Molefantin derivatives useful in the treatment of cancer

Abstract

Formula I: [Formula 1] TIFF2024517443000025.tif3259[where, R 1 and R 2 is as defined herein. Use of said compounds in the treatment of disease is also disclosed.

Description

[Technical field]

[0001] The present invention relates to molephantin derivatives, pharmaceutical formulations containing molephantin derivatives, and medical uses of molephantin derivatives (eg, in the treatment of cancer, such as colorectal and gastric cancer). [Background technology]

[0002] The listing or discussion of a prior-published document in this specification should not necessarily be construed as an admission that the document is part of the prior art or is common general knowledge.

[0003] Today, over 60% of anticancer drugs are derived in some way from plants. Notable plant-derived anticancer drugs used in clinical practice include the vinca alkaloids vinblastine and vincristine, the camptothecin derivatives topotecan and irinotecan, and paclitaxel (Taxol), which are isolated or derived from Catharanthus roseus G. Don. (Apocynaceae), Camptotheca acuminate Decne (Campanulaceae), and Taxus brevifolia Nutt. (Yew family), respectively. However, these drugs are often associated with side effects such as alopecia, skin reactions, fatigue, and muscle / joint pain.

[0004] The number of new cancer cases in low- and middle-income countries is expected to rise by more than 80% by 2040. Given this increase, as well as the problems of drug resistance and harmful side effects of current treatments, new and efficient anticancer drugs are needed.

[0005] Elephantopus tomentosus Linn. is a species of perennial flowering plant belonging to the Asteraceae family. It is native to North America but has spread widely throughout the pantropics. In Malaysia, extracts of the whole plant are used as a diuretic, analgesic, antipyretic, anthelmintic, and anti-inflammatory agent. The leaves of the plant are also applied externally to relieve pain.

[0006] Phytochemical studies on E. tomentosus L. have led to the isolation of compounds such as triterpenes, flavonoids, alkaloids, caffeoylquinic acids, and sesquiterpene lactones. Tomenphantopins A and B, two of the earliest sesquiterpene lactones isolated from E. tomentopus L., showed EDs of 2.5 μg / ml and 5.0 μg / ml, respectively, against human KB oral cancer cells. 50 They showed cytotoxic activity at ED values ​​of 3.0 μg / ml and 2.7 μg / ml, respectively (Hayashi T, et al., Phytochemistry, vol. 26, 1987, 1065-1068). Since then, many other sesquiterpene lactones have been isolated. Tomenphantine A and B showed ED values ​​of 3.0 μg / ml and 2.7 μg / ml, respectively. 50 It was found that the proliferation of the KB cell line was inhibited at IC values ​​of 44.8 μM and 11.2 μM, respectively (Hayashi T, et al., J Nat Prod, vol. 62, 1999, 302-304). Tomenphantopine D and molefantin had inhibitory activity against the human myeloid leukemia cell line K562 and the human hepatoma cell line (SMMC-7221). 50 values ​​of 7.9 μM and 5.8 μM for molefantin, respectively. 50 However, tomentosines C, E, and F were inactive (Mei WL et al., Two new Germacranolides from Elephantopus tomentosus, Phytochemistry Letters, vol. 5, 2012, 800-803 and Wang B, et al., Two New Sesquiterpene Lactones from Elephantopus tomentosus, Chinese Journal of Chemistry, vol. 30, 2012, 1320-1322).

[0007] Although several bioactive compounds isolated from E. tomentosus L have shown cancer cytotoxicity and antitumor activity, these compounds have not yet been evaluated in clinical trials. In vitro studies of the mechanistic actions of these compounds, as well as in vivo studies in animal models, are lacking. Therefore, it is currently not possible to predict whether any of the bioactive compounds isolated from E. tomentosus will actually be effective in treating cancer in vivo or not. Summary of the Invention

[0008] The present invention relates to derivatives of molefantin, which itself may be isolated from E. tomentosus L. The derivatives may be prepared by esterification and surprisingly have improved anti-cancer activity both in vitro and in vivo.

