0032
C₁₇H₁₉NO₃—HCl
286.1
[M + H]⁺

D

XPA-0033
C₁₇H₁₃F₃O₃

321.22
[M − H]⁻
D

XPA-0034
C₁₉H₂₀O₃

295.27
[M − H]⁻
D

XPA-0035
C₁₈H₁₈O₄
299.2
[M + H]⁺
297.13
[M − H]⁻
D

XPA-0036
C₁₉H₂₁NO₃—HCl
312.2
[M + H]⁺

D

XPA-0037
C₁₉H₂₁NO₆
300.4
[M + H]⁺

D

XPA-0039
C₂₀H₂₀O₃

307.28
[M − H]⁻
D

XPA-0040
C₂₁H₂₂O₃

321.34
[M − H]⁻
D

XPA-0042
C₂₃H₂₄O₃

347.37
[M − H]⁻
D

XPA-0043
C₁₈H₂₀O₃
285.1
[M + H]⁺

H

XPA-0044
C₁₈H₂₀O₃
285.1
[M + H]⁺

H

XPA-0047
C₁₈H₁₅F₃O₃
337.2
[M + H]⁺

H

XPA-0048
C₂₀H₂₂O₃
311.2
[M + H]⁺

H

XPA-0053
C₂₁H₂₂O₃
323.2
[M + H]⁺

H

XPA-0054
C₂₂H₂₄O₃
337.3
[M + H]⁺

H

XPA-0056
C₂₄H₂₆O₃
363.3
[M + H]⁺

H

XPA-0057
C₁₉H₂₂O₃
299.2
[M + H]⁺

A

XPA-0058
C₁₉H₂₂O₃
299.2
[M + H]⁺

A

XPA-0059
C₁₈H₂₀O₄
301.2
[M + H]⁺

A

XPA-0060
C₁₉H₂₃NO₃
314.3
[M + H]⁺

A

XPA-0061
C₁₉H₁₇F₃O₃
351.2
[M + H]⁺

A

XPA-0062
C₂₁H₂₄O₃
325.3
[M + H]⁺

A

XPA-0063
C₂₀H₂₂O₄
327.2
[M + H]⁺

A

XPA-0064
C₂₁H₂₅NO₃
340.4
[M + H]⁺

A

XPA-0065
C₁₉H₂₁NO₄
328.5
[M + H]⁺

A

XPA-0067
C₂₂H₂₄O₃
337.3
[M + H]⁺

A

XPA-0068
C₂₃H₂₆O₃
351.3
[M + H]⁺

A

XPA-0070
C₂₅H₂₈O₃
377.4
[M + H]⁺

A

XPA-0076
C₂₆H₂₆O₃
387.7
[M + H]⁺

H

XPA-0079
C₂₄H₂₃NO₄
390.6
[M + H]⁺

H

XPA-0132
C₂₁H₂₄O₃
307.5
[M − OH]⁺

G

XPA-0140
C₂₅H₂₈O₃
359.6
[M − OH]⁺

G

XPA-0146
C₂₂H₂₆O₃
307.5
[M − Ome]⁺

I

XPA-0154
C₂₆H₃₀O₃
359.6
[M − Ome]⁺

I

XPA-0160
C₂₈H₃₀O₃
307.5
[M − Obn]⁺

I

XPA-0168
C₃₂H₃₄O₃
359.6
[M − OBn]⁺

I

XPA-0174
C₂₁H₂₄O₂S
323.5
[M − OH]⁺

G

XPA-0182
C₂₅H₂₈O₂S
375.6
[M − OH]⁺

G

XPA-0188
C₂₂H₂₆O₂S
323.5
[M − OMe]⁺

I

XPA-0196
C₂₆H₃₀O₂S
375.6
[M − OMe]⁺

I

XPA-0230
C₂₃H₂₉NO₂
352.6
[M + H]⁺

N

XPA-0238
C₂₇H₃₃NO₂
404.7
[M + H]⁺

N

XPA-0280
C₂₃H₂₃FO₂
351.3
[M + H]⁺

C

XPA-0282
C₁₇H₁₇FO₃

287.18
[M − H]⁻
D

XPA-0285
C₁₇H₁₂F₄O₃

339.22
[M − H]⁻
D

XPA-0294
C₂₃H₂₃FO₃

365.39
[M − H]⁻
D

XPA-0299
C₁₈H₁₄F₄O₃

353.31
[M − H]⁻
H

XPA-0300
C₂₀H₂₁FO₃
329.2
[M + H]⁺

H

XPA-0308
C₂₄H₂₅FO₃
381.3
[M + H]⁺

H

XPA-0309
C₁₉H₂₁FO₃
317.2
[M + H]⁺

A

XPA-0310
C₁₉H₂₁FO₃
317.2
[M + H]⁺

A

XPA-0313
C₁₉H₁₆F₄O₃
369.2
[M + H]⁺

A

XPA-0314
C₂₁H₂₃FO₃
343.3
[M + H]⁺

A

XPA-0322
C₂₅H₂₇FO₃
395.3
[M + H]⁺

A

XPA-0328
C₂₆H₂₅FO₃
405.6
[M + H]⁺

H

XPA-0505
C₁₆H₁₉NO₂
258.1
[M + H]⁺

B

XPA-0506
C₁₆H₁₉NO₂
258.1
[M + H]⁺

B

XPA-0510
C₁₈H₂₁NO₂
284.1
[M + H]⁺

B

XPA-0511
C₁₈H₁₈O₃
283.1
[M + H]⁺

B

XPA-0512
C₁₈H₂₁NO₂
296.2
[M + H]⁺

B

XPA-0518
C₂₂H₂₅NO₂
336.3
[M + H]⁺

B

XPA-0519
C₁₆H₁₇NO₂
256.1
[M + H]⁺

C

XPA-0520
C₁₆H₁₇NO₂
256.1
[M + H]⁺

C

XPA-0524
C₁₈H₁₉NO₂
282.1
[M + H]⁺

C

XPA-0532
C₂₂H₂₃NO₂
334.3
[M + H]⁺

C

XPA-0533
C₁₆H₁₇NO₃
272.1
[M + H]⁺
270.18
[M − H]⁻
D

XPA-0534
C₁₆H₁₇NO₃
272.1
[M + H]⁺
270.18
[M − H]⁻
D

XPA-0535
C₁₅H₁₅NO₄
274.1
[M + H]⁺
272.12
[M − H]⁻
D

XPA-0537
C₁₆H₁₂F₃NO₃
324.1
[M + H]⁺
322.22
[M − H]⁻
D

XPA-0541
C₂₀H₂₄N₂O₈
301.4
[M + H]⁺

D

XPA-0544
C₂₀H₂₁NO₃

322.3
[M − H]⁻
D

XPA-0546
C₂₂H₂₃NO₃

348.37
[M − H]⁻
D

XPA-0547
C₁₇H₁₉NO₃
286.2
[M + H]⁺

H

XPA-0551
C₁₇H₁₄F₃NO₃
338.2
[M + H]⁺

H

XPA-0558
C₂₁H₂₃NO₃
338.2
[M + H]⁺

H

XPA-0560
C₂₃H₂₅NO₃
364.3
[M + H]⁺

H

XPA-0561
C₁₈H₂₁NO₃
300.2
[M + H]⁺

A

XPA-0562
C₁₈H₂₁NO₃
300.2
[M + H]⁺

A

XPA-0563
C₁₇H₁₉NO₄
302.2
[M + H]⁺

A

XPA-0565
C₁₈H₁₆F₃NO₃
352.2
[M + H]⁺

A

XPA-0566
C₂₀H₂₃NO₃
326.3
[M + H]⁺

A

XPA-0569
C₁₈H₂₀N₂O₄
329.5
[M + H]⁺

A

XPA-0571
C₂₁H₂₃NO₃
338.2
[M + H]⁺

A

XPA-0572
C₂₂H₂₅NO₃
352.3
[M + H]⁺

A

XPA-0574
C₂₄H₂₇NO₃
378.3
[M + H]⁺

A

XPA-0580
C₂₅H₂₅NO₃
388.7
[M + H]⁺

XPA-0644
C₂₄H₂₇NO₃
378.3
[M + H]⁺

G

XPA-0658
C₂₅H₂₉NO₃
392.7
[M + H]⁺

I

XPA-0672
C₃₁H₃₃NO₂
468.7
[M + H]⁺

I

XPA-0786
C₁₆H₁₆FNO₃

288.17
[M − H]⁻
D

XPA-0789
C₁₆H₁₁F₄NO₃

340.21
[M − H]⁻
D

XPA-0798
C₂₂H₂₂FNO₃
368.3
[M + H]⁺
366.37
[M − H]⁻
D

XPA-0803
C₁₇H₁₃F₄NO₃
356.2
[M + H]⁺

H

XPA-0804
C₁₉H₂₀FNO₃
330.2
[M + H]⁺

H

XPA-0814
C₁₈H₂₀FNO₃
318.2
[M + H]⁺

A

XPA-0817
C₁₈H₁₅F₄NO₃
370.2
[M + H]⁺

A

XPA-0818
C₂₀H₂₂FNO₃
344.2
[M + H]⁺

A

XPA-0826
C₂₄H₂₆FNO₃
396.3
[M + H]⁺

A

XPA-0832
C₂₅H₂₄FNO₃
406.6
[M + H]⁺

H

XPA-1009
C₁₄H₈F₄O₃

299.12
[M − H]⁻
D

XPA-1011
C₁₅H₁₃FO₃

259.15
[M − H]⁻
D

XPA-1012
C₁₄H₁₁FO₃

245.13
[M − H]⁻
D

XPA-1013
C₁₆H₁₅FO₃

273.15
[M − H]⁻
D

XPA-1014
C₁₇H₁₉NO₃
286.2
[M + H]⁺
284.2
[M − H]⁻
D

XPA-1015
C₁₉H₂₃NO₃
314.2
[M + H]⁺

A

XPA-1016
C₁₈H₁₃F₅O₃
n.a
[M + H]⁺
371.3
[M − H]⁻
D

XPA-1017
C₁₇H₁₈FNO₃
304.2
[M + H]⁺

A

XPA-1018
C₁₄H₁₃NO₃
244.1
[M + H]⁺

H

XPA-1019
C₁₅H₁₅NO₃
258.1
[M + H]⁺

H

XPA-1020
C₁₆H₁₇NO₃
272.1
[M + H]⁺

H

XPA-1021
C₁₈H₂₁NO₃
300.2
[M + H]⁺

H

XPA-1034
C₁₇H₁₂F₅NO₃
374.2
[M + H]⁺
372.3
[M − H]⁻
D

XPA-1035
C₁₉H₁₆F₅NO₃
402.3
[M + H]⁺

A

XPA-1246
C₁₈H₂₀O₃
285.2
[M + H]⁺

A

XPA-1247
C₁₆H₁₃F₃O₃
311.2
[M + H]⁺

A

XPA-1248
C₁₈H₁₉FO₃
303.2
[M + H]⁺

A

XPA-1249
C₁₆H₁₆O₃

255.18
[M − H]⁻
D

XPA-1250
C₁₉H₂₂FNO₃
332.2
[M + H]⁺

A

XPA-1251
C₁₉H₂₂O₃
299.2
[M + H]⁺

H

XPA-1252
C₁₅H₁₄FNO₃
276.1
[M + H]⁺

A

XPA-1253
C₁₅H₁₁F₄NO₃
330.1
[M + H]⁺

A

XPA-1254
C₁₅H₁₄FNO₃

274.15
[M − H]⁻
D

XPA-1255
C₁₃H₁₀FNO₃

246.12
[M − H]⁻
D

XPA-1256
C₁₃H₇F₄NO₃

300.1
[M − H]⁻
D

XPA-1257
C₁₆H₁₇NO₃
272.1
[M + H]⁺

H

XPA-1258
C₁₇H₁₈O₃
271.1
[M + H]⁺

H

XPA-1259
C₁₃H₈F₃NO₃
284
[M + H]⁺
282.1
[M − H]⁻
D

XPA-1261
C₁₄H₁₀F₃NO₃
298.1
[M + H]⁺

H

XPA-1262
C₁₉H₁₆ClF₃O₃
385.2
[M + H]⁺

A

XPA-1263
C₁₈H₁₅ClF₃NO₃
386.2
[M + H]⁺

A

XPA-1264
C₁₇H₁₃ClF₃NO₃
372.2
[M + H]⁺

H

XPA-1265
C₁₈H₁₄F₅NO₃
388.2
[M + H]⁺

H

XPA-1266
C₂₀H₂₄O₂
265.4
[M − OMe]⁺

I

XPA-1267
C₂₁H₂₂O₄
339.6
[M + H]⁺

A

XPA-1268
C₁₉H₁₈O₄

309.45
[M − H]⁻
D

XPA-1269
C₂₁H₂₃ClO₃
359.6
[M + H]⁺

A

XPA-1270
C₂₅H₂₇ClO₃
411.6
[M + H]⁺

A

XPA-1271
C₂₁H₂₃BrO₃
403.56/405.55
[M + H]⁺

A

XPA-1273
C₁₉H₁₉ClO₃

329.44
[M − H]⁻
D

XPA-1274
C₂₃H₂₃ClO₃

381.57
[M − H]⁻
D

XPA-1275
C₁₉H₁₉BrO₃

373.49
[M − H]⁻
D

XPA-1276
C₂₃H₂₃BrO₃

425.55
[M − H]⁻
D

XPA-1277
C₁₉H₂₁ClO₂
299.4
[M − OH]⁺

B

XPA-1278
C₂₃H₂₅ClO₂
351.6
[M − OH]⁺

B

XPA-1279
C₁₉H₂₁BrO₂
343.45/354.43
[M − OH]⁺

B

XPA-1280
C₂₃H₂₅BrO₂
395.56/397.55
[M − OH]⁺

B

XPA-1281
C₂₃H₂₄N₂O₃
377.6
[M + H]⁺

I

XPA-1282
C₁₈H₂₁NO₃
300.5
[M + H]⁺

I

XPA-1289
C₂₃H₂₄O₄

363.61
[M − H]⁻
D

XPA-1292
C₂₀H₂₂O₃

309.48
[M − H]⁻
D

XPA-1293
C₂₀H₂₄O₂
296.5
[M + H]⁺

B

XPA-1300
C₂₃H₂₄BrNO₃
442.56/443.53
[M + H]⁺

A

XPA-1301
C₂₀H₂₁BrO₃
389.51/391.50
[M + H]⁺

A

XPA-1302
C₂₁H₂₂N₂O₃
351.6
[M + H]⁺

A*

XPA-1303
C₂₃H₂₆N₂O₃
379.6
[M + H]⁺

H

XPA-1304
C₂₂H₂₄N₂O₃
365.6
[M + H]⁺

A

XPA-1305
C₂₂H₂₄N₂O₃
365.6
[M + H]⁺

A

XPA-1306
C₂₄H₂₇NO₃
378.7
[M + H]⁺

A

XPA-1307
C₂₃H₂₆N₂O₃
379.6
[M + H]⁺

A

XPA-1308
C₃₀H₃₇NO₄
376.67/358.62
[M − BOC + 2H]⁺

G

[M − BOC − OH + H]⁺

XPA-1309
C₂₆H₃₃NO₄
324.56/306.50
[M − BOC + 2H]⁺

G

[M − BOC − OH + H]⁺

XPA-1310
C₂₇H₃₅NO₄
338.59/306.51
[M − BOC + 2H]⁺

I

[M − BOC − OH + H]⁺

XPA-1312
C₂₅H₂₉NO₂
376.7
[M + H]⁺

M

XPA-1315
C₂₂H₂₇NO₂
338.6
[M + H]⁺

M

XPA-1316
C₂₆H₃₁NO₂
390.7
[M + H]⁺

M

XPA-1317
C₂₈H₃₁NO₂
414.7
[M + H]⁺

M

XPA-1318
C₃₂H₃₅NO₂
466.7
[M + H]⁺

M

XPA-1320
C₂₃H₂₃BrO₃

425.57/427.57
[M − H]⁻
D

XPA-1321
C₂₂H₂₂BrNO₃

426.56/428.56
[M − H]⁻
D

XPA-1322
C₂₁H₂₂N₂O₃
351.6
[M + H]⁺

D

XPA-1323
C₂₁H₂₂N₂O₃
351.6
[M + H]⁺

D

XPA-1324
C₂₂H₂₃NO₃
350.6
[M + H]⁺

D

XPA-1327
C₂₂H₂₄BrNO₂
414.58/416.57
[M + H]⁺

B

XPA-1328
C₂₁H₂₄N₂O₂
337.6
[M + H]⁺

B

XPA-1329
C₂₁H₂₄N₂O₂
337.6
[M + H]⁺

B

XPA-1330
C₂₂H₂₅NO₂
336.6
[M + H]⁺

B

XPA-1331
C₂₇H₃₀O₄
419.7
[M + H]⁺

I

XPA-1332
C₂₁H₂₂N₂O₃
351.6
[M + H]⁺
349.54
[M − H]⁻
D

XPA-1333
C₂₃H₂₇NO₂
350.6
[M + H]⁺

B

XPA-1334
C₂₄H₂₇NO₃
378.6
[M + H]⁺

A

XPA-1335
C₂₃H₂₅NO₃
364.6
[M + H]⁺

D

XPA-1337
C₂₁H₂₂N₂O₂
335.6
[M + H]⁺

C

XPA-1338
C₂₅H₂₆D₅NO₂S
364.7
[M − SCD3]⁺

C

XPA-1339
C₂₃H₂₅NO₂
348.6
[M + H]⁺

C

XPA-1340
C₂₀H₂₃FO₃
331.3
[M + H]⁺

A

XPA-1341
C₁₈H₁₉FO₃
303.2
[M + H]⁺

A

XPA-1342
C₁₆H₁₇NO₃
272.1
[M + H]⁺

A

XPA-1343
C₂₀H₁₇F₅O₃
401.3
[M + H]⁺

A

XPA-1344
C₁₉H₂₀BrNO₃
390.50/392.51
[M + H]⁺

A

XPA-1345
C₁₇H₁₈O₃
271.1
[M + H]⁺

H

XPA-1346
C₁₅H₁₂F₃NO₃
312.1
[M + H]⁺

A

XPA-1347
C₁₃H₁₁NO₃
230.1
[M + H]⁺
228.15
[M − H]⁻
D

XPA-1826
C₁₆H₁₆O₃

255.18
[M − H]⁻
D

XPA-1827
C₁₅H₁₄O₃

241.17
[M − H]⁻
D

XPA-1830
C₂₀H₂₄O₃
313.3
[M + H]⁺

A

XPA-1831
C₁₈H₂₀O₃
285.2
[M + H]⁺

A

XPA-1832
C₁₇H₁₈O₃
271.1
[M + H]⁺

A

XPA-1855
C₁₈H₂₀O₃

283.21
[M − H]⁻
D

XPA-1856
C₂₀H₂₄O₃
313.3
[M + H]⁺

A

XPA-1857
C₁₉H₂₂O₃
299.2
[M + H]⁺

H

XPA-1885
C₁₇H₁₉NO₃
286.2
[M + H]⁺

A

XPA-1886
C₂₀H₂₃FO₃
331.2
[M + H]⁺

A

XPA-1887
C₁₄H₁₂O₃

227.16
[M − H]⁻
D

XPA-1890
C₁₅H₁₅NO₃
258.1
[M + H]⁺
256.17
[M − H]⁻
D

XPA-1891
C₁₈H₁₉FO₃

301.21
[M − H]⁻
D

XPA-1892
C₁₆H₁₅FO₃

273.17
[M − H]⁻
D

XPA-1893
C₁₈H₂₀FNO₃
318.2
[M + H]⁺

H

XPA-1894
C₁₆H₁₁ClF₃NO₃
358.1
[M + H]⁺
356.2
[M − H]⁻
D

XPA-I-0001
C₂₁H₂₂BrNO
384.21/386.20
[M + H]⁺

F

XPA-I-0002
C₁₆H₁₂F₄O₃
329.2
[M + H]⁺

A

XPA-I-0004
C₁₇H₁₇FO₃
289.1
[M + H]⁺

A

XPA-I-0005
C₁₆H₁₅FO₃
275.1
[M + H]⁺

A

XPA-I-0008
C₁₅H₁₅NO₃
258.1
[M + H]⁺

A

XPA-I-0009
C₁₄H₁₃NO₃
244
[M + H]⁺
242.15
[M − H]⁻
D

XPA-I-0011
C₁₅H₁₅NO₃
258.1
[M + H]⁺
256.17
[M − H]⁻
D

XPA-I-0013
C₁₇H₁₉NO₃
286.2
[M + H]⁺

A

XPA-I-0014
C₁₇H₁₉NO₃
286.2
[M + H]⁺
284.2
[M − H]⁻
D

XPA-I-0015
C₁₉H₂₃NO₃
314.2
[M + H]⁺

A

TABLE 64

Com-

Pro-

pound

ce-

No.
Formula

¹H-NMR
dure

XPA-
C₃₂H₃₄O₂S

¹H NMR (400 MHz, CDCl₃) δ 7.63-7.59
I

0210

(m, 2H), 7.39-7.27 (m, 7H), 7.10-

7.04 (m, 2H), 7.04-6.99 (m, 2H), 4.13

(s, 2H), 3.87-3.80 (m, 2H), 3.43-

3.36 (m, 2H), 2.11 (q, J = 3.2 Hz, 3H),

1.93 (d, J = 2.9 Hz, 6H), 1.87-1.70

(m, 6H).

XPA-
C₃₀H₂₉FO₃

¹H NMR (400 MHz, CDCl₃) δ 7.87
H

0336

(dd, J = 11.1, 2.0 Hz, 1H), 7.78 (ddd,

J = 8.6, 2.1, 1.2 Hz, 1H), 7.46-7.31 (m,

5H), 7.23-7.16 (m, 2H), 6.99-6.91

(m, 3H), 5.35 (s, 2H), 2.58-2.43 (m,

1H), 1.95-1.70 (m, 5H), 1.47-1.18

(m, 5H).

XPA-
C₂₉H₂₈FNO₃

¹H NMR (400 MHz, CDCl₃) δ 8.63 (d,
H

0840

J = 1.9 Hz, 1H), 8.05 (dd, J = 9.9, 2.0

Hz, 1H), 7.45-7.33 (m, 7H), 7.16-7.10

(m, 2H), 5.37 (s, 2H), 2.12 (p, J =

3.2 Hz, 3H), 1.94 (d, J = 2.9 Hz, 6H),

1.86-1.69 (m, 6H).

XPA-
C₂₅H₂₇BrO₃

¹H NMR (400 MHz, CDCl₃) δ 8.05-7.95
A

1272

(m, 2H), 7.61 (d, J = 2.3 Hz, 1H),

7.31 (dd, J = 8.5, 2.3 Hz, 1H), 7.02

(d, J = 8.5 Hz, 1H), 6.95-6.87 (m, 2H),

4.35 (q, J = 7.1 Hz, 2H), 2.12 (s, 3H),

1.91 (d, J = 2.9 Hz, 6H), 1.78 (q, J =

12.5 Hz, 6H), 1.38 (d, J = 7.1 Hz, 2H).

XPA-
C₁₉H₁₉ClO₂

¹H NMR (400 MHz, CDCl₃) δ 9.85 (s,
C

1283

1H), 7.81-7.73 (m, 2H), 7.28 (dd, J =

9.8, 2.2 Hz, 1H), 7.10-7.04 (m, 1H),

6.99 (d, J = 8.3 Hz, 1H), 6.92 (dd, J =

6.8, 1.9 Hz, 2H), 2.45 (s, 1H), 1.89-1.64

(m, 6H), 1.37-1.11 (m, 6H).

XPA-
C₂₃H₂₃ClO₂

¹H NMR (400 MHz, CDCl₃) δ 9.92 (s,
C

1284

1H), 7.88-7.80 (m, 2H), 7.46 (d, J =

2.3 Hz, 1H), 7.30 (dd, J = 8.6, 2.3 Hz,

1H), 7.08 (d, J = 8.5 Hz, 1H), 7.02-

6.94 (m, 2H), 2.13 (s, 3H), 1.92 (d, J =

2.9 Hz, 6H), 1.78 (q, J = 12.6 Hz,

6H).

XPA-
C₁₉H₁₉BrO₂

¹H NMR (400 MHz, CDCl₃) δ 9.92
C

1285

(s, 1H), 7.89-7.80 (m, 2H), 7.50 (d, J =

2.1 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz,

1H), 7.04 (d, J = 8.3 Hz, 1H), 7.01-

6.95 (m, 2H), 2.52 (s, 1H), 1.99-1.70

(m, 5H), 1.48-1.17 (m, 5H).

XPA-
C₂₃H₂₃BrO₂

¹H NMR (400 MHz, CDCl₃) δ 9.92 (s,
C

1286

1H), 7.88-7.81 (m, 2H), 7.62 (d, J =

2.3 Hz, 1H), 7.34 (dd, J = 8.5, 2.3 Hz,

1H), 7.06 (d, J = 8.5 Hz, 1H), 7.02-

6.97 (m, 2H), 2.13 (s, 3H), 1.91 (d,

J = 2.9 Hz, 6H), 1.78 (q, J = 12.7 Hz,

6H).

XPA-
C₂₃H₂6O₃

¹H NMR (400 MHz, CDCl₃) δ 8.00-7.95
J

1287

(m, 2H), 7.45 (d, J = 2.2 Hz, 1H),

7.12 (dd, J = 8.3, 2.2 Hz, 1H), 6.93-6.86

(m, 3H), 6.82 (dd, J = 17.7, 11.1

Hz, 1H), 5.76 (dd, J = 17.7, 1.3 Hz, 1H),

5.23 (dd, J = 11.1, 1.3 Hz, 1H), 4.35

(q, J = 7.1 Hz, 2H), 2.59-2.46 (m, 1H),

1.89 (td, J = 9.8, 5.2 Hz, 4H), 1.77

(d, J = 12.9 Hz, 1H), 1.47-1.33 (m, 7H),

1.32-1.19 (m, 1H).

XPA-
C₂₅H₂₈O₄

¹H NMR (400 MHz, CDCl₃) δ 8.02-7.91
A

1288

(m, 2H), 6.99-6.89 (m, 6H), 4.32

(q, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.84

(d, J = 3.0 Hz, 6H), 1.61 (t, J = 10.8 Hz,

6H), 1.34 (t, J = 7.1 Hz, 3H).

XPA-
C₂₃H₂₆O₄

¹H NMR (400 MHz, CDCl₃) δ 8.03-7.97
K

1290

(m, 2H), 7.14 (dd, J = 8.3, 2.3 Hz,

1H), 7.10 (d, J = 2.2 Hz, 1H), 6.96-6.88

(m, 3H), 4.36 (qd, J = 7.1, 0.7 Hz,

2H), 4.02 (dd, J = 4.1, 2.6 Hz, 1H), 3.02

(ddd, J = 5.7, 4.1, 0.7 Hz, 1H), 2.69

(ddd, J = 5.7, 2.6, 0.7 Hz, 1H), 2.56-2.43

(m, 1H), 1.80 (d, J = 48.9 Hz, 5H),

1.47-1.18 (m, 8H).

XPA-
C₂₂H₂₆O₃

¹H NMR (400 MHz, CDCl₃) δ 8.00-7.92
A

1291

(m, 2H), 7.10 (d, J = 2.2 Hz, 1H),

7.04 (dd, J = 8.3, 2.3 Hz, 1H), 6.91-6.83

(m, 3H), 4.35 (q, J = 7.1 Hz, 2H),

2.54-2.40 (m, 1H), 2.15 (s, 3H), 1.95-

1.70 (m, 5H), 1.46-1.18 (m, 8H).

XPA-
C₂₇H₂₈O₃

¹H NMR (400 MHz, CDCl₃) δ 8.04-7.97
H

1294

(m, 2H), 7.45-7.30 (m, 5H), 7.10

(d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.2,

2.3 Hz, 1H), 6.91-6.83 (m, 3H), 5.34

(s, 2H), 2.48 (s, 1H), 2.14 (s, 3H),

1.94-1.70 (m, 5H), 1.49-1.18 (m, 5H).

XPA-
C₂₄H₂₈O₃

¹H NMR (400 MHz, CDCl₃) δ 8.00-7.94
L

1295

(m, 2H), 7.01 (dd, J = 8.3, 2.2 Hz,

1H), 6.93-6.86 (m, 3H), 6.77 (d, J =

2.2 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H),

2.46 (s, 1H), 1.96-1.69 (m, 6H),

1.46-1.17 (m, 8H), 0.86-0.74 (m, 2H),

0.69-0.59 (m, 2H).

XPA-
C₂₇H₃₀O₂-HCl

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.27
I

1296

(m, 7H), 7.07 (d, J = 2.3 Hz, 1H),

6.99 (dd, J = 8.2, 2.4 Hz, 1H), 6.90-6.84

(m, 2H), 6.83 (d, J = 8.2 Hz, 1H),

4.55 (s, 2H), 4.50 (s, 2H), 2.53-2.40

(m, 1H), 2.20 (s, 3H), 1.95-1.69 (m,

5H), 1.48-1.15 (m, 5H).

XPA-
C₂₁H₂₆O₂O₃

¹H NMR (400 MHz, CDCl₃) δ 7.25 (d,
I

1297

J = 8.0 Hz, 2H), 7.07 (d, J = 2.3 Hz,

1H), 6.99 (dd, J = 8.3, 2.3 Hz, 1H),

6.89-6.84 (m, 2H), 6.82 (d, J = 8.3 Hz,

1H), 4.40 (s, 2H), 3.38 (s, 3H),

2.52-2.39 (m, 1H), 2.19 (s, 3H), 1.96-

1.80 (m, 4H), 1.75 (d, J = 12.1 Hz, 1H),

1.48-1.19 (m, 5H).

XPA-
C₂₀H₂₂O₂

¹H NMR (400 MHz, CDCl₃) δ 9.90
C

1298

(s, 1H), 7.84-7.78 (m, 2H), 7.12 (d, J =

2.2 Hz, 1H), 7.09-7.04 (m, 1H),

6.98-6.93 (m, 2H), 6.92 (d, J = 8.2 Hz,

1H), 2.55-2.41 (m, 1H), 2.15 (s, 3H),

1.95-1.70 (m, 5H), 1.50-1.17 (m,

5H).

XPA-
C₂₄H₂₅BrO₃

¹H NMR (400 MHz, CDCl₃) δ 8.31
A

1299

(d, J = 2.1 Hz, 1H), 7.87

(dd, J = 8.6, 2.1 Hz, 1H),

7.40-7.34 (m, 2H), 7.03-6.96

(m, 2H), 6.84 (d, J = 8.6 Hz, 1H),

3.91 (s, 3H), 2.11 (q, J = 3.1 Hz, 3H),

1.92 (d, J = 2.9 Hz, 6H), 1.84-1.70

(m, 6H).

XPA-
C₃₁H₃₉NO₄

¹H NMR (400 MHz, CDCl₃) δ 7.36-
I

1311

7.29 (m, 4H), 7.03-6.94 (m, 4H), 4.15

(s, 4H), 3.08 (s, 3H), 2.10 (q, J =

3.2 Hz, 3H), 1.91 (d, J = 2.9 Hz, 6H),

1.86-1.69 (m, 6H), 1.45 (s, 9H).

XPA-
C₂₁H₂₅NO₂

¹H NMR (400 MHz, CDCl₃) δ
M

1313

7.52-7.44 (m, 2H), 7.34-7.28 (m, 2H),

7.04-6.98 (m, 2H), 6.98-6.92 (m, 2H),

4.14 (d, J = 9.2 Hz, 2H), 3.85 (d, J =

9.3 Hz, 2H), 3.57 (s, 2H), 2.10 (p,

J = 3.2 Hz, 3H), 1.91 (d, J = 2.9 Hz,

6H), 1.84-1.71 (m, 6H).

XPA-
C₁₉H₂₁BrO₂

¹H NMR (400 MHz, CDCl₃) δ 7.64 (d,
B

1325

J = 2.1 Hz, 1H), 7.22 (dt, ] = 8.3, 1.4

Hz, 1H), 7.19-7.12 (m, 2H), 6.94-6.86

(m, 3H), 4.65 (d, J = 5.7 Hz, 2H),

2.48 (td, J = 8.4, 4.3 Hz, 1H), 1.96-1.69

(m, 5H), 1.47-1.16 (m, 5H).

XPA-
C₂₃H₂₅BrO₂

¹H NMR (400 MHz, CDCl₃) δ 7.65
B

1326

(d, J = 2.0 Hz, 1H), 7.35-7.28 (m, 2H),

7.23 (ddt, J = 8.4, 2.2, 0.7 Hz, 1H),

6.96-6.88 (m, 3H), 4.66 (d, J = 5.9 Hz,

2H), 2.09 (s, 3H), 1.90 (d, J = 2.9 Hz,

6H), 1.84-1.70 (m, 6H), 1.66 (t, J =

5.9 Hz, 1H).

XPA-
C₂₃H₂₃D₅N₂O₂S

¹H NMR (400 MHz, CDCl₃) δ 8.37
C

1336

(d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.4 Hz,

1H), 7.45-7.37 (m, 2H), 7.14-7.04

(m, 2H), 4.66 (s, 2H), 2.11 (p, J = 3.1

Hz, 3H), 1.93 (d, J = 2.9 Hz, 6H),

1.85-1.71 (m, 6H).

XPA-
C₂₂H₂₃BrO₃

¹H NMR (400 MHz, CDCl₃) δ
F

I-0017

7.43-7.38 (m, 2H), 7.35-7.30 (m, 2H),

6.97-6.91 (m, 2H), 6.90-6.84 (m,

2H), 2.10 (s, 3H), 1.90 (d, J = 2.9 Hz,

6H), 1.84-1.69 (m, 6H).

XPA-
C₂₂H₂₄O₄O₃

¹H NMR (400 MHz, CDCl₃) δ 10.36
A

I-0019

(s, 1H), 8.12-7.98 (m, 2H), 7.80 (d, J =

2.4 Hz, 1H), 7.43 (dd, J = 8.5, 2.4

Hz, 1H), 7.07-6.99 (m, 2H), 6.93 (d, J =

8.5 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H),

2.56 (s, 1H), 1.97-1.81 (m, 4H), 1.77

(d, J = 13.1 Hz, 1H), 1.51-1.20 (m, 8H).

For illustrative purposes the synthesis and characterisation of the following examples are described in detail.

XPA-0006: (4-(4-cyclohexylphenoxy)phenyl)methanol

embedded image

Ethyl 4-(4-cyclohexylphenoxy)benzoate (4.82 g, 14.86 mmol, 1 equiv) was dissolved in dry THE (74.3 mL, 0.2 M) under argon and stirring and the resulting solution was cooled to 0° C. with an ice bath. DIBAL-H (31.9 mL, 37.15 mmol, 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 (SiO₂, gradient petroleum ether/AcOEt) to yield 4.07 g of (4-(4-cyclohexylphenoxy)phenyl)methanol (97%).

MS: m/z [M-OH]⁺, calc for [C₁₉H₂₁O]⁺=265.16; found 265.11

¹H-NMR (300 MHz, CDCl₃) δ 7.38-7.28 (m, 2H), 7.23-7.12 (m, 2H), 7.02-6.87 (m, 4H), 4.65 (s, 2H), 2.56-2.40 (m, 1H), 2.00-1.71 (m, 5H), 1.51-1.15 (m, 5H).

¹³C-NMR (75 MHz, CDCl₃) δ 157.3, 154.9, 143.3, 135.4, 128.7, 128.0, 118.8, 118.6, 65.0, 43.9, 34.7, 26.9, 26.2.

XPA-0028: 4-(4-(adamantan-1-yl)phenoxy)benzaldehyde

embedded image

To (4-(4-(adamantan-1-yl)phenoxy)phenyl)methanol (1.49 g, 4.47 mmol, 1 equiv), dissolved in DCM (22.5 mL, 0.2 M) under vigorous stirring, was added MnO2 (1.56 g, 17.9 mmol, 2-4 equiv) and the resulting suspension was heated to 40° C. and left 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 (SiO₂, gradient petroleum ether/AcOEt) to yield 1.1 g of 4-(4-(adamantan-1-yl)phenoxy)benzaldehyde (74%).

MS: m/z [M+H]⁺, calc for [C₂₃H₂₅O₂]⁺=333.18; found 333.26

¹H-NMR (300 MHz, CDCl₃) δ 9.91 (s, 1H), 7.90-7.72 (m, 2H), 7.47-7.33 (m, 2H), 7.13-6.97 (m, 4H), 2.19-2.05 (m, 3H), 1.97-1.86 (m, 6H), 1.87-1.64 (m, 7H).

¹³C-NMR (75 MHz, CDCl₃) δ 190.8, 163.6, 152.6, 148.3, 131.9, 131.1, 126.6, 120.0, 117.4, 43.3, 36.7, 36.0, 28.9.

XPA-0060: 4-(4-(2-(dimethylamino)ethyl)phenoxy)benzoate

embedded image

To 4-(2-(dimethylamino)ethyl)phenol (5.16 g, 31.25 mmol, 1.25 equiv) and ethyl 4-fluorobenzoate (4.2 g, 25 mmol, 1 equiv), dissolved in DMSO (50 mL, 0.5 M) under argon and stirring, was added K₂CO₃(5.2 g, 37.5 mmol, 1.5 equiv) and the mixture was heated to 120° 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 Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt/NEt₃) to yield 6.27 g of ethyl 4-(4-(2-(dimethylamino)ethyl)phenoxy)benzoate (80%).

MS: m/z [M+H]⁺, calc for [C₁₉H₂₄NO₃]⁺=314.18; found 314.27

¹H-NMR (300 MHz, CDCl₃) δ 7.96-7.84 (m, 2H), 7.27-7.08 (m, 2H), 6.98-6.79 (m, 4H), 4.28 (q, J=7.1 Hz, 2H), 2.85-2.67 (m, 2H), 2.58-2.41 (m, 2H), 2.26 (s, 6H), 1.31 (t, J=7.1 Hz, 3H).

¹³C-NMR (75 MHz, CDCl₃) δ 166.2, 161.9, 153.9, 136.4, 131.6, 130.1, 124.7, 120.1, 117.1, 61.4, 60.8, 45.4, 33.5, 14.4.

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

embedded image

To 4-(tetrahydro-2H-pyran-4-yl)phenol (0.85 g, 4.75 mmol, 1 equiv) and ethyl 4-fluorobenzoate (0.80 g, 4.75 mmol, 1 equiv), dissolved in DMSO (15 mL, 0.5 M) under argon and stirring, was added K₂CO₃(0.98 g, 7.13 mmol, 1.5 equiv) and the mixture was heated to 120° 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 Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield 1.01 g of ethyl 4-(4-(tetrahydro-2H-pyran-4-yl)phenoxy)benzoate 65%.

MS: m/z [M+H]⁺, calc for [C₂₀H₂₃O₄]⁺=327.16; found 327.24

¹H-NMR (300 MHz, CDCl₃) δ 7.96-7.90 (m, 2H), 7.24-7.12 (m, 2H), 6.97-6.87 (m, 4H), 4.29 (q, J=7.1 Hz, 2H), 4.09-3.95 (m, 2H), 3.54-3.39 (m, 2H), 2.70 (tq, J=10.2, 5.4 Hz, 1H), 1.84-1.63 (m, 4H), 1.31 (t, J=7.1 Hz, 3H).

¹³C NMR (75 MHz, CDCl₃) δ 166.2, 161.9, 154.0, 142.1, 131.6, 128.2, 124.8, 120.1, 117.2, 68.4, 60.8, 41.0, 34.1, 14.4.

XPA-0064: ethyl 4-(4-(1-methylpiperidin-4-yl)phenoxy)benzoate

embedded image

To 4-(1-methylpiperidin-4-yl)phenol (0.84 mg, 4.38 mmol, 1 equiv) and ethyl 4-fluorobenzoate (0.74 g, 4.38 mmol, 1 equiv), dissolved in DMSO (8.76 mL, 0.5 M) under argon and stirring, was added K₂CO₃(0.91 g, 6.57 mmol, 1.5 equiv) and the mixture was heated to 120° 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 Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient DCM/MeOH) to yield 1.0 g of ethyl 4-(4-(1-methylpiperidin-4-yl)phenoxy)benzoate (67%).

MS: m/z [M+H]⁺, calc for [C₂₁H₂₆NO₃]⁺=340.19; found 340.35

¹H-NMR (300 MHz, CDCl₃) δ 7.92 (d, J=8.9 Hz, 2H), 7.29-7.09 (m, 2H), 7.00-6.80 (m, 4H), 4.28 (q, J=7.1 Hz, 2H), 3.06-2.86 (m, 2H), 2.51-2.36 (m, 1H), 2.29 (s, 3H), 2.14-1.95 (m, 2H), 1.78 (ddd, J=10.5, 7.2, 3.4 Hz, 4H), 1.31 (t, J=7.1 Hz, 3H).

¹³C-NMR (75 MHz, CDCl₃) δ 166.2, 161.9, 153.9, 142.4, 131.6, 128.3, 124.7, 120.0, 117.1, 60.8, 56.3, 46.3, 41.3, 33.4, 14.4.

XPA-0036: 4-(4-(1-methylpiperidin-4-yl)phenoxy)benzoic acid

embedded image

To ethyl 4-(4-(1-methylpiperidin-4-yl)phenoxy)benzoate (0.25 g, 0.73 mmol, 1 equiv), dissolved in EtOH (5 mL, 0.5 M) was added NaOH aq 2M (0.73 mL, 1.46 mmol, 2 equiv) and the reaction was left to stir till completion. The reaction was then partitioned between AcOEt and HCl aq (1 M). The aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then recrystallized from 1 M HCl to yield, after iteration, 219.5 mg of 4-(4-(1-methylpiperidin-4-yl)phenoxy)benzoic acid-HCl salt (96%).

MS: m/z [M+H]⁺, calc for [C₁₉H₂₂NO₃]⁺=312.16; found 312.19

¹H-NMR (300 MHz, DMSO-d₆) δ 12.60 (brs, 1H), 11.02 (brs, 1H), 7.99-7.90 (m, 2H), 7.33 (d, J=8.2 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 7.05-6.95 (m, 2H), 3.55-3.27 (m, 2H), 3.20-2.99 (m, 2H), 2.92-2.70 (m, 4H), 2.19-1.83 (m, 4H).

¹³C-NMR (300 MHz, DMSO-d₆) δ 167.2, 161.6, 154.1, 141.0, 132.1, 128.9, 125.6, 120.6, 117.5, 53.9, 42.9, 38.1, 30.3.

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

embedded image

To 4-(1-adamentyl)phenol (2 g, 8.76 mmol, 1 equiv) and 1,4-dibromobenzene (5.16 g, 21.90 mmol, 2.5 equiv), dissolved in DMF (44 ml, 0.2 M), was added Cs₂CO₃(5.7 g, 17.51 mmol, 2 equiv), CuI (83.4 mg, 0.44 mmol, 10 mol %) and tBuXPos (744 mg, 1.752 mmol, 20 mol %). 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 Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield 2.33 g (69%) of the desired (3r,5r,7r)-1-(4-(4 bromophenoxy)phenyl)adamantane.

¹H NMR (400 MHz, CDCl₃) δ 7.43-7.38 (m, 2H), 7.35-7.30 (m, 2H), 6.97-6.91 (m, 2H), 6.90-6.84 (m, 2H), 2.10 (s, 3H), 1.90 (d, J=2.9 Hz, 6H), 1.84-1.69 (m, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 156.4, 154.2, 147.0, 132.6, 126.3, 120.2, 118.7, 115.2, 43.3, 36.8, 35.9, 29.0.

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

embedded image

To 4-(1-adamentyl)phenol (2.89 g, 12.66 mmol, 1.5 equiv) and 1,4-dibromopyridine (2 g, 8.44 mmol, 1 equiv), dissolved in DMSO (42 ml, 0.5 M) under argon and stirring, was added K₂CO₃(2.92 g, 21.1 mmol, 1.5 equiv) and the mixture was heated at 80° 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 Na₂SO₄, filtered and concentrated under vacuum. The residue was recrystallized in hexanes to yield 1.9 g (59%) of 2-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)-5-bromopyridine.

MS: m/z [M+H]⁺, calc for [C₂₁H₂₃BrNO]⁺=384.10/386.09; found 384.21/386.20

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=2.5 Hz, 1H), 7.74 (dd, J=8.7, 2.6 Hz, 1H), 7.42-7.34 (m, 2H), 7.10-7.02 (m, 2H), 6.81 (d, J=8.7 Hz, 1H), 2.16-2.03 (m, 3H), 1.92 (d, J=2.9 Hz, 6H), 1.79 (dd, J=11.5, 8.4 Hz, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 162.8, 151.4, 148.4, 148.0, 141.8, 126.3, 120.4, 113.3, 113.0, 43.3, 36.8, 36.0, 29.00.

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

embedded image

(3r,5r,7r)-1-(4-(4 bromophenoxy)phenyl)adamantane (0.5 g, 1.30 mmol, 1 equiv) was dissolved in dry THF (6.5 ml, 0.2 M) under argon and stirring and the resulting solution was cooled to −78° C. with a dry ice/acetone bath. n-BuLi (1.1 equiv, 2.1 M in hexane) was then added dropwise and the mixture left to stir at that temperature for 30 min then at −50° C. till full consumption 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 3-oxetanone (0.17 ml, 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 NH₄Cl aq. sat., the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash chromatography (SiO₂, gradient petroleum ether/AcOEt) to yield 350 mg (71%) of 3-(4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)phenyl)oxetan-3-ol.

MS: m/z [M-OH]⁺, calc for [C₂₅H₂₇O₂]⁺=359.49; found 359.59

¹H NMR (400 MHz, CDCl₃) δ 7.50-7.60 (m, 2H), 7.40-7.30 (m, 2H), 7.10-7.05 (m, 2H), 7.00-6.90 (m, 2H), 5.00-4.90 (m, 4H), 2.45 (s, 3H), 2.20-2.10 (m, 6H), 1.85-1.75 (m, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 157.5, 154.4, 146.9, 136.7, 126.2, 126.0, 118.7, 118.6, 85.6, 75.8, 43.3, 36.8, 35.9, 29.0.

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

embedded image

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

MS: m/z [M+H]⁺, calc for [C₂₃H₂₇N₂O₃]⁺=379.20; found 379.63

¹H NMR (400 MHz, CDCl₃) δ 8.55 (s, 2H), 7.46-7.37 (m, 2H), 7.07-6.98 (m, 2H), 4.51 (q, J=7.2 Hz, 2H), 2.10 (q, J=3.2 Hz, 3H), 1.91 (d, J=2.9 Hz, 6H), 1.85-1.70 (m, 6H), 1.45 (t, J=7.1 Hz, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 162.85, 153.96, 151.77, 150.32, 149.27, 146.50, 127.02, 119.06, 62.63, 43.22, 36.66, 36.09, 28.87, 14.30.

XPA-0146: 3-(4-(4-cyclohexylphenoxy)phenyl)-3-methoxyoxetane

embedded image

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

MS: m/z [M-OMe]⁺, calc for [C₂₁H₂₃O₂]⁺=307.17; found 307.46

¹H NMR (400 MHz, CDCl₃) δ 7.40-7.34 (m, 2H), 7.21-7.16 (m, 2H), 7.05-7.00 (m, 2H), 6.99-6.93 (m, 2H), 4.91 (d, J=6.7 Hz, 2H), 4.83 (d, J=6.7 Hz, 2H), 3.13 (s, 3H), 2.49 (ddt, J=11.7, 6.6, 3.7 Hz, 1H), 1.87 (ddt, J=15.6, 8.4, 2.6 Hz, 4H), 1.75 (dtt, J=12.6, 3.1, 1.6 Hz, 1H), 1.50-1.33 (m, 4H), 1.25 (dtt, J=11.3, 8.0, 4.0 Hz, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 157.6, 154.5, 143.6, 133.8, 128.1, 127.4, 119.2, 118.3, 80.9, 80.6, 51.6, 43.9, 34.6, 26.9, 26.1.

XPA-1284: ethyl 4-(4-cyclohexyl-2-vinylphenoxy)benzoate

embedded image

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

¹H NMR (400 MHz, CDCl₃) δ 8.00-7.95 (m, 2H), 7.45 (d, J=2.2 Hz, 1H), 7.12 (dd, J=8.3, 2.2 Hz, 1H), 6.93-6.86 (m, 3H), 6.82 (dd, J=17.7, 11.1 Hz, 1H), 5.76 (dd, J=17.7, 1.3 Hz, 1H), 5.23 (dd, J=11.1, 1.3 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.59-2.46 (m, 1H), 1.89 (td, J=9.8, 5.2 Hz, 4H), 1.77 (d, J=12.9 Hz, 1H), 1.47-1.33 (m, 7H), 1.32-1.19 (m, 1H).

¹³C NMR (101 MHz, CDCl₃) δ 166.2, 162.4, 150.1, 145.1, 131.6, 130.8, 129.9, 127.7, 125.0, 124.3, 121.2, 116.2, 115.6, 60.8, 44.2, 34.6, 26.9, 26.1, 14.4.

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

embedded image

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

¹H NMR (400 MHz, CDCl₃) δ 8.03-7.97 (m, 2H), 7.14 (dd, J=8.3, 2.3 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.96-6.88 (m, 3H), 4.36 (qd, J=7.1, 0.7 Hz, 2H), 4.02 (dd, J=4.1, 2.6 Hz, 1H), 3.02 (ddd, J=5.7, 4.1, 0.7 Hz, 1H), 2.69 (ddd, J=5.7, 2.6, 0.7 Hz, 1H), 2.56-2.43 (m, 1H), 1.94-1.69 (m, 5H), 1.47-1.18 (m, 8H).

¹³C NMR (101 MHz, CDCl₃) δ 166.1, 162.1, 151.6, 145.4, 131.7, 129.5, 127.6, 124.7, 123.9, 120.3, 116.4, 60.8, 50.7, 48.1, 44.1, 34.6, 34.5, 26.8, 26.1, 14.4.

XPA-1295: 4-(4-cyclohexyl-2-cyclopropylphenoxy)benzoate

embedded image

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

¹H NMR (400 MHz, CDCl₃) δ 8.00-7.94 (m, 2H), 7.01 (dd, J=8.3, 2.2 Hz, 1H), 6.93-6.86 (m, 3H), 6.77 (d, J=2.2 Hz, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.46 (s, 1H), 1.96-1.69 (m, 6H), 1.46-1.17 (m, 8H), 0.86-0.74 (m, 2H), 0.69-0.59 (m, 2H).

¹³C NMR (101 MHz, CDCl₃) δ 166.3, 162.8, 151.5, 145.2, 135.4, 131.5, 124.9, 124.1, 123.9, 120.9, 115.9, 60.7, 44.2, 34.6, 26.9, 26.1, 14.4, 9.8, 8.0.

XPA-1317: 3-(benzyloxy)-3-(4-(4-cyclohexylphenoxy)phenyl)azetidine

embedded image

To tert-butyl 3-(benzyloxy)-3-(4-(4-cyclohexylphenoxy)phenyl)azetidine-1-carboxylate (60 mg, 0.12 mmol, 1 equiv) was dissolved in a mixture of 1,4-dioxane and aq 1 M HCl (0.6 ml, 0.2 M, 4:1 mixture). The reaction mixture was then stirred till completion at 80° C. It was then partitioned between AcOEt and aq. sat. NaHCO₃, the aqueous layer was extracted twice more and the combined organic phases were then washed with Brine, dried over Na₂SO₄, filtered and concentrated under vacuum to yield 40 mg (82%) of 3-(benzyloxy)-3-(4-(4-cyclohexylphenoxy)phenyl)azetidine.

MS: m/z [M+H]⁺, calc for [C₂₈H₃₁NO₂]⁺=414.24; found 414.72

¹H NMR (400 MHz, CDCl₃) δ 7.51-7.42 (m, 2H), 7.39-7.23 (m, 5H), 7.21-7.14 (m, 2H), 7.07-7.01 (m, 2H), 6.99-6.94 (m, 2H), 4.18 (s, 2H), 4.05 (d, J=8.7 Hz, 2H), 3.90 (d, J=8.6 Hz, 2H), 2.50 (tt, J=8.4, 3.6 Hz, 1H), 1.95-1.80 (m, 4H), 1.76 (dtt, J=12.7, 3.2, 1.6 Hz, 1H), 1.49-1.20 (m, 5H).

¹³C NMR (101 MHz, CDCl₃) δ 157.5, 154.6, 143.5, 138.1, 135.2, 131.9, 128.4, 128.0, 127.7, 127.6, 119.1, 118.4, 67.1, 65.9, 57.5, 43.9, 34.7, 26.9, 26.2.

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

embedded image

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

MS: m/z [M+H]⁺, calc for [C₂₆H₃₂NO₂]⁺=404.57; found 404.72

¹H NMR (400 MHz, CDCl₃) δ 7.43-7.37 (m, 2H), 7.34-7.29 (m, 2H), 7.04-6.98 (m, 2H), 6.98-6.93 (m, 2H), 3.67-3.57 (m, 2H), 3.42-3.33 (m, 2H), 3.03 (s, 3H), 2.44 (s, 3H), 2.09 (q, J=3.2 Hz, 3H), 1.91 (d, J=2.9 Hz, 6H), 1.84-1.69 (m, 6H).

¹³C NMR (101 MHz, CDCl₃) δ 157.0, 154.6, 146.6, 135.4, 127.7, 126.1, 118.5, 118.5, 76.3, 66.2, 51.3, 46.2, 43.3, 36.8, 35.8, 29.0.

NOVEL AROMATIC MOLECULES

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

International Classifications

Abstract

Description

Claims

Priority Claims (1)

PCT Information