Enhancers of notch signaling and their use in treatment of cancers and malignancies medicable by upregulation of notch

Abstract

To provide compounds which act as Notch signaling enhancers and can be used to treat cancers and other diseases which cannot be treated by Notch signaling inhibitors, or to provide compounds which render possible an alternative treatment to Notch signaling inhibitors, of the respective diseases.SOLUTION: There is provided use for enhancing Notch signaling in an individual, of a compound showing the general formula (I) and / or a pharmaceutically acceptable salt or ester thereof, for the treatment of a disease selected from the group of dermatological disorders including atopic dermatitis, dermatological disorders including psoriasis, immune related disorders, cancer, squamous cell carcinoma, cutaneous and lung squamous cell carcinoma, head and neck cancer, non-melanoma skin cancer, basal cell carcinoma and actinic keratosis, neuroendocrine tumors, neuroendocrine small cell carcinoma and carcinoid tumors, thyroid carcinomas, muscular disorders, muscular dystrophy and impaired regeneration capacity after injury; use in immunotherapy for cancer.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds that are enhancers of Notch signaling and are useful for the treatment of Notch-associated malignancies such as cancer, degenerative muscle diseases, skin diseases such as psoriasis and atopic dermatitis, and immunological disorders, and for use in the immunotherapy of cancer. [Background technology]

[0002] Background of the Invention Notch signaling is a short-range intercellular signaling pathway that plays a crucial role in embryonic development and adult tissue homeostasis. Depending on the cellular context, Notch signaling is involved in regulating cell fate determination, differentiation, apoptosis, and proliferation, as well as stem cell maintenance. The presence and intensity of Notch signaling within the cellular framework are tightly controlled in time and space. Consequently, aberrant Notch activity can lead to various disease states. Although Notch was historically identified as an oncogene, studies within the last decade have demonstrated the tumor suppressor role of Notch signaling (Koch and Radtke, 2010) (South et al., 2012). Notch functions as a tumor suppressor, particularly in tissues where Notch signaling induces differentiation, such as the skin and neuroendocrine organs. Thus, activation or increase of Notch signaling in cancers, including but not limited to squamous cell carcinoma of the skin and lung (Wang et al., 2011), head and neck cancer (Agrawal et al., 2011; Stransky et al., 2011), thyroid cancer (Yu et al., 2013) or neuroendocrine tumors such as small cell carcinoma of the neuroendocrine system (Sriuranpong et al., 2001) and carcinoid tumors (Greenblatt et al., 2007), induces differentiation and blocks cancer cell proliferation.

[0003] Therefore, the development of tools for controlling Notch signaling is highly desirable. The present invention involves the use of a family of small molecules disclosed herein that can enhance Notch signaling, leading to potential applications. Applications can be carried out in both human and veterinary medicine.

[0004] technical level WO 2013 / 093885 discloses 6-(4-tert-butylphenoxy)pyridin-3-amine and its derivatives having Notch signaling pathway inhibitory properties for the treatment and / or prevention of cancer, wherein the cancer is a Notch-dependent cancer, preferably selected from the group including T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), breast cancer, pancreatic cancer, prostate cancer, melanoma, brain tumor, tumor angiogenesis, and colorectal cancer.

[0005] A limited number of small molecules characterized by Notch signaling activation have been reported in the literature, including valproic acid (D.Y. Greenblatt, The Oncologist 2007, 12, 942–951; Mohammed et al., The Oncologist 2011, 16, 835–843), resveratrol (S.N. Pinchot, Cancer 2011, 117, 7, 1386–1398), phenethyl isothiocyanate (S.-H. Kim, PLoS One 2011, 6, 10), and several flavonoids, such as chrysin (X.M. Yu, Cancer 2013, 119, 4) or hesperetin (P.N. Patel, Ann Surg Oncol 2014). However, some of these molecules only exhibited Notch-enhancing activity at high concentrations. Many of the compounds listed here are already in clinical trials and are being investigated as anti-cancer drugs across several tumor types.

[0006] Another approach to upregulating Notch signaling involves the use of Notch ligand mimetic peptides, such as JAG-1 protein peptide fragments (BJ Nickoloff, Cell Death and Differentiation 2002, 9, 842-855). Nevertheless, this tool for inducing Notch signaling is still under development and is currently only available for research purposes.

[0007] There is a need for potent Notch signaling enhancers that can be used to treat and prevent Notch-related diseases, preferably dermatological diseases, immunological disorders, muscle diseases such as muscular dystrophies and impaired regenerative capacity after injury, and cancers such as squamous cell carcinoma, neuroendocrine tumors, thyroid cancer, and for immunotherapy against cancer.

[0008] The following patent applications and scientific publications may be of interest in the context of the present application: WO 98 / 42328, PCT / US98 / 06037: "Di-aryl ethers and their derivatives as anti-cancer agents" WO 93 / 24442, PCT / JP93 / 00710:: "Medicine containing benzoic acid derivative as testosterone 5-reductase inhibitor and novel benzoic acid derivative" This application discloses several benzoic acid derivatives that serve as testosterone 5-reductase inhibitors and can be used, inter alia, to treat prostate cancer (prostate cancer). WO 94 / 05153, PCT / US93 / 08096: "Herbicidal benzene compounds" US 5438033, PCT / US92 / 04644, WO 92 / 22203: "Substituted pyridine herbicides" Additional patent applications and patents disclosing specific molecular structures are listed in the section Structures Tested in Notch Reporter Assays. Chemical and Pharmaceutical Bulletin 1999, 47, 8, 1073-1080, S. Igarashi et al: "A novel class of inhibitors for human steroid 5-reductase: phenoxybenzoic acid derivatives. I" Bioorganic and Medicinal Chemistry Letters 2011, 21, 4215-4219, C. De Savi et al.: “Selective non zinc binding inhibitors of MMP13” Bioorganic and Medicinal Chemistry Letters 2012, 22, 1788-1792, T. Nakamura et al.: “Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P3 agonist”

[0009] However, all of the compounds known so far that are used as enhancers of Notch signaling and that treat diseases associated therewith have the aforementioned drawbacks.

[0010] Therefore, one object of the present invention is to provide compounds that act as enhancers of Notch signaling and can be used to treat cancers and other diseases that cannot be treated with Notch signaling inhibitors, or to provide compounds that enable alternative treatments to Notch signaling inhibitors for each disease, particularly the cancers described in WO 2013 / 093885. A further object of the present invention is to provide compounds that act as enhancers of Notch signaling, which are capable of treating the above-mentioned diseases and which preferably do not exhibit the drawbacks of known compounds. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows Notch signaling enhancing activity in a luciferase assay driven by Notch1. [Figure 2-1] Figure 2-1, together with Figures 2-2 and 2-3, shows studies using V126 in different settings within a luciferase reporter assay. [Figure 2-2] Figure 2-2, together with Figure 2-1 and Figure 2-3, shows studies using V126 in different settings within a luciferase reporter assay. [Figure 2-3] Figure 2-3, together with Figure 2-1 and Figure 2-2, shows studies using V126 in different settings within a luciferase reporter assay. [Figure 3] FIG. 3 shows the increase in involucrin expression at the protein level. [Figure 4-1] Figure 4-1, together with Figure 4-2, shows that V126 was able to double the number of MZB compared to the control, but had no effect on the number of FoB. [Figure 4-2] Figure 4-2, together with Figure 4-1, shows that V126 was able to double the number of MZB compared to the control, but had no effect on the number of FoB. [Figure 5-1] Figure 5-1 together with Figure 5-2 demonstrates that V126 induces increased IFNγ production and secretion in vitro. [Figure 5-2] Figure 5-2, together with Figure 5-1, demonstrates that V126 induces increased IFNγ production and secretion in vitro. Summary of the Invention

[0012] Detailed Description of the Invention The present invention relates to the use of compounds having the general formula (I) and / or pharmaceutically acceptable salts or esters thereof to enhance Notch signaling in an individual: JPEG2025183310000001.jpg36166In formula, X is an aromatic ring selected from a phenylene ring, CH, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one or two N atoms, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; R 1 is H; linear and branched, unsubstituted and substituted C1-C 16 alkyl; straight-chain and branched, unsubstituted and substituted C2-C8 alkenyl; straight-chain and branched, unsubstituted and substituted C2-C8 alkynyl; substituted and unsubstituted C3-C8 cycloalkyl; substituted and unsubstituted C5-C8 cycloalkenyl; adamantyl and norbornyl, wherein the substituents of the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from the group F, Cl, Br, I, -CN, -NCO, -NCS, N3, and the designated groups may be mono- or polysubstituted; R 2 ~R 5 are independently selected from H, F, Cl, Br, I; linear and branched, unsubstituted and substituted C1-C4 alkyl, C2-C4 alkenyl and C2-C4 alkynyl, cyclopropyl and cyclobutyl, and the substituents of the groups designated alkyl, alkenyl, alkynyl, cyclopropyl and cyclobutyl are selected from F, Cl, Br and I; Y is O or S; Z is selected from F, Cl, Br, I, linear and branched, unsubstituted and substituted C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, cyclopropyl and cyclobutyl, and the substituents on the groups designated alkyl, alkenyl, alkynyl, cyclopropyl and cyclobutyl may be selected from F, Cl, Br and I; R 6 is OR 7 , N.R. 8 R 9 , NHOH; R 7 is selected from H and straight-chain and branched C1-C6 alkyl; R 8 and R 9 are each independently selected from H and straight-chain and branched C1-C6 alkyl.

[0013] As used herein, the term "substituted" includes both partial and full substitution.

[0014] Within the most general embodiment of the invention defined above, when X is a phenylene ring, the following embodiment A is preferred: R 1 is linear and branched, unsubstituted and substituted C4-C 16 alkyl; straight-chain and branched, substituted and unsubstituted C4-C8 alkenyl; straight-chain and branched, unsubstituted and substituted C4-C8 alkynyl; substituted and unsubstituted C4-C8 cycloalkyl; substituted and unsubstituted C5-C8 cycloalkenyl; adamantyl and norbornyl, wherein the substituents of the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from the group F, Cl, Br, I, -CN, -NCO, -NCS, N3, and the designated groups may be mono- or polysubstituted.

[0015] In a further embodiment within the most general embodiment defined above, when X is a phenylene ring as shown in formula Ia, the following embodiment B is preferred: JPEG2025183310000002.jpg56166B1: the phenylene ring X is unsubstituted or monosubstituted (i.e., contains 0 or 1 substituent Z in addition to H); and / or B2: the phenylene ring X is not substituted with I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B3: the phenylene ring X is not substituted with Br (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B4: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B5: the phenylene ring X is not substituted with I (substituent Z); and / or B6: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z); and / or B6: the phenylene ring X is not substituted by —CH3 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); and / or B7: the phenylene ring X is not substituted by —CH 3 , —C 2 H 5 , C 3 H 7 , and / or C 4 H 9 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); B8: The phenylene ring X is not substituted with -CH3, -C2H5, C3H7, and / or C4H9.

[0016] The above preferred embodiments within the most general embodiment also include combinations of embodiment A with each of embodiments B1, B2, B3, B4, B5, B6, B7, and B8.

[0017] When X is a phenylene ring, R 1 is a higher acyclic or cyclic aliphatic group of C4 or more, i.e., R 1 It has been found to be advantageous if is a radical selected from the radicals mentioned above in embodiment A.

[0018] As known to those skilled in the art, the term "alkyl" includes methyl (C1 alkyl), ethyl (C2 alkyl), n-propyl, isopropyl (C3 alkyl), n-butyl, isobutyl, sec-butyl, and tert-butyl (C4 alkyl), n-pentyl (amyl), 2-pentyl (sec-pentyl), 3-pentyl; 2-methylbutyl, 3-methylbutyl (isopentyl or isoamyl), 3-methylbut-2-yl, 2-methylbut-2-yl; 2,2-dimethylpropyl (neopentyl) (C5 alkyl), hexyl (C6 alkyl), including all isomers, heptyl (C7 alkyl), including all isomers, octyl (C8 alkyl), including all isomers, nonyl (C9 alkyl), including all isomers, decyl (C 10 alkyl), undecyl group (C 11 alkyl), dodecyl group (C 12 alkyl), tridecyl (C 13 alkyl), tetradecyl (C 14 alkyl), pentadecyl group (C 15 alkyl), as well as the hexadecyl group (C 16 refers to saturated aliphatic hydrocarbon groups, including alkyl.

[0019] As known to those skilled in the art, the term "alkenyl" refers to an aliphatic unsaturated hydrocarbon group, including ethenyl (C2 alkenyl), n-propenyl, isopropenyl (C3 alkenyl), n-butenyl, isobutenyl, sec-butenyl, and tert-butenyl (C4 alkenyl), pentenyl groups (C5 alkenyl) including all isomers, hexenyl groups (C6 alkenyl) including all isomers, heptenyl groups (C7 alkenyl) including all isomers, and octenyl groups (C8 alkenyl) including all isomers.

[0020] The term "alkynyl" refers to the above C2-C8 groups having a triple bond instead of a double bond and is known to those skilled in the art. Examples include ethynyl (C2 alkynyl), n-propynyl and isopropynyl (C3 alkynyl), the various isomers of butynyl (C4 alkynyl), the various isomers of pentynyl (C5 alkynyl), the various isomers of hexynyl (C6 alkynyl), the various isomers of heptynyl (C7 alkynyl), and the various isomers of octynyl (C8 alkynyl).

[0021] "Cycloalkyl" or "cycloalkyl ring" refers to an aliphatic cyclic saturated alkyl group, such as cyclopropyl (C3 cycloalkyl), cyclobutyl (C4 cycloalkyl), cyclopentyl (C5 cycloalkyl), cyclohexyl (C6 cycloalkyl), cycloheptyl (C7 cycloalkyl), and cyclooctyl (C8 cycloalkyl). Each hydrogen on the carbon of a cycloalkyl may be replaced by a substituent.

[0022] "Cycloalkenyl" or "cycloalkenyl ring" refers to a cyclic unsaturated (one or more double carbon-carbon bonds) aliphatic or aromatic group, such as cyclopropenyl (C cycloalkenyl), cyclobutenyl (C cycloalkenyl), cyclopentenyl (C cycloalkenyl), cyclohexenyl (C cycloalkenyl), cycloheptenyl (C cycloalkenyl), and cyclooctenyl (C cycloalkenyl). Each hydrogen on a cycloalkyl carbon may be replaced by a substituent.

[0023] Substituent R 2 , R 3 , R 4 , and R 5 When they are not H, they can be in the 2, 3, 5, and 6 positions relative to the ether group. Preferably, R 2 , R 3 , R 4 , and R 5 are all H or R 2 , R 3 , R 4 , and R5 In the context of the present invention, "R" as used throughout this application is a substituted or unsubstituted group, wherein one or two of the groups are not H and are selected from the substituents defined above. 2 ~R 5 are independently selected from 2 , R 3 , R 4 , and R 5 One, two, three or four of these are other than H, and R 2 , R 3 , R 4 , and R 5 It means that each of the above can mean any of the defined meanings for each aspect.

[0024] Carbonyl-derived group -C(Y)R linked to aromatic ring 6 can be at the 2-, 3-, or 4-position relative to the ether bridge, preferably at the 4-position. This means that in a preferred embodiment, C(Y)R 6 This also applies to formula (Ia), which is a phenoxybenzoic acid derivative in which the group is in the 4-position (p-position) relative to the ether bridge.

[0025] The substituent Z can be in the 2-, 3-, 4-, 5-, and 6-position relative to the ether group.

[0026] The term "six-membered aromatic heterocycle containing one or two N atoms" refers to a heterocycle containing either one N atom or two N atoms. This heterocycle is selected from pyridine, pyridazine, pyrimidine, and pyrazine. In the compound of formula (I), the aromatic heterocycle is linked to O through a chemical bond at an ether bridge, and is linked to a carbonyl-derived group at another position of the heterocycle, indicating that at least two H atoms of the aromatic heterocycle are replaced by chemical bonds. Additional H atoms, for example, one, two, three, or four, preferably one H atom, may be replaced by a Z group.

[0027] In an embodiment of the present invention, the compound that enhances Notch signaling belongs to the family of phenoxybenzoic acid and phenoxynicotinic acid and their derivatives. Those skilled in the art will be aware of suitable derivatives. Known examples include esters and amides.

[0028] In a further aspect, the present invention relates to compounds as defined in relation to formula (I) and / or pharmaceutically acceptable salts or esters thereof, including all of the preferred, more preferred, even more preferred, most preferred and second preferred aspects, for the treatment of diseases associated with reduced Notch signalling activity.

[0029] In a preferred embodiment of the present invention, R 1 ~R 9 The symbols X, Y, and Z have the following meanings: X is an aromatic ring selected from a phenylene ring, CH, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one or two N atoms, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; R 1 is H; linear and branched, unsubstituted and substituted C1-C 12 alkyl; straight-chain and branched, unsubstituted and substituted C2-C8 alkenyl; straight-chain and branched, unsubstituted and substituted C2-C8 alkynyl; substituted and unsubstituted C3-C8 cycloalkyl; substituted and unsubstituted C5-C8 cycloalkenyl; adamantyl and norbornyl, wherein the substituents of the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from the group F, Cl, Br, I, -CN, -NCO, -NCS, N3, and the designated groups may be mono- or polysubstituted (i.e., when the designated groups are substituted, they may carry one, two or several of the designated substituents); R 2 ~R 5are independently selected from H, F, Cl, Br, I; unsubstituted and substituted C1-C2 alkyl, C2 alkenyl, C2 alkynyl, and the designated alkyl, alkenyl, and alkynyl groups may be substituted with F (i.e., when the designated group is substituted, the substituent is F); Y is O or S; Z is selected from F, Cl, Br, I; unsubstituted and substituted C1-C2 alkyl, C2 alkenyl, C2 alkynyl, and the substituents of the designated alkyl, alkenyl, and alkynyl groups can be F (i.e., when the designated group is substituted, the substituent is F); R 6 is OR 7 , N.R. 8 R 9 , NHOH; R 7 is selected from H and straight-chain and branched C1-C4 alkyl; And here, R 1 , R 2 ~R 5 and at least one of Z is a substituent other than H; R 8 and R 9 are each independently selected from H and straight-chain and branched C1-C4 alkyl.

[0030] Within the scope of the preferred embodiments of the invention defined above, when X is a phenylene ring, the following embodiment A is preferred: R 1 is linear and branched, unsubstituted and substituted C4-C 12alkyl; straight-chain and branched, substituted and unsubstituted C4-C8 alkenyl; straight-chain and branched, unsubstituted and substituted C4-C8 alkynyl; substituted and unsubstituted C4-C8 cycloalkyl; substituted and unsubstituted C5-C8 cycloalkenyl; adamantyl and norbornyl, wherein the substituents of the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from the group F, Cl, Br, I, -CN, -NCO, -NCS, N3, and the designated groups may be mono- or polysubstituted.

[0031] In a further embodiment within the preferred embodiments defined above, when X is a phenylene ring, the following embodiment B is preferred: B1: the phenylene ring X is unsubstituted or monosubstituted (i.e., contains 0 or 1 substituent Z in addition to H); and / or B2: the phenylene ring X is not substituted with I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B3: the phenylene ring X is not substituted with Br (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B4: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B5: the phenylene ring X is not substituted with I (substituent Z); and / or B6: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z); and / or B6: the phenylene ring X is not substituted by —CH3 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); and / or B7: the phenylene ring X is not substituted by —CH 3 , —C 2 H 5 , C 3 H 7 , and / or C 4 H 9 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); B8: The phenylene ring X is not substituted with -CH3, -C2H5, C3H7, and / or C4H9.

[0032] The above preferred embodiments within the scope of the above defined preferred embodiments also include combinations of embodiment A with each of embodiments B1, B2, B3, B4, B5, B6, B7, and B8.

[0033] When X is a phenylene ring, R 1 is a higher acyclic or cyclic aliphatic group of C4 or more, i.e., R 1 It has been found to be advantageous if is a radical selected from the radicals mentioned above in embodiment A.

[0034] In a more preferred embodiment of the present invention, R 1 ~R 9 The symbols X, Y, and Z have the following meanings: X is an aromatic ring selected from a phenylene ring, CH, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one or two N atoms, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; R 1 is selected from H; straight-chain and branched, unsubstituted and substituted C1-C8 alkyl; straight-chain and branched, unsubstituted and substituted C2-C6 alkenyl; straight-chain and branched, unsubstituted and substituted C2-C6 alkynyl; substituted and unsubstituted C3-C6 cycloalkyl; substituted and unsubstituted C5-C6 cycloalkenyl; adamantyl and norbornyl, wherein the substituents of the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from the group F, Cl, Br, I, -CN, -NCO, -NCS, N3, and the designated groups may be mono- or polysubstituted (i.e., when the designated groups are substituted, they may carry one, two, or several of the designated substituents); R 2 ~R 5are independently selected from H, F, Cl, Br, I; unsubstituted and substituted C1-C2 alkyl, C2 alkenyl, and C2 alkynyl, and the substituents of the designated alkyl, alkenyl, and alkynyl groups can be F (i.e., when the designated group is substituted, the substituent is F); Y is O or S; Z is selected from F, Cl, Br, I; unsubstituted and substituted C1-C2 alkyl, C2 alkenyl, and C2 alkynyl, and the substituents of the designated alkyl, alkenyl, and alkynyl groups can be F (i.e., when the designated group is substituted, the substituent is F); R 6 is OR 7 , N.R. 8 R 9 , NHOH; R 7 is selected from H and straight-chain and branched C1-C4 alkyl; R 8 and R 9 are each independently selected from H and straight-chain and branched C1-C4 alkyl.

[0035] Within the scope of the more preferred embodiments of the invention defined above, when X is a phenylene ring, the following embodiment A is preferred: R 1 is selected from straight-chain and branched, unsubstituted and substituted C4-C8 alkyl; straight-chain and branched, substituted and unsubstituted C4-C6 alkenyl; straight-chain and branched, unsubstituted and substituted C4-C6 alkynyl; substituted and unsubstituted C4-C6 cycloalkyl; substituted and unsubstituted C5-C6 cycloalkenyl; adamantyl and norbornyl, wherein the substituents for the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from the group F, Cl, Br, I, -CN, -NCO, -NCS, N3, and the designated groups may be mono- or polysubstituted (i.e., when the designated groups are substituted, they may bear one, two or several of the designated substituents).

[0036] In a further embodiment within the more preferred embodiments of the invention defined above, when X is a phenylene ring, the following embodiment B is preferred: B1: the phenylene ring X is unsubstituted or monosubstituted (i.e., contains 0 or 1 substituent Z in addition to H); and / or B2: the phenylene ring X is not substituted with I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B3: the phenylene ring X is not substituted with Br (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B4: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B5: the phenylene ring X is not substituted with I (substituent Z); and / or B6: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z); and / or B6: the phenylene ring X is not substituted by —CH3 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); and / or B7: the phenylene ring X is not substituted by —CH 3 , —C 2 H 5 , C 3 H 7 , and / or C 4 H 9 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); B8: The phenylene ring X is not substituted with -CH3, -C2H5, C3H7, and / or C4H9.

[0037] The above preferred embodiments within the more preferred embodiments also include combinations of embodiment A with each of embodiments B1, B2, B3, B4, B5, B6, B7, and B8.

[0038] When X is a phenylene ring, R 1 is a higher acyclic or cyclic aliphatic group of C4 or more, i.e., R 1It has been found to be advantageous if is a radical selected from the radicals mentioned above in embodiment A.

[0039] In an even more preferred embodiment of the present invention, R 1 ~R 9 The symbols X, Y, and Z have the following meanings: X is an aromatic ring selected from a phenylene ring, CH, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one N atom, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; R 1 is selected from H; straight-chained and branched, unsubstituted and substituted C1-C6 alkyl; straight-chained and branched, unsubstituted and substituted C2-C6 alkenyl; straight-chained and branched, unsubstituted and substituted C2-C6 alkynyl; substituted and unsubstituted C3-C6 cycloalkyl; substituted and unsubstituted C5-C6 cycloalkenyl; adamantyl and norbornyl, wherein the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl may be substituted with F (i.e., when the designated group is substituted, the substituent is F), and the designated groups may be mono- or polysubstituted (i.e., when the designated group is substituted, they may contain one, two, or more F); R 2 ~R 5 are independently selected from H; F, Cl, Br, I; unsubstituted and substituted C1-C2 alkyl, C2 alkenyl, and C2 alkynyl, and the substituents of the designated alkyl, alkenyl, and alkynyl groups can be F (i.e., when the designated group is substituted, the substituent is F); Y is O or S; Z is selected from F, Cl, Br, I; unsubstituted and substituted C1-C2 alkyl, C2 alkenyl, and C2 alkynyl, and the substituents of the designated alkyl, alkenyl, and alkynyl groups can be F (i.e., when the designated group is substituted, the substituent is F); R 6 is OR 7 , N.R. 8 R 9 , NHOH; R 7 is selected from H and straight-chain and branched C1-C4 alkyl; R 8 and R 9 are each independently selected from H and straight-chain and branched C1-C4 alkyl.

[0040] Within the scope of the above even more preferred embodiments of the present invention, when X is a phenylene ring, the following embodiment A is preferred: R 1 is selected from straight-chained and branched, unsubstituted and substituted C4, C5, and C6 alkyl; straight-chained and branched, substituted and unsubstituted C4, C5, and C6 alkenyl; straight-chained and branched, unsubstituted and substituted C4, C5, and C6 alkynyl; substituted and unsubstituted C4, C5, and C6 cycloalkyl; substituted and unsubstituted C5 and C6 cycloalkenyl; adamantyl and norbornyl, wherein the substituents for the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl, and norbornyl are selected from the group F, Cl, Br, I, -CN, -NCO, -NCS, N3, and the designated groups may be mono- or polysubstituted (i.e., when the designated groups are substituted, they may hold one, two, or several of the designated substituents).

[0041] In a further embodiment within the even more preferred embodiments defined above, when X is a phenylene ring, the following embodiment B is preferred: B1: the phenylene ring X is unsubstituted or monosubstituted (i.e., contains 0 or 1 substituent Z in addition to H); and / or B2: the phenylene ring X is not substituted with I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B3: the phenylene ring X is not substituted with Br (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B4: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B5: the phenylene ring X is not substituted with I (substituent Z); and / or B6: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z); and / or B6: the phenylene ring X is not substituted by —CH3 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); and / or B7: the phenylene ring X is not substituted by —CH 3 , —C 2 H 5 , C 3 H 7 , and / or C 4 H 9 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); B8: The phenylene ring X is not substituted with -CH3, -C2H5, C3H7, and / or C4H9.

[0042] The above preferred embodiments within the scope of the even more preferred embodiments also include combinations of embodiment A with each of embodiments B1, B2, B3, B4, B5, B6, B7, and B8.

[0043] When X is a phenylene ring, R 1 is a higher acyclic or cyclic aliphatic group of C4 or more, i.e., R 1 It has been found to be advantageous if is a radical selected from the radicals mentioned above in embodiment A.

[0044] In the most preferred embodiment of the present invention, R 1~R 9 The symbols X, Y, and Z have the following meanings: X is an aromatic ring selected from a phenylene ring, CH, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one N atom, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; R 1 is selected from H; straight-chain and branched, unsubstituted and substituted C1-C6 alkyl; substituted and unsubstituted C3-C6 cycloalkyl; adamantyl and norbornyl, where the substituents of the designated groups alkyl, cycloalkyl, adamantyl and norbornyl can be F (i.e., when the designated groups are substituted, the substituents are F), and the designated groups can be mono- or polysubstituted (i.e., when the designated groups are substituted, they contain one, two, or several F); R 2 ~R 5 are independently selected from H; F; unsubstituted and substituted C1-C2 alkyl, and the substituent on a group designated as alkyl may be F (i.e., if a group designated as alkyl is substituted, the substituent is F); Y is O; Z is selected from F, Cl, Br, I; unsubstituted and substituted C1-C2 alkyl, and groups designated as alkyl may be substituted with F (i.e., when a group designated as alkyl is substituted, the substituent is F); R 6 is OR 7 , N.R. 8 R 9 Selected from; R 7 is selected from H and straight-chain and branched C1-C4 alkyl; R 8 and R 9 are each independently selected from H and straight-chain and branched C1-C4 alkyl.

[0045] In a second preferred embodiment, the substituents X, R 2 ~R 5 , Y, Z, and R 6 ~R 9 has the same meaning as defined for the most preferred embodiment, and R 1 is selected from straight-chain and branched, unsubstituted and substituted C1-C6 alkyl; substituted and unsubstituted C3-C6 cycloalkyl; adamantyl and norbornyl, and the substituents of the designated alkyl, cycloalkyl, adamantyl and norbornyl groups can be F (i.e., if the designated group is substituted, the substituent is F), and the designated groups may be mono- or polysubstituted (i.e., if the designated group is substituted, they contain one, two, or several F).

[0046] Within the scope of the first and second preferred embodiments of the invention defined above, when X is a phenylene ring, the following embodiment A is preferred: R 1 is selected from H; straight-chain and branched, unsubstituted and substituted C4, C5, and C6 alkyl; substituted and unsubstituted C4, C5, and C6 cycloalkyl; adamantyl and norbornyl, where the substituents of the designated groups alkyl, cycloalkyl, adamantyl, and norbornyl can be F (i.e., if the designated group is substituted, the substituents are F), and the designated groups can be mono- or polysubstituted, i.e., the designated group can carry one, two, or several F (the most preferred embodiment); or R 1is selected from straight-chain and branched, unsubstituted and substituted C4, C5, and C6 alkyl; substituted and unsubstituted C4, C5, and C6 cycloalkyl; adamantyl and norbornyl, where the substituents of the designated alkyl, cycloalkyl, adamantyl, and norbornyl groups can be F (i.e., if the designated group is substituted, the substituent is F), and the designated group can be mono- or polysubstituted (i.e., the designated group can carry one, two, or several F) (second preferred embodiment).

[0047] In a further embodiment within the first and second preferred embodiments defined above, when X is a phenylene ring, the following embodiment B is preferred: In a further embodiment within the most general embodiment defined above, when X is a phenylene ring, the following embodiment B is preferred: B1: the phenylene ring X is unsubstituted or monosubstituted (i.e., contains 0 or 1 substituent Z in addition to H); and / or B2: the phenylene ring X is not substituted with I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B3: the phenylene ring X is not substituted with Br (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B4: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o'); and / or B5: the phenylene ring X is not substituted with I (substituent Z); and / or B6: the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z); and / or B6: the phenylene ring X is not substituted by —CH3 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); and / or B7: the phenylene ring X is not substituted by —CH 3 , —C 2 H 5 , C 3 H 7 , and / or C 4 H 9 (substituent Z) in the 2- and 6-positions relative to the ether group (positions o and o′); B8: The phenylene ring X is not substituted with -CH3, -C2H5, C3H7, and / or C4H9.

[0048] The above preferred embodiments within the scope of the first and second preferred embodiments also include combinations of embodiment A with each of embodiments B1, B2, B3, B4, B5, B6, B7, and B8.

[0049] When X is a phenylene ring, R 1 is a higher acyclic or cyclic aliphatic group of C4 or more, i.e., R 1 It has been found to be advantageous if is a radical selected from the radicals mentioned above in embodiment A.

[0050] In another preferred embodiment of the present invention, R 1 is selected from H; straight-chain and branched, unsubstituted and substituted C1-C6 alkyl, preferably straight-chain and branched, substituted and unsubstituted C1-C5 alkyl; substituted and unsubstituted C3-C6 cycloalkyl; adamantyl and norbornyl, wherein the designated alkyl, cycloalkyl, adamantyl and norbornyl groups may be substituted with F (i.e., when the designated group is substituted, the substituent is F), and the designated groups may be mono- or polysubstituted (i.e., the designated group may carry one, two, or several F), and R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9 has the meaning defined in said general, said preferred, said more preferred, said even more preferred, said most preferred or said second most preferred aspect.

[0051] Within the scope of the preferred embodiments of the invention defined above, when X is a phenylene ring, the following embodiment A is preferred: R 1 is selected from H, straight-chain and branched, unsubstituted and substituted C4, C5, and C6 alkyl; substituted and unsubstituted C4, C5, and C6 cycloalkyl, preferably C5 and C6 cycloalkyl; adamantyl and norbornyl, where the substituents of the designated alkyl, cycloalkyl, adamantyl, and norbornyl groups can be F (i.e., if the designated group is substituted, the substituents are F), and the designated groups can be mono- or polysubstituted (i.e., the designated group can carry one, two, or several F); and R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9 has the meaning defined in the preferred, more preferred, even more preferred, most preferred, or second most preferred embodiment; and the substituents and substitution patterns of the phenylene ring X are as described in embodiments B1, B2, B3, B4, B5, B6, and B7.

[0052] The preferred embodiments above also include combinations of embodiment A with each of embodiments B1, B2, B3, B4, B5, B6, B7, and B8.

[0053] When X is a phenylene ring, R 1 is a higher acyclic or cyclic aliphatic group of C4 or more, i.e., R 1 It has been found to be advantageous if is a radical selected from the radicals mentioned above in embodiment A.

[0054] In another preferred embodiment of the present invention, R 1is selected from straight-chain and branched, unsubstituted and substituted C1-C6 alkyl, preferably straight-chain and branched, substituted and unsubstituted C1-C5 alkyl; substituted and unsubstituted C3-C6 cycloalkyl; adamantyl and norbornyl, wherein the designated alkyl, cycloalkyl, adamantyl and norbornyl groups may be substituted with F (i.e., when the designated group is substituted, the substituent is F), and the designated groups may be mono- or polysubstituted (i.e., the designated group may carry one, two or several F), and R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9 has the meaning defined in said general, said preferred, said more preferred, said even more preferred, said most preferred or said second most preferred aspect.

[0055] Within the scope of the preferred embodiments of the invention defined above, when X is a phenylene ring, the following embodiment A is preferred: R 1 is selected from straight-chain and branched, unsubstituted and substituted C4, C5, and C6 alkyl; substituted and unsubstituted C4, C5, and C6 cycloalkyl, preferably C5 and C6 cycloalkyl; adamantyl and norbornyl, where the substituents of the designated groups alkyl, cycloalkyl, adamantyl, and norbornyl can be F (i.e., if the designated group is substituted, the substituents are F), and the designated groups can be mono- or polysubstituted (i.e., the designated group can carry one, two, or several F); and R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9has the meaning defined in the general, preferred, more preferred, even more preferred, most preferred, or second most preferred embodiment; and the substituents and substitution patterns of the phenylene ring X are as described in embodiments B1, B2, B3, B4, B5, B6, and B7.

[0056] The preferred embodiments above also include combinations of embodiment A with each of embodiments B1, B2, B3, B4, B5, B6, B7, and B8.

[0057] When X is a phenylene ring, R 1 is a higher acyclic or cyclic aliphatic group of C4 or more, i.e., R 1 It has been found to be advantageous if is a radical selected from the radicals mentioned above in embodiment A.

[0058] In another preferred embodiment of the present invention, R 1 is a group selected from -C(CH3)3, -C(CH3)2C2H5, cyclohexyl, and adamantanyl, and R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9 has the meaning defined in the general, preferred, more preferred, even more preferred, most preferred, or second preferred aspect, including the definitions when X is a substituted or unsubstituted phenylene group.

[0059] In another preferred embodiment of the present invention, the carbonyl derivative group -C(Y)R 6 is in 4th place against Etherbridge, and R 1 , R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9has the meaning defined in the general, preferred, more preferred, even more preferred, most preferred, or second preferred aspect, including the definitions when X is a substituted or unsubstituted phenylene group.

[0060] In another preferred embodiment of the invention, X is an aromatic ring selected from a phenylene ring CH, wherein one or more H atoms may be independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one N atom, wherein one or more H atoms may be independently replaced by one or more substituents Z; and R 1 , R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9 has the meaning defined in the general, preferred, more preferred, even more preferred, most preferred, or second preferred aspect, including the definitions when X is a substituted or unsubstituted phenylene group.

[0061] In another preferred embodiment of the invention, X is an aromatic ring selected from a phenylene ring CH, wherein one or more H atoms may be independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one N atom at the 2-position relative to the ether bridge, wherein one or more H atoms may be independently replaced by one or more substituents Z; and R 1 , R 2 ~R 5 , X, Y, Z, R 6 , R 7 , and R 8 and R 9 has the meaning defined in the general, preferred, more preferred, even more preferred, most preferred, or second preferred aspect, including the definitions when X is a substituted or unsubstituted phenylene group.

[0062] In a further preferred embodiment of the present invention, R 1 is H or CH3, if X is a phenylene group, then R 2 ~R 5 and at least one of Z is a substituent other than H. This applies to any of the general, preferred, more preferred, even more preferred, most preferred, or second preferred aspects of the invention.

[0063] The term "individual" as used in the context of the present application includes animals of any kind, preferably mammals, and even more preferably humans.

[0064] Preferred compounds of the invention that exhibit activity in enhancing Notch signaling are illustrated below: In some cases, the compounds may be classified into the general group of compounds of the invention defined in relation to general formula I, or into the previously defined groups of preferred, more preferred, even more preferred, most preferred, or second preferred compounds. JPEG2025183310000003.jpg228166JPEG2025183310000004.jpg23166·Journal of Materials Chemistry C: Materials for Optical and Electronic Devices (2013), 1 (34), 5315-5321, Hachisuga et al.: "Flying-seed-like liquid crystals 3: new guideline for the induction of mesomorphism by using bulky groups instead of long alkyl chains.” ·Jpn. Kokai Tokkyo Koho (2012), JP 2012056851 A 20120322, Ito et al.: “Photochemical preparation of aromatic carboxylic acids from aromatic compounds using anthraquinone compounds.” JPEG2025183310000005.jpg158166JPEG2025183310000006.jpg139166·WO 93 / 24442, PCT / JP93 / 00710: "Medicine containing benzoic acid derivative as testosterone 5-reductase inhibitor and novel benzoic acid derivative."

[0065] The present invention also relates to compounds having general formula (I) and / or pharmaceutically acceptable salts or esters thereof, as well as the individual compounds depicted above, in all of their preferred, more preferred, even more preferred, most preferred, and second preferred embodiments, for enhancing Notch signaling in an individual.

[0066] In a further aspect of the invention, the invention relates to compounds as defined in relation to formula (I) and / or pharmaceutically acceptable salts or esters thereof, and the individual compounds illustrated above, including all of the preferred, more preferred, even more preferred, most preferred and second preferred embodiments, for the treatment of diseases associated with reduced Notch signaling activity.

[0067] The present invention also includes a method of treating a disease in an individual comprising administering to the individual a compound having general formula (I) and / or a pharmaceutically acceptable salt or ester thereof, as well as the individual compounds illustrated above, in all of its general, preferred, more preferred, even more preferred, most preferred, and second preferred embodiments.

[0068] Diseases treatable by the compounds of the present invention include diseases selected from the group of dermatological disorders including atopic dermatitis, psoriasis; immune-related disorders; cancers including, but not limited to, squamous cell carcinomas such as squamous cell carcinoma of the skin and lung, head and neck cancer, non-melanoma skin cancer, basal cell carcinoma and actinic keratosis, neuroendocrine tumors such as small cell neuroendocrine carcinoma and carcinoid tumors, thyroid cancer; and muscular dystrophies and muscle disorders including impaired regenerative capacity after injury; and the compounds of the present invention can be used in the immunotherapy of cancer.

[0069] In the context of the present application, the phrase "reduced regenerative capacity after injury" preferably relates to muscle damage caused by: diseases such as muscular dystrophy; exposure to myotoxin agents such as hypivacaine or lidocaine; sharp or blunt trauma such as a puncture or contusion; ischemia; exposure to high or low temperatures; or muscle contraction itself, such as in exercise-induced muscle damage and regeneration, especially after eccentric exercise.

[0070] Diseases preferably treated by the compounds of the present invention include atopic dermatitis, psoriasis, squamous cell carcinomas, including squamous cell carcinoma of the skin and lung, non-melanoma skin cancer, head and neck cancer, basal cell carcinoma and actinic keratosis.

[0071] The diseases most preferably treated by the compounds of the present invention include immune-related disorders.

[0072] In a further most preferred embodiment of the present invention, said compounds are used in the immunotherapy of cancer.

[0073] Within the teachings of the present invention, the diseases described above in their general, preferred and most preferred embodiments are treatable by administering the compounds of the present invention, as they result from reduced Notch signaling.

[0074] Preferably, the compounds of the present invention, particularly when X is a phenylene ring, are not used to treat prostate cancer (prostate cancer).

[0075] In a further aspect of the present invention, the present invention relates to compounds defined in relation to formula (I) and / or their pharmaceutically acceptable salts or esters, and the individual compounds illustrated above, including all of the preferred, more preferred, even more preferred, most preferred, and second most preferred embodiments, for the treatment of diseases selected from the group consisting of dermatological disorders, including atopic dermatitis and psoriasis; immune-related disorders; squamous cell carcinomas, such as squamous cell carcinomas of the skin and lung, head and neck cancer, non-melanoma skin cancer, basal cell carcinoma and actinic keratosis, neuroendocrine tumors, such as small cell carcinomas of neuroendocrine carcinoma and carcinoid tumors, and thyroid cancer, and muscular disorders, including muscular dystrophies and impaired regenerative capacity after injury, and for use in cancer immunotherapy. Preferably, the present invention does not relate to the compounds described above, especially when X is a phenylene ring, for the treatment of prostate cancer (prostate cancer).

[0076] Diseases preferably treated by the compounds of the present invention include atopic dermatitis, psoriasis, squamous cell carcinomas, including squamous cell carcinoma of the skin and lung, non-melanoma skin cancer, head and neck cancer, basal cell carcinoma and actinic keratosis.

[0077] The diseases most preferably treated by the compounds of the present invention include immune-related disorders.

[0078] In a further most preferred embodiment of the present invention, said compounds are used in the immunotherapy of cancer.

[0079] The present invention also relates to compounds that are the compounds defined in relation to formula (I) and / or pharmaceutically acceptable salts or esters thereof, and the individual compounds illustrated above, including all of the preferred, more preferred, even more preferred, most preferred, and second most preferred embodiments, for use as a medicament, except for compounds that are known to be capable of use as a medicament (have known pharmaceutical activity).

[0080] Compounds described in the art as having biological activity are compounds of formula (Ia), wherein R 2 ~R 5 are all H, the phenylene ring is not substituted by Z, and —C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR 7 and R 7 is H and R 1 is H or CH. These compounds are disclosed in US 2004 / 0180889 in the context of treating Pin-1-related diseases, including some cancer diseases. No biological activity of these compounds is indicated in this application.

[0081] Further compounds of formula (I) that are known to have pharmaceutical activity are compounds of formula (Ia) wherein R 2 ~R 5 are all H, the phenylene ring is not substituted by Z, and —C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR 7 and R 7 is H and R 1 is isopropyl or cyclohexyl; and compounds of formula (Ia), wherein R 2 ~R 5 are all H, the phenylene ring is substituted with Cl (substituent Z) at the 2-position relative to the ether bridge, and -C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR7 and R 7 is H and R 1 is H, isopropyl, or norbornyl; and compounds of formula (Ia), wherein R 2 ~R 5 are all H, the phenylene ring is substituted with F (substituent Z) at the 2-position relative to the ether bridge, and -C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR 7 and R 7 is H and R 1 is a compound in which V169 is methyl. The above compounds (including the compound V169 mentioned in this application) are described in WO 93 / 24442 as testosterone 5-reductase inhibitors and can be used in particular for the treatment of prostate cancer (prostate cancer).

[0082] Nevertheless, the present invention also relates to compounds so defined in connection with formula (I), including all preferred, more preferred, even more preferred, most preferred, and second preferred embodiments. Compounds that are so known are not an embodiment of the present invention.

[0083] Such known compounds are compounds V058, V119, V124, V126, V128, V134, V142, V151, and V169.

[0084] Still further such known compounds of formula (I) are compounds of formula (Ia), wherein R 2 ~R 5 are all H, the phenylene ring is not substituted by Z, and —C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR 7 and R 7 is H and R 1 is isopropyl or cyclohexyl; and compounds of formula (Ia), wherein R 2 ~R 5are all H, the phenylene ring is substituted with Cl (substituent Z) at the 2-position relative to the ether bridge, and -C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR 7 and R 7 is H and R 1 is H, isopropyl, or norbornyl; and compounds of formula (Ia), wherein R 2 ~R 5 are all H, the phenylene ring is substituted with F (substituent Z) at the 2-position relative to the ether bridge, and -C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR 7 and R 7 is H and R 1 is a compound wherein V169 is methyl. The above compounds (including compound V169 referred to in this application) are described in WO 93 / 24442.

[0085] Further compounds so described in the art are compounds of formula (Ia), wherein R 2 ~R 5 are all H, the phenylene ring is not substituted by Z, and —C(Y)R 6 is in 4th position relative to the ether bridge, Y is O, and R 6 is OR 7 and R 7 is H and R 1 is H or CH. These compounds are disclosed in US 2004 / 0180889.

[0086] The present invention also relates to compounds defined in relation to formula (I) and / or pharmaceutically acceptable salts or esters thereof, including all of the general, preferred, more preferred, even more preferred, most preferred, and second most preferred embodiments, for use as drugs in combination therapy, and to compounds that are the individual compounds depicted above, administered in combination with another treatment, including, but not limited to, surgery, radiation therapy, chemotherapy, targeted therapy, and immunotherapy. The present invention also includes the use of the compounds defined above in combination therapy for the treatment of diseases selected from the group consisting of dermatological disorders, including atopic dermatitis and psoriasis; immune-related disorders; squamous cell carcinomas, such as squamous cell carcinoma of the skin and lung, head and neck cancer, non-melanoma skin cancer, basal cell carcinoma and actinic keratosis, neuroendocrine tumors, such as small cell carcinoma of neuroendocrine carcinoma and carcinoid tumors, and thyroid cancer; muscular dystrophies and muscle disorders, including those with reduced regenerative capacity after injury, and for use in cancer immunotherapy. Preferably, the present invention does not relate to the compounds described above for the treatment of prostate cancer, especially when X is a phenylene ring.

[0087] The term "combination therapy" encompasses both sequential and simultaneous combinations of therapies.

[0088] The compounds can be used to enhance Notch signaling as described below.

[0089] The Notch receptor is synthesized as a 300 kDa precursor and cleaved by a furin-like convertase in the trans-Golgi compartment. The resulting extracellular / intraluminal N-terminal fragment and transmembrane / intracellular C-terminal fragment are noncovalently assembled into the mature heterodimeric receptor. The extracellular / intraluminal portion of Notch undergoes extensive N- and O-linked glycosylation during Notch synthesis and secretion, which is important for proper folding of the receptor and subsequent interaction of the receptor with its ligand. After transport to the cell surface, Notch signaling is initiated by ligand binding and endocytosis, which generates the force necessary to expose an otherwise inaccessible ADAM10 / TACE / Kuz / SUP-17 cleavage site in the extracellular portion of the Notch C-terminal fragment. Cleavage at this site produces Notch extracellular truncation (NEXT), an activated, membrane-anchored form of Notch. NEXT is then cleaved by the intramembrane aspartyl protease complex γ-secretase, releasing the Notch intracellular signaling fragment, the Notch intracellular domain (NICD). This cleavage can occur at the cell surface and within the endosomal transport pathway. In the absence of NICD, many of Notch's target genes are maintained in an actively repressed state through the formation of transcriptional complexes containing the CSL transcription factor and various corepressors (CoReps). Upon nuclear translocation of NICD, CSL-bound corepressors are released, allowing the assembly of transcriptionally active complexes consisting of CSL, NICD, Mastermind (Mam), and coactivators (CoAct), leading to the activation of Notch target genes.

[0090] This overview provides a brief overview of the major conserved features of Notch synthesis and signaling. Details of the biochemical mechanisms involved are omitted for clarity, the schematic locations relative to Notch are not intended to precisely depict the topology of Notch within various membrane compartments, and the glycosylation symbols and transcription complex diagrams are illustrative and do not suggest the location of specific glycosylation sites or protein-protein interactions.

[0091] Without wishing to be bound by this theory, it is believed that compounds of the present invention that have the property of enhancing Notch signaling stabilize the CSL-NICD complex, leading to activation of Notch target genes.

[0092] Under pathological conditions (i.e., when an individual is suffering from a disease as defined herein), administration of a Notch signaling enhancing compound of the present invention results in either normalization of levels of Notch target genes (similar to those seen in healthy individuals) or even levels higher than those seen in healthy individuals.

[0093] As used herein, the phrase "enhance Notch signaling" refers to the effect on the intracellular luciferase reporter assay driven by Notch, which determines the Notch signaling enhancing properties of the compounds of the present invention.The Notch-driven luciferase reporter assay is composed of HeLa cells engineered to express the full-length Notch1 receptor, and engineered with a CSL-driven firefly luciferase expression construct and a Notch-independent Renilla luciferase construct for normalization.These cells are co-cultured with engineered HeLa cells that express the Notch ligand Dll4 to induce Notch signaling, thereby inducing the expression of firefly luciferase enzyme.The intensity of the luciferase reporter signal is considered to be a measure of Notch signaling.

[0094] A compound is considered to have the effect of enhancing Notch signaling when the compound results in a ≧1.5-fold increase, preferably a ≧2.0-fold increase, more preferably a ≧2.5-fold increase, and most preferably a ≧3.0-fold increase in luciferase reporter signal in the context of the indicated Notch-dependent luciferase reporter assay compared to DMSO.

[0095] Although Notch was historically identified as an oncogene, studies within the last decade have demonstrated the tumor-suppressive role of Notch signaling (Koch and Radtke, 2010) (South et al., 2012). Notch functions as a tumor suppressor, particularly in tissues where Notch signaling induces differentiation, such as skin and neuroendocrine organs. Activation or increase in Notch signaling in cancers, including but not limited to, squamous cell carcinoma of the skin and lung (Wang et al., 2011), head and neck cancer (Agrawal et al., 2011; Stransky et al., 2011), thyroid cancer (Yu et al., 2013), and neuroendocrine tumors, such as small cell carcinoma of the neuroendocrine system (Sriuranpong et al., 2001) and carcinoid tumors (Greenblatt et al., 2007), induces differentiation and blocks cancer cell proliferation.

[0096] Some of the compounds of the present invention and / or their salts or esters exist in different stereoisomeric forms, all of which are objects of the present invention.

[0097] The following are exemplary salts of the compounds of the invention that are encompassed herein: The list of different salts provided below is not intended to be complete or limiting.

[0098] The compounds of the invention containing one or more acidic groups can be used in accordance with the invention, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts, more precisely examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids.

[0099] Compounds of the present invention that contain one or more basic groups, ie, protonatable groups, can exist and be used according to the present invention in the form of their inorganic or organic acid addition salts.

[0100] The compounds of the present invention containing a carboxylic acid or thiocarboxylic acid group can be used according to the present invention in the form of their respective esters. The esters are of formula (I), in which the H of the carboxy or thiocarboxy group is replaced by an organic residue. Suitable organic residues are known to those skilled in the art. Preferred organic residues include: Unsubstituted or at least monosubstituted alkyl, preferably C1-C 10 Alkyl, alkenyl, preferably C2-C 10 Alkenyl, alkynyl, preferably C3-C 10 Alkynyl and unsubstituted or at least monosubstituted, saturated or unsaturated, non-aromatic or aromatic rings having 3 to 6 C atoms, which may contain one or more heteroatoms from the group N, S or O, and when more than one heteroatom is present, the heteroatoms may be the same or different, optionally further substituted substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, N, S, O, carboxy, sulfonyl, etc.

[0101] Examples of the aromatic group include aryl groups such as a phenyl group and heteroaryl groups, and the aryl and heteroaryl groups may be substituted, preferably with the above-mentioned substituents.

[0102] The term "C1-C4 alkyl" refers to methyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

[0103] "C 3-7 cycloalkyl" or "C 3-7 "Cycloalkyl ring" means a cyclic alkyl chain having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, etc. Each hydrogen on the cycloalkyl carbon may be replaced by a substituent.

[0104] "Heterocyclyl" or "heterocycle" means a cyclopentane, cyclohexane, or cycloheptane ring (fully saturated, partially saturated, or unsaturated, aromatic or non-aromatic ring) that may contain up to a maximum number of double bonds, in which at least one to four carbon atoms are replaced by heteroatoms selected from the group consisting of sulfur (including -S(O)-, -S(O)-), oxygen, and nitrogen (including =N(O)-), and the ring is connected to the remainder of the molecule through a carbon or nitrogen atom. Examples of heterocycles include, but are not limited to, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolidine, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, azepine, or homopiperazine. "Heterocycle" also refers to azetidine.

[0105] Examples of suitable salts include hydrochloride, hydrobromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, napthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetate, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art.

[0106] The term "pharmaceutically acceptable" means approved by a regulatory authority, such as the EMEA (Europe) and / or the FDA (USA) and / or any other country's regulatory authority, for use in animals, preferably humans.

[0107] Compounds of the present invention which contain several basic groups may simultaneously give rise to different salts.

[0108] When the compounds of the present invention contain both an acidic group and a basic group in the molecule, the present invention also encompasses internal salts or betaines in addition to the salt forms mentioned.

[0109] Each salt of the compound of the present invention can be obtained by conventional methods known to those skilled in the art, for example, by contacting the compound with an organic or inorganic acid or base in a solvent or dispersion medium, or by anion or cation exchange with another salt.

[0110] Furthermore, the present invention encompasses all salts of the compounds of the present invention which may not be immediately suitable for use in medicines due to poor physiological compatibility, but which may be used, for example, as intermediates in chemical reactions for the preparation of pharmaceutically acceptable salts or which may be suitable for studying the Notch signaling activity of the compounds of the present invention in any suitable manner, such as in a suitable in vitro assay.

[0111] The present invention further includes all solvates and tautomers of the compounds of the present invention.

[0112] The present invention further encompasses derivatives / prodrugs of the compounds of the present invention (including salts thereof) which contain physiologically acceptable cleavable groups and which are metabolized to the compounds of the present invention in animals, preferably mammals, and most preferably humans.

[0113] The present invention further includes metabolites of the compounds of the present invention.

[0114] The term "metabolite" refers to any molecule derived from any of the compounds of the invention in a cell or organism, preferably a mammal.

[0115] Preferably, the term relates to a molecule that is different from any molecule present in any such cell or organism under physiological conditions.

[0116] The structures of the metabolites of the compounds of the invention will be apparent to all skilled in the art by using any suitable method.

[0117] Compounds of general formula (I) can be prepared according to methods published in the literature or analogous methods, respectively.

[0118] Methods for synthesizing the above compounds are described, for example, in Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Thieme-Verlag, Stuttgart or Organic Reactions, John Wiley & Sons, New York.

[0119] Depending on the circumstances of each individual case, in order to avoid side reactions during the synthesis of compounds of general formula (I), it may be necessary or advantageous to temporarily block functional groups by introducing protecting groups and deprotecting them at a later stage of the synthesis, or to introduce functional groups in the form of precursor groups which are converted into the desired functional group at a later stage. Such synthetic strategies and in each individual case suitable protecting groups and precursor groups are known to those skilled in the art.

[0120] If desired, the compounds of formula (I) may be purified by customary purification procedures, such as by recrystallization or chromatography. The starting compounds for the preparation of the compounds of formula (I) are commercially available or can be prepared according to or analogous to literature procedures.

[0121] Detailed protocols for the preparation of compounds of the present invention are described below.

[0122] The present invention also relates to pharmaceutical compositions comprising a compound as defined in relation to formula (I), including all of the preferred, more preferred, even more preferred, most preferred, and second preferred embodiments, admixed with an inert carrier, wherein the inert carrier is a pharmaceutical carrier.

[0123] The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle administered with a drug. Such pharmaceutical carriers can be sterile liquids, such as water and oils. Oils include those of petroleum, animal, vegetable, or synthetic origin, including, but not limited to, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline and aqueous dextrose and glycerin solutions are preferred liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, and the like. If desired, the composition can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions may take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. The compositions may be formulated as suppositories with conventional binders and carriers, such as triglycerides. Oral formulations may include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such compositions contain a therapeutically effective amount of the drug, preferably in purified form, together with an appropriate amount of carrier to provide the form for proper administration to the patient. The formulation should suit the mode of administration.

[0124] Furthermore, the present invention provides a method for the preparation of a substituted phenol and an electron-deficient aromatic (heteroaromatic) halide, preferably by the method of S NThe present invention relates to a method for preparing the compounds of the present invention, comprising coupling via Ar coupling. The biaryl ethers thus synthesized are further derivatized by procedures including hydrolysis, esterification, and amidation. The compounds can be purified by acid-base extraction, silica gel column chromatography, or precipitation / recrystallization, or other purification methods known to those skilled in the art, such as preparative thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC).

[0125] The compounds of the present invention and their pharmaceutically acceptable salts, optionally in combination with other pharmaceutically active compounds suitable for enhancing Notch signaling and / or treating or preventing the above-mentioned diseases, or in combination with other drugs known to those skilled in the art suitable for enhancing Notch signaling and / or treating or preventing those diseases, can be administered to animals, preferably mammals, particularly humans, as pharmaceuticals on their own, mixed with each other, or in the form of pharmaceutical preparations.

[0126] Various delivery systems are known, such as encapsulation in liposomes, microparticles, and microcapsules, and can be used to administer the compounds of the present invention to enhance Notch signaling and / or treat the described diseases.

[0127] Even if delivery is not directly to the central nervous system, it is advantageous to select and / or modify the method of administration so that the pharmaceutical compound crosses the blood-brain barrier.

[0128] Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.

[0129] The compounds may be administered by any convenient route, such as by infusion, by bolus injection, or by absorption through epithelial or mucocutaneous linings, and may be administered together with other biologically active agents.

[0130] Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical composition of the present invention into the central nervous system by any suitable route, such as intraventricular and intrathecal injection. Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be used, such as by using an inhaler or nebulizer and formulating with an aerosolizing agent.

[0131] In another embodiment, the drug can be delivered in a vesicle, particularly a liposome (Langer (1990) Science 249: 1527-1533; Treat et al. (1989) Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler, eds., Liss, New York, 353-365; Lopez-Berestein, ibid., 317-327).

[0132] In yet another embodiment, the drug can be delivered by a sustained release system, in one embodiment, a pump can be used (Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14: 201-240; Buchwald et al. (1980) Surgery 88: 507-516; Saudek et al. (1989) N. Engl. J. Med. 321: 574-579). In another embodiment, polymeric materials may be used (Medical Applications of Controlled Release, Langer and Wise, eds., CRC Press, Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball, eds., Wiley, New York (1984); Ranger and Peppas (1983) Macromol. Sci. Rev. Macromol. Chem. 23: 61; Levy et al. (1985) Science 228: 190-192; During et al. (1989) Ann. Neurol. 25: 351-356; Howard et al. (1989) J. Neurosurg. 71: 858-863). In yet another embodiment, a controlled-release system may be placed in proximity to the target of treatment, i.e., the brain, thus requiring only a fraction of the systemic dose (e.g., Goodson, 1984, In: Medical Applications of Controlled Release, supra, Vol. 2, 115-138). Other controlled-release systems are discussed in the review by Langer (1990, Science 249: 1527-1533).

[0133] In order to select an appropriate administration regimen, one skilled in the art will also take into consideration the administration routes selected for other known drugs used to enhance Notch signaling or treat the above-mentioned diseases.

[0134] For example, drugs taken orally have been released as both tablets / liquids and as intravenous solutions.

[0135] To select an appropriate dose, one skilled in the art will select a dose that has been shown to be non-toxic in preclinical and / or clinical trials and may follow or vary from a pre-given value.

[0136] The precise dosage to be employed in the formulation will also depend on the route of administration and the severity of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for intravenous administration are typically about 20 to 500 micrograms of active compound per kilogram of body weight. Suitable dosage ranges for intranasal administration are typically about 0.01 to 1 mg per kilogram of body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0137] Experimental results General Procedure A JPEG2025183310000007.jpg24166 where Hal is selected from F and Cl.

[0138] A solution of each phenol and benzoic acid derivative or a carboxylic acid derivative of an aromatic 6-membered heterocycle having one or two N atoms, respectively, as defined in relation to Formula (I), or a substituted derivative thereof, in a suitable solvent, preferably a polar aprotic solvent, most preferably DMSO, was stirred, preferably with the addition of anhydrous K2CO3, at a temperature between 80 and 120 °C, depending on the substrate, until complete conversion of the limiting reactant. The reaction was quenched by the addition of water and extracted with an organic solvent (preferably Et2O, EtOAc, and DCM, depending on the substrate). The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, and evaporated under reduced pressure. The crude product was purified by flash column chromatography to give the desired biaryl ether.

[0139] General Procedure B JPEG2025183310000008.jpg24166In formula, R 6 is an alkoxy group, preferably OC2H5.

[0140] Hydrolysis of esters: A solution of each ester, preferably the ethyl ester, in EtOH / 0.5 M NaOH was stirred at a temperature between 40 and 120 °C, preferably 80 °C, depending on the substrate, until the starting material was completely consumed. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in water, acidified, and extracted with a suitable organic solvent (preferably EtOAC or DCM). The combined organic layers were washed with saturated aqueous NaCl solution, dried over NaSO, and evaporated under reduced pressure. The crude product was purified by silica gel column chromatography or recrystallization to give the desired carboxylic acid.

[0141] General Procedure C JPEG2025183310000009.jpg23166In formula, R 6 is an alkoxy group, preferably OC2H5.

[0142] Amidation of esters: To a sealed tube was added a solution of the respective ester, preferably the ethyl ester, and preferably calcium chloride in a suitable solvent, preferably MeOH, and a solution of NH in a suitable solvent, preferably MeOH. The mixture was stirred at a temperature between 40°C and 120°C, preferably 80°C, depending on the substrate, until the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc and saturated aqueous NHCl solution. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over NaSO, and evaporated under reduced pressure. The crude product was purified by flash column chromatography to give the desired amide.

[0143] Ethyl 6-(4-(tert-butyl)phenoxy)nicotinate (V042) General Procedure A: Ethyl 6-chloronicotinate (840 mg, 4.53 mmol, 1.00 equiv.), 4-(tert-butyl)phenol (875 mg, 5.82 mmol, 1.29 equiv.), and K2CO3 (958 mg, 6.93 mmol, 1.53 equiv.) were stirred in DMSO (5 mL) for 24 h at 100 °C. Purification by column chromatography (EtOAc / petroleum ether 1 / 15) afforded the desired product as a colorless solid (1.23 g, 4.10 mmol, 90%). HRMS (ESI) m / z calcd. for C 18 H 22 No. 3 + [M+H] + 300.1594, Actual value: 300.1589; 1H NMR (400 MHz, deuterated chloroform) δ 8.88-8.79 (m, 1H), 8.26 (dd, J = 8.6, 2.4 Hz, 1H), 7.46-7.39 (m, 2H), 7.13-7.04 (m, 2H), 6.91 (dd, J = 8.6, 0.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H).

[0144] 6-(4-(tert-butyl)phenoxy)nicotinic acid (V058) General Procedure B: Ethyl 6-(4-(tert-butyl)phenoxy)nicotinate (V042) (1.22 g, 4.08 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (12 mL) and 0.5 M NaOH (12 mL) for 2 h at 80 °C. The acidified crude product was cotton-filtered with DCM to give the pure desired product (1.10 g, 4.05 mmol, 99%) as a colorless solid without further purification. HRMS (ESI) m / z calcd. for C 16 H 16 No. 3 - [MH] - 270.1136, Actual value: 270.1134; 1 H NMR (400 MHz, deuterated chloroform) δ 11.38 (s, 1H), 8.84 (m, 1H), 8.33-8.30 (m, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 6.95 (d, J = 8.7 Hz, 1H), 1.35 (s, 9H).

[0145] Ethyl 6-(4-(tert-pentyl)phenoxy)nicotinate (V111) General Procedure A: Ethyl 6-chloronicotinate (205 mg, 1.10 mmol, 1.00 equiv.), 4-(tert-pentyl)phenol (238 mg, 1.45 mmol, 1.31 equiv.), and K2CO3 (240 mg, 1.73 mmol, 1.57 equiv.) were stirred in DMSO (2 mL) at 80 °C for 4 days. Purification by column chromatography (EtOAc / petroleum ether 1:20) afforded the desired product as a colorless oil (332 mg, 1.06 mmol, 96%). HRMS (ESI) m / z calcd. for C 19 H 24 No. 3 + [M+H] + 314.1751, Actual value: 314.1753; 1 H NMR (400 MHz, deuterated chloroform) δ 8.85 (d, J = 2.1 Hz, 1H), 8.25 (dd, J = 8.6, 2.4 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.6 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.65 (q, J = 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.29 (s, 6H), 0.71 (t, J = 7.4 Hz, 3H).

[0146] Ethyl 6-(4-cyclohexylphenoxy)nicotinate (V112) General Procedure A: Ethyl 6-chloronicotinate (206 mg, 1.11 mmol, 1.00 equiv.), 4-cyclohexylphenol (252 mg, 1.43 mmol, 1.29 equiv.), and K2CO3 (243 mg, 1.76 mmol, 1.58 equiv.) were stirred in DMSO (2 mL) at 80 °C for 4 days. Purification by column chromatography (EtOAc / petroleum ether 1 / 20) afforded the desired product as a colorless solid (333 mg, 1.02 mmol, 92%). HRMS (ESI) m / z calcd. for C 20 H 24 No. 3 + [M+H] + 326.1751, Actual value: 326.1757; 1 H NMR (400 MHz, deuterated chloroform) δ 8.89 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 6.93 (d, J = 8.5 Hz, 1H), 4.41 (q, J = 6.7 Hz, 2H), 2.59-2.54 (m, 1H), 1.96-1.88 (m, 4H), 1.81-1.77 (m, 1H), 1.51-1.39 (m, 7H), 1.33-1.23 (m, 1H).

[0147] 6-(4-Cyclohexylphenoxy)nicotinic acid (V117) General Procedure B: Ethyl 6-(4-cyclohexylphenoxy)nicotinate (V112) (172 mg, 0.53 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (15 mL) and 0.5 M NaOH (12 mL) for 6.5 h at 80 °C. The acidified crude product was purified by recrystallization from DCM to give the desired product as a colorless solid (72 mg, 0.24 mmol, 46%). HRMS (ESI) m / z calcd. for C 18 H 20 No. 3+ [M+H] + 298.1438, Actual value: 298.1441; 1 H NMR (400 MHz, deuterated chloroform) δ 8.92 (d, J = 2.1 Hz, 1H), 8.31 (dd, J = 8.7, 2.3 Hz, 1H), 7.26 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.7 Hz, 1H), 2.61-2.47 (m, 1H), 1.9-1.85 (m, 4H), 1.77-1.74 (m, 1H), 1.44-1.35 (m, 4H), 1.32-1.20 (m, 1H).

[0148] 6-(4-(tert-pentyl)phenoxy)nicotinic acid (V119) General Procedure B: Ethyl 6-(4-(tert-pentyl)phenoxy)nicotinate (V111) (203 mg, 0.65 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (2 mL) and 0.5 M NaOH (2 mL) for 30 min at 80 °C. The acidified crude product was filtered through a cotton swab with EtOAc to give the pure desired product (185 mg, 0.65 mmol, 100%) as a colorless solid without further purification. HRMS (ESI) m / z calcd. for C 17 H 20 No. 3 + [M+H] + 286.1438, Actual value: 286.1448; 1 H NMR (400 MHz, deuterated chloroform) δ 8.64 (m, 1H), 8.17-8.06 (m, 1H), 7.22 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 6.66 (d, J = 8.6 Hz, 1H), 1.51 (q, J = 7.4 Hz, 2H), 1.15 (s, 6H), 0.57 (t, J = 7.4 Hz, 3H).

[0149] Ethyl 4-(4-(tert-butyl)phenoxy)benzoate (V122) General Procedure A: Ethyl 4-fluorobenzoate (808 mg, 4.80 mmol, 1.00 equiv.), 4-(tert-butyl)phenol (935 mg, 6.22 mmol, 1.30 equiv.), and K2CO3 (2.22 g, 16.05 mmol, 3.34 equiv.) were stirred in DMSO (5 mL) for 10 days at 100 °C. Purification by column chromatography (EtOAc / petroleum ether 1:20) afforded the desired product as a colorless oil (1.01 g, 3.39 mmol, 71%). HRMS (ESI) m / z calcd. for C 19 H 23 O3 + [M+H] + 299.1642, Actual value: 299.1648; 1 H NMR (400 MHz, deuterated chloroform) δ 8.00 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H).

[0150] 6-(4-(tert-butyl)phenoxy)nicotinamide (V124) General Procedure C: Calcium chloride hexahydrate (82 mg, 0.37 mmol, 1.11 equiv.) and ethyl 6-(4-(tert-butyl)phenoxy)nicotinate (V042) (101 mg, 0.34 mmol, 1.00 equiv.) in MeOH (0.5 mL) were stirred with 7 M NH3 in MeOH (0.5 mL, 3.50 mmol, 10 equiv.) for 21 h at 80 °C. Purification by silica gel column chromatography (DCM / MeOH 4%) afforded the desired product as a colorless solid (64 mg, 0.24 mmol, 70%). HRMS (ESI) m / z calcd. for C 16 H 19 N2O2 + [M+H] + 271.1441, Actual value: 271.1456; 1 H NMR (400 MHz, deuterated chloroform) δ 8.61 (d, J = 1.9 Hz, 1H), 8.14 (dd, J = 8.6, 2.3 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 1H), 6.32 (s, 2H), 1.33 (s, 9H).

[0151] 4-(4-(tert-butyl)phenoxy)benzoic acid (V126) General Procedure B: Ethyl 4-(4-(tert-butyl)phenoxy)benzoate (V122) (727 mg, 2.44 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (7.5 mL) and 0.5 M NaOH (7.5 mL) for 1 h at 80 °C. The acidified crude product was cotton-filtered with DCM to give the pure desired product (614 mg, 2.27 mmol, 93%) as a colorless solid without further purification. HRMS (ESI) m / z calcd. for C 17 H 19 O3 + [M+H] +271.1329, Actual value: 271.1330; 1 H NMR (400 MHz, deuterated chloroform) δ 8.07 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 1.35 (s, 9H).

[0152] Ethyl 6-(p-tolyloxy)nicotinate (V128) General Procedure A: Ethyl 6-chloronicotinate (207 mg, 1.12 mmol, 1.00 equiv.), p-cresol (164 mg, 1.52 mmol, 1.36 equiv.), and K2CO3 (235 mg, 1.70 mmol, 1.53 equiv.) were stirred in DMSO (1.5 mL) at 80 °C for 4 days. Purification by column chromatography (EtOAc / petroleum ether 1:10) afforded the desired product as a colorless solid (271 mg, 1.05 mmol, 94%). HRMS (ESI) m / z calcd. for C 15 H 16 No. 3 + [M+H] + 258.1125, Actual value: 258.1131; 1 H NMR (400 MHz, deuterated chloroform) δ 8.82 (m, 1H), 8.25 (dd, J = 8.6, 2.4 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0153] Ethyl 6-(4-(tert-butyl)-2-methylphenoxy)nicotinate (V131) General Procedure A: Ethyl 6-chloronicotinate (210 mg, 1.13 mmol, 1.00 equiv.), 4-(tert-butyl)-2-methylphenol (245 mg, 1.49 mmol, 1.32 equiv.), and K2CO3 (247 mg, 1.79 mmol, 1.58 equiv.) were stirred in DMSO (2 mL) at 80 °C for 3 days. Purification by column chromatography (EtOAc / petroleum ether 1:20) afforded the desired product as a colorless oil (259 mg, 0.83 mmol, 73%). HRMS (ESI) m / z calcd. for C 19 H 24 No. 3 + [M+H] + 314.1751, Actual value: 314.1759; 1 H NMR (400 MHz, deuterated chloroform) δ 8.92-8.78 (m, 1H), 8.25 (dd, J = 8.7, 2.4 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.27-7.23 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 8.7, 0.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.15 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.34 (s, 9H).

[0154] 6-(4-(tert-butyl)-2-methylphenoxy)nicotinic acid (V134) General Procedure B: Ethyl 6-(4-(tert-butyl)-2-methylphenoxy)nicotinate (V131) (160 mg, 0.51 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (4 mL) and 0.5 M NaOH (2 mL) for 1.5 h at 80 °C. The acidified crude product was cotton-filtered with DCM to give the pure desired product (146 mg, 0.51 mmol, 100%) as a colorless solid without further purification. HRMS (ESI) m / z calcd. for C17 H 20 No. 3 + [M+H] + 286.1438, Actual value: 286.1435; 1 H NMR (400 MHz, deuterated chloroform) δ 9.76 (s, 1H), 8.93 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 8.7, 2.4 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 7.29-7.25 (m, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 2.16 (s, 3H), 1.34 (s, 9H).

[0155] Ethyl 4-(4-(tert-butyl)phenoxy)-3-fluorobenzoate (V138) General Procedure A: Ethyl 3,4-difluorobenzoate (348 mg, 1.87 mmol, 1.00 equiv.), 4-(tert-butyl)phenol (336 mg, 2.24 mmol, 1.20 equiv.), and K2CO3 (388 mg, 2.80 mmol, 1.50 equiv.) were stirred in DMSO (2 mL) for 22 h at 100 °C. Purification by column chromatography (EtOAc / petroleum ether 1 / 40) afforded the desired product as a colorless oil (451 mg, 1.43 mmol, 76%). HRMS (ESI) m / z calcd. for C 19 H 22 O3F + [M+H] + 317.1547, Actual value: 317.1549; 1 H NMR (400 MHz, deuterated chloroform) δ 7.85 (dd, J = 11.2, 2.0 Hz, 1H), 7.80-7.73 (m, 1H), 7.42-7.35 (m, 2H), 7.02-6.94 (m, 3H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.33 (s, 9H).

[0156] 4-(4-(tert-butyl)phenoxy)-3-fluorobenzoic acid (V142) General Procedure B: Ethyl 4-(4-(tert-butyl)phenoxy)-3-fluorobenzoate (V138) (341 mg, 1.08 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (3 mL) and 0.5 M NaOH (2 mL) for 1.5 h at 80 °C. The acidified crude product was purified by column chromatography (DCM / MeOH 5%) to give the desired product as a colorless solid (207 mg, 0.72 mmol, 67%). HRMS (ESI) m / z calcd. for C 17 H 16 O3F - [MH] - 287.1089, Actual value: 287.1084; 1 H NMR (400 MHz, deuterated chloroform) δ 7.91 (dd, J = 11.0, 2.0 Hz, 1H), 7.86-7.79 (m, 1H), 7.47-7.37 (m, 2H), 7.05-6.99 (m, 2H), 6.96 (t, J = 8.3 Hz, 1H), 1.34 (s, 9H).

[0157] Ethyl 4-(4-(tert-pentyl)phenoxy)benzoate (V149) General Procedure A: Ethyl 4-fluorobenzoate (308 mg, 1.83 mmol, 1.00 equiv.), 4-(tert-pentyl)phenol (380 mg, 2.32 mmol, 1.26 equiv.), and K2CO3 (383 mg, 2.77 mmol, 1.51 equiv.) in DMSO (4 mL) were stirred at 80 °C for 1 day and then at 120 °C for 2 days. Purification by column chromatography (EtOAc / petroleum ether 1:20) afforded the desired product as a colorless oil (476 mg, 1.52 mmol, 83%). HRMS (ESI) m / z calcd. for C 20 H25 O3 + [M+H] + 313.1798, Actual value: 313.1808; 1 H NMR (400 MHz, deuterated chloroform) δ 8.06-7.98 (m, 2H), 7.37-7.30 (m, 2H), 7.02-6.99 (m, 2H), 6.99-6.96 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.65 (q, J = 7.4 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.30 (s, 9H), 0.71 (t, J = 7.4 Hz, 3H).

[0158] Ethyl 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)benzoate (V150) General Procedure A: Ethyl 4-fluorobenzoate (311 mg, 1.85 mmol, 1.00 equiv.), 4-(3r,5r,7r)-adamantan-1-yl)phenol (522 mg, 2.29 mmol, 1.24 equiv.), and K2CO3 (394 mg, 2.85 mmol, 1.54 equiv.) were stirred in DMSO (4 mL) for 1 day at 80 °C, then for 2 days at 120 °C. Purification by column chromatography (EtOAc / petroleum ether 1:20) afforded the desired product as a colorless solid (551 mg, 1.46 mmol, 79%). HRMS (ESI) m / z calcd. for C 25 H 29 O3 + [M+H] + 377.2111, Actual value: 377.2122; 1H NMR (400 MHz, deuterated chloroform) δ 8.06-7.98 (m, 2H), 7.40-7.33 (m, 2H), 7.03-6.99 (m, 2H), 7.00-6.96 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 2.12 (m, 3H), 1.93 (m, 6H), 1.83-1.75 (m, 6H), 1.39 (t, J = 7.1 Hz, 3H).

[0159] 4-(4-(tert-pentyl)phenoxy)benzoic acid (V151) General Procedure B: Ethyl 4-(4-(tert-pentyl)phenoxy)benzoate (V149) (265 mg, 0.85 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (2.5 mL) and 0.5 M NaOH (2.5 mL) for 9 h at 80 °C. The acidified crude product was purified by recrystallization from EtOAc to give the desired product as a colorless solid (210 mg, 0.74 mmol, 87%). HRMS (ESI) m / z calcd. for C 18 H 19 O3 - [MH] - 283.1340, Actual value: 283.1343; 1 H NMR (400 MHz, deuterated chloroform) δ 8.12-8.01 (m, 2H), 7.39-7.31 (m, 2H), 7.03-7.01 (m, 2H), 7.01-6.98 (m, 2H), 1.66 (q, J = 7.4 Hz, 2H), 1.31 (s, 9H), 0.71 (t, J = 7.4 Hz, 3H).

[0160] 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)benzoic acid (V152) JPEG2025183310000027.jpg22166 General Procedure B: Ethyl 4-(4-((3r,5r,7r)-adamantan-1-yl)phenoxy)benzoate (V150) (314 mg, 0.83 mmol, 1.00 equiv) was stirred in a mixture of EtOH (2.5 mL) and 0.5 M NaOH (2.5 mL) at 80 °C for 1 day. The acidified crude product was purified by recrystallization from EtOAc to give the desired product as a colorless solid (227 mg, 0.65 mmol, 78%). HRMS (ESI) m / z calcd. for C 23 H 23 O3 - [MH] - 347.1653, Actual value: 347.1648; 1 H NMR (400 MHz, deuterated chloroform) δ 8.06-8.03 (m, 2H), 7.40-7.36 (m, 2H), 7.04-7.01 (m, 2H), 7.01-6.98 (m, 2H), 2.11 (m, 3H), 1.93 (m, 6H), 1.78 (m, 6H).

[0161] Ethyl 4-(4-cyclohexylphenoxy)benzoate (V168) General Procedure A: Ethyl 4-fluorobenzoate (316 mg, 1.88 mmol, 1.00 equiv.), 4-cyclohexylphenol (412 mg, 2.34 mmol, 1.24 equiv.), and K2CO3 (418 mg, 3.03 mmol, 1.61 equiv.) were stirred in DMSO (4 mL) at 120 °C for 2 days. Purification by column chromatography (EtOAc / petroleum ether 1 / 20) afforded the desired product as a colorless oil (483 mg, 1.49 mmol, 79%). HRMS (ESI) m / z calcd. for C 21 H 25 O3 + [M+H] + 325.1798, Actual value: 325.1801; 1H NMR (400 MHz, deuterated chloroform) δ 8.07-7.96 (m, 2H), 7.23-7.20 (m, 2H), 7.00-6.96 (m, 4H), 4.36 (q, J = 7.1 Hz, 2H), 2.54-2.49 (m, 1H), 1.96-1.80 (m, 4H), 1.80-1.72 (m, 1H), 1.47-1.37 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H), 1.31-1.21 (m, 1H).

[0162] 4-(4-Cyclohexylphenoxy)benzoic acid (V169) General Procedure B: Ethyl 4-(4-cyclohexylphenoxy)benzoate (V168) (236 mg, 0.73 mmol, 1.00 equiv.) was stirred in a mixture of EtOH (3 mL) and 0.5 M NaOH (3 mL) for 5 h at 80 °C. The acidified crude product was purified by recrystallization from EtOAc to give the desired product as a colorless solid (158 mg, 0.53 mmol, 73%). HRMS (ESI) m / z calcd. for C 19 H 19 O3 - [M-H] - 295.1340, Actual value: 295.1339; 1 H NMR (400 MHz, deuterated chloroform) δ 8.06 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.24-6.98 (m, 4H), 2.55-2.49 (m, 1H), 1.91-1.85 (m, 4H), 1.78-1.75 (m, 1H), 1.47-1.35 (m, 4H), 1.31-1.21 (m, 1H).

[0163] biological activity The Notch signaling enhancing activity of each of the preferred molecules illustrated above in a Notch1-driven luciferase assay is shown in Figure 1. A brief description of this Notch reporter assay is provided in the caption of Figure 1. The derivative V126 was tested as a representative compound in further experiments.

[0164] Figure 2 shows a study using V126 in different settings within a luciferase reporter assay. V126 potently enhanced Notch signaling already at concentrations of 1 M, whereas valproic acid, a previously reported Notch enhancer, showed no effect within the screened concentration range (up to 40 M) (Figure 2a). To exclude that V126 directly enhanced the activity of the luciferase enzyme, we validated the Notch reporter assay by administering V126 treatment immediately before the readout. Short-term treatment yielded values ​​within the range of DMSO control levels, whereas a corresponding 20-hour treatment with V126 resulted in the expected upregulation of luciferase levels in the exact same readout (Figure 2b). This strongly suggests that the increase in luciferase levels is indeed due to enhanced expression of the reporter gene. Furthermore, the ability of V126 to upregulate Notch signaling was further confirmed by the fact that the Notch-enhancing activity of V126 could be partially and completely rescued by equimolar combination treatment with the γ-secretase inhibitor DAPT or the Notch inhibitor CB103, respectively (Fig. 2c). Testing of V126 in luciferase assays driven by Notch2 receptor isoforms (N2FL, full-length Notch2 receptor) or a truncated, constitutively active Notch1 receptor (N1ICD, Notch1 intracellular domain) demonstrated that V126 could not only enhance signaling from different Notch receptor isoforms but also enhance the signaling cascade occurring downstream of ligand-induced activation of Notch signaling (Fig. 2d and e).

[0165] Activation of Notch in skin is known to drive keratinocyte differentiation and result in the induction of differentiation markers such as involucrin (C. Nowell, Cold Spring Harb Perspect Med. 2013, 3, 12), (GP Dotto, Oncogene 2008, 27, 5115-5123). Therefore, V126 was further investigated by treating the human squamous cell carcinoma cell line SCC13 at a concentration of 10⇓M. Increased expression of involucrin at the protein level was detected after 48 hours of incubation with V126 (Figure 3), suggesting that V126 promotes differentiation in this cancer cell line by upregulating Notch signaling.

[0166] In the spleen, marginal zone B cells (MZB) and follicular B cells (FoB) are the two major types of mature B cells, both of which arise from the same precursor cell, the transitional B cell (TB). Notch2 signaling has been reported to play a crucial role in MZB development (S. Pillai, Nat. Rev. I mmunol. 2009, 9, 767-777), and increased Notch2 signaling in the spleen leads to the expansion of the MZB compartment (F. Hampel, Blood 2011, 118, 24, 6321-6331). In contrast, FoB development is not dependent on Notch signaling. To evaluate the effects of V126 in vivo, C57BL / 6N mice were intraperitoneally injected with 25 mg / kg V126 once daily for one week. The effect of V126 on different B cell compartments in these mice was analyzed by flow cytometry of splenocytes, showing that V126 was able to double the number of MZB compared to controls but had no effect on the number of FoB (Fig. 4 ).

[0167] In conclusion, these results demonstrate that V126 enhances Notch signaling in vitro and in vivo.

Claims

1. A compound having the general formula (I) and / or a pharmaceutically acceptable salt or ester thereof: During the ceremony, X is a phenylene ring C 6 H 4 wherein one or more H atoms are optionally independently replaced by one or more substituents Z; or X is a 6-membered aromatic heterocycle containing one or two N atoms, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; When X is a heterocycle containing one or two N atoms: R 1 is H; linear and branched, unsubstituted and substituted C 1 -C 16 Alkyl; straight and branched, unsubstituted and substituted C 2 -C 8 Alkenyl; straight and branched, unsubstituted and substituted C 2 -C 8 Alkynyl; substituted and unsubstituted C 3 -C 8 Cycloalkyl; substituted and unsubstituted C 5 -C 8 cycloalkenyl; adamantyl and norbornyl, and the substituents of the groups designated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from F, Cl, Br, I, -CN, -NCO, -NCS, N 3 and the designated group may be mono- or polysubstituted; R 2 ~R 5 are independently H, F, Cl, Br, I; straight-chain and branched, unsubstituted and substituted C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl and C 2 -C 4 selected from alkynyl, cyclopropyl, and cyclobutyl, with the substituents for groups designated alkyl, alkenyl, alkynyl, cyclopropyl, and cyclobutyl being selected from F, Cl, Br, and I; Y is O or S; Z is F, Cl, Br, I, linear and branched, unsubstituted and substituted C 1 -C 4 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 selected from alkynyl, cyclopropyl and cyclobutyl, and the substituents for the groups designated alkyl, alkenyl, alkynyl, cyclopropyl and cyclobutyl may be selected from F, Cl, Br and I; R 6 is OR 7 , N.R. 8 R 9 , NHOH; R 7 is H and linear and branched C 1 -C 6 alkyl; R 8 and R 9 are each independently H and straight-chain and branched C 1 -C 6 selected from alkyl, For the treatment of a disease in an individual selected from the group consisting of atopic dermatitis, dermatological disorders including psoriasis, immune-related disorders, cancer, squamous cell carcinoma, squamous cell carcinoma of the skin and lung, head and neck cancer, non-melanoma skin cancer, basal cell carcinoma and actinic keratosis, neuroendocrine tumors, neuroendocrine small cell carcinoma and carcinoid tumors, thyroid cancer, myopathies, muscular dystrophies, decreased regenerative capacity after injury; the compound for use in immunotherapy of cancer.

2. When X is a phenylene ring, the phenylene ring X is not substituted with I (substituent Z) at the 2- and 6-positions relative to the ether group, and / or R 1 is H or CH 3 If R 2 ~R 5 and at least one of Z is a substituent other than H, and / or R 1 Linear and branched, unsubstituted and substituted C 4 -C 16 Alkyl; straight and branched, substituted and unsubstituted C 4 -C 8 Alkenyl; straight and branched, unsubstituted and substituted C 4 -C 8 Alkynyl; substituted and unsubstituted C 4 -C 8 Cycloalkyl; substituted and unsubstituted C 5 -C 8 cycloalkenyl; adamantyl and norbornyl; substituents for the groups designated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from F, Cl, Br, I, —CN, —NCO, —NCS, N 3 2. The compound of claim 1, wherein the compound is selected from the group:

3. When X is a phenylene ring, the phenylene ring X is not substituted with F, Cl, Br, or I (substituent Z) at the 2- and 6-positions relative to the ether group, and R 1 is H or CH 3 If R 2 ~R 5 and Z is a substituent other than H.

4. When X is a heterocycle containing one or two N atoms: R 1 is H; linear and branched, unsubstituted and substituted C 1 -C 12 Alkyl; straight and branched, unsubstituted and substituted C 2 -C 8 Alkenyl; straight and branched, unsubstituted and substituted C 2 -C 8 Alkynyl; substituted and unsubstituted C 3 -C 8 Cycloalkyl; substituted and unsubstituted C 5 -C 8 cycloalkenyl; adamantyl and norbornyl; substituents for the groups designated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from F, Cl, Br, I, —CN, —NCO, —NCS, N 3 and the designated group may be mono- or polysubstituted; R 2 ~R 5 are independently H, F, Cl, Br, I; unsubstituted and substituted C 1 -C 2 Alkyl, C 2 Alkenyl, C 2 alkynyl, wherein the groups designated alkyl, alkenyl, and alkynyl are optionally substituted with F; Z is F, Cl, Br, I; unsubstituted and substituted C 1 -C 2 Alkyl, C 2 Alkenyl and C 2 selected from alkynyl, where the substituents of groups designated alkyl, alkenyl, and alkynyl may be F; R 7 is H and linear and branched C 1 -C 4 alkyl; R 8 and R 9 are each independently H and straight-chain and branched C 1 -C 4 selected from alkyl, A compound according to any one of claims 1 to 3 and / or a pharmaceutically acceptable salt or ester thereof.

5. R 1 is H; linear and branched, unsubstituted and substituted C 1 -C 8 Alkyl; straight and branched, unsubstituted and substituted C 2 -C 6 Alkenyl; straight and branched, unsubstituted and substituted C 2 -C 6 Alkynyl; substituted and unsubstituted C 3 -C 6 Cycloalkyl; substituted and unsubstituted C 5 -C 6 cycloalkenyl; adamantyl and norbornyl; substituents for the groups designated alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl are selected from F, Cl, Br, I, —CN, —NCO, —NCS, N 3 and the designated group may be mono- or polysubstituted; R 2 ~R 5 are independently H, F, Cl, Br, I; unsubstituted and substituted C 1 -C 2 Alkyl, C 2 Alkenyl, and C 2 alkynyl, wherein the substituents of the groups designated alkyl, alkenyl, and alkynyl may be F; A compound according to any one of claims 1 to 4 and / or a pharmaceutically acceptable salt or ester thereof.

6. X is a 6-membered aromatic heterocycle containing one N atom, wherein one or more H atoms are optionally independently replaced by one or more substituents Z; R 1 is H; linear and branched, unsubstituted and substituted C 1 -C 6 Alkyl; straight and branched, unsubstituted and substituted C 2 -C 6 Alkenyl; straight and branched, unsubstituted and substituted C 2 -C 6 Alkynyl; substituted and unsubstituted C 3 -C 6 Cycloalkyl; substituted and unsubstituted C 5 -C 6 cycloalkenyl; adamantyl and norbornyl; the designated groups alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, adamantyl and norbornyl may be substituted by F, and the designated groups may be mono- or polysubstituted, 6. A compound according to any one of claims 1 to 5 and / or a pharmaceutically acceptable salt or ester thereof.

7. R 1 is H; linear and branched, unsubstituted and substituted C 1 -C 6 Alkyl; substituted and unsubstituted C 3 -C 6 cycloalkyl; adamantyl and norbornyl; the substituents of the designated groups alkyl, cycloalkyl, adamantyl and norbornyl may be F, and the designated groups may be mono- or polysubstituted; R 2 ~R 5 are independently H; F; unsubstituted and substituted C 1 -C 2 alkyl, where the substituent of the group designated as alkyl may be F; Y is O; Z is F, Cl, Br, I; unsubstituted and substituted C 1 -C 2 alkyl, wherein the group designated alkyl is optionally substituted with F; R 6 is OR 7 , N.R. 8 R 9 Selected from: A compound according to any one of claims 1 to 6 and / or a pharmaceutically acceptable salt or ester thereof.

8. The compound according to any one of claims 1 to 7, wherein the individual is a mammal, preferably a human.

9. A compound according to any one of claims 1 to 7 for the treatment of a disease associated with reduced Notch signalling activity.

10. A compound according to any one of claims 1 to 7 for use as a medicament.

11. A compound according to any one of claims 1 to 7.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or ester thereof, admixed with an inert carrier.

13. The composition of claim 12 is for use in immunotherapy of cancer, and is treatable for diseases selected from the group consisting of dermatological disorders including atopic dermatitis, psoriasis; immune-related disorders; cancers including, but not limited to, squamous cell carcinoma, squamous cell carcinoma of the skin and lung, head and neck cancer, non-melanoma skin cancer, basal cell carcinoma and actinic keratosis, neuroendocrine tumors, small cell neuroendocrine carcinoma and carcinoid tumors, thyroid cancer; and myopathies, muscular dystrophies, and impaired regenerative capacity after injury.

14. 13. The composition according to claim 11 or 12, wherein the disease is a disease in a mammal, preferably a human.

15. The substituted phenol and the electron-deficient aromatic halide or heteroaromatic halide are preferably reacted with S N 6. A process for the preparation of compounds according to any one of claims 1 to 5, comprising the steps of coupling via Ar coupling and derivatizing the obtained biaryl ether by procedures known to those skilled in the art, preferably by hydrolysis, esterification and amidation.

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