[0009] Accordingly, the present invention provides the following numbered clauses:

[0010] Article 1. Formula I: [ka] [In the formula, R 1 and R 2 are each independently H, -C(O)R 3 , or -C(O)C 1-6 alkyl, where the latter group is unsubstituted or selected from halo and R 4 or is substituted with one or more groups selected from Or, R 1 is -C(O)R 3 or -C(O)C 1-6 alkyl, where the latter group is unsubstituted or selected from halo and R 4 and R 2 represents -C(O)C(=CH2)CH3, R 3represents, if present, an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or is selected from the group consisting of NO, particularly halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups; R 4 represents, if present, an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or selected from the group consisting of halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups. or a pharma- ceutically acceptable salt or solvate thereof.

[0011] Article 2. R 1 and R 2 are each independently H, -C(O)R 3 , or -C(O)C 1-3 alkyl, where the latter group is unsubstituted or includes halo and R 4 or is substituted by one or more groups selected from Or, R 1 But -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group is unsubstituted or includes halo and R 4 and R 2 represents -C(O)C(=CH2)CH3, and optionally R 1 and R 2 are each independently -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group is unsubstituted or includes halo and R 4or is substituted with one or more groups selected from Or, R 1 But -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group is unsubstituted or selected from halo and R 4 and R 2 indicates -C(O)C(=CH2)CH3; A compound of formula I as defined in clause 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0012] Article 3. R 3 represents, when present, an aryl or heterocyclic ring system, where each of the aryl and heterocyclic ring systems is unsubstituted or is selected from the group consisting of NO, particularly halo and C. 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups. A compound of formula I as defined in clause 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof.

[0013] Article 4. R 3 is, if present, aryl, where aryl is unsubstituted or is selected from the group consisting of NO, particularly halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups. A compound of formula I as defined in clause 3, or a pharma- ceutically acceptable salt or solvate thereof.

[0014] Article 5. R 3is, if present, phenyl, where phenyl is unsubstituted or substituted by one or more groups selected from NO, in particular F and C alkyl, where C alkyl is unsubstituted or substituted by one or more halo groups; A compound of formula I as defined in clause 4, or a pharma- ceutically acceptable salt or solvate thereof.

[0015] Article 6. R 2 indicates -C(O)C(=CH2)CH3; A compound of formula I as defined in any one of clauses 1 to 5, or a pharma- ceutically acceptable salt or solvate thereof.

[0016] Article 7. R 1 But -C(O)R 3 R 2 But -C(O)R 3 or -C(O)C(=CH2)CH3, A compound of formula I as defined in any one of clauses 1 to 6, or a pharma- ceutically acceptable salt or solvate thereof.

[0017] Article 8. The following compounds: [Table 1] [Table 2] selected from the list consisting of A compound of formula I as defined in clause 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0018] Article 9. The following compounds: [Table 3] [Table 4] selected from the list consisting of A compound of formula I as defined in clause 8, or a pharma- ceutically acceptable salt or solvate thereof.

[0019] Article 10. A pharmaceutical formulation comprising a compound of formula I as defined in any one of clauses 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof, in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0020] Article 11. A compound of formula I as defined in any one of clauses 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof, for use in medicine.

[0021] Article 12. 13. Use of a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, as defined in any one of clauses 1 to 9, for the manufacture of a medicament for treating cancer.

[0022] Article 13. A compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, as defined in any one of clauses 1 to 9 for use in the treatment of cancer.

[0023] Article 14. A method of treating cancer comprising administering an effective amount of a compound of formula I as defined in any one of clauses 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof.

[0024] Article 15. The cancer is selected from the group consisting of adrenal gland cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, CNS tumors, breast cancer, Castleman's disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastric cancer, cancer), gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, renal cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g. acute lymphocytic, acute myeloid, chronic lymphocytic, chronic myelogenous, chronic myelomonocytic), liver cancer, lung cancer (e.g. small cell or non-small cell), pulmonary carcinoid tumor, lymphoma (e.g. of the skin), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, gastric cancer 15. The use according to clause 12, the compound according to clause 13 or the method according to clause 14, wherein the cancer is selected from one or more of the group selected from: cervical cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, Wilms' tumor.

[0025] Article 16. The use, compound or method according to clause 15, wherein said cancer is selected from colorectal cancer and gastric cancer. [Brief description of the drawings]

[0026] [Figure 1A] 1A-B show dose-response curves in different cancer cell lines to generate absolute IC50 values ​​for compounds NYH001-NYH005. [Figure 1B] 1A-B show dose-response curves in different cancer cell lines to generate absolute IC50 values ​​for compounds NYH001-NYH005. [Figure 1C] 1A-B show dose-response curves in different cancer cell lines to generate absolute IC50 values ​​for compounds NYH001-NYH005. [Figure 2A]Figures 2A-E show clonogenic assays showing colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent standard error of the mean of three independent experiments. *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2B] Figures 2A-E show clonogenic assays showing colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent standard error of the mean of three independent experiments. *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2C] Figures 2A-E show clonogenic assays showing colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent standard error of the mean of three independent experiments. *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2D] Figures 2A-E show clonogenic assays showing colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent standard error of the mean of three independent experiments. *P≦0.05, **P≦0.01, and ***P≦0.001. [Figure 2E] Figures 2A-E show clonogenic assays showing colony formation of different cancer cells treated with various concentrations of compounds NYH001-NYH005. Error bars represent standard error of the mean of three independent experiments. *P≦0.05, **P≦0.01, and ***P≦0.001. [Diagram 3] Figure 3 shows live cell imaging of DLD-1 cells treated with DMSO (control) or compound NYH001-0003. Growth inhibition, mitotic arrest, and cell death were induced in compound-treated cells. [Figure 4A]Figure 4A-D shows that NYH001-NYH005 inhibits cancer cell migration in a transwell migration assay. The figure shows representative images of migrated cells (scale bar = 50 μm) and quantitative analysis of migrated cells after eluting the crystal violet stain and measuring the absorbance at 590 nm. Data are taken from three independent experiments and are shown as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001. [Figure 4B] Figure 4A-D shows that NYH001-NYH005 inhibits cancer cell migration in a transwell migration assay. The figure shows representative images of migrated cells (scale bar = 50 μm) and quantitative analysis of migrated cells after eluting the crystal violet stain and measuring the absorbance at 590 nm. Data are taken from three independent experiments and are shown as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001. [Figure 4C] Figure 4A-D shows that NYH001-NYH005 inhibits cancer cell migration in a transwell migration assay. The figure shows representative images of migrated cells (scale bar = 50 μm) and quantitative analysis of migrated cells after eluting the crystal violet stain and measuring the absorbance at 590 nm. Data are taken from three independent experiments and are shown as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001. [Figure 4D] Figure 4A-D shows that NYH001-NYH005 inhibits cancer cell migration in a transwell migration assay. The figure shows representative images of migrated cells (scale bar = 50 μm) and quantitative analysis of migrated cells after eluting the crystal violet stain and measuring the absorbance at 590 nm. Data are taken from three independent experiments and are shown as mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.001. [Figure 5A]Figure 5A-B shows that NYH001-NYH005 inhibits cancer cell invasion. The figure shows representative images of invasive cells (scale bar = 50 μm) and quantitative analysis of invasive cells after elution of crystal violet stain and measuring absorbance at 590 nm. [Figure 5B] Figure 5A-B shows that NYH001-NYH005 inhibits cancer cell invasion. The figure shows representative images of invasive cells (scale bar = 50 μm) and quantitative analysis of invasive cells after elution of crystal violet stain and measuring absorbance at 590 nm. [Figure 6] Figure 6 shows that NYH001-NYH005 induce cell cycle arrest in G2 / M and S phase in DLD-1 cells. DLD-1 cells treated with DMSO or compounds for 24 hours were analyzed by flow cytometry to determine cell cycle distribution. [Figure 7] Figure 7 shows the dose-dependent effect of compounds NYH001-003 on the expression of apoptosis- and autophagy-related proteins in DLD-1 cells. Cells were treated with DMSO and either 1, 2.5, and 5 μM of NYH001, 002, or 003 for 24 h. Western blot was performed to check the protein levels of cleaved PARP, cleaved caspase 3 and 7, LC3B, and ATG7. β-tubulin was used as a loading control. [Figure 8] FIG. 8 shows images of dose-dependent growth inhibition of DLD-1 tumor spheroids treated with DMSO (control) or compound NYH001-003. [Figure 9] FIG. 9 shows a plot of dose-dependent growth inhibition of DLD-1 tumor spheroids treated with DMSO (control) or compound NYH001-003. [Figure 10A] FIG. 10 shows that NYH001-NYH003 can inhibit cell motility in a dose-dependent manner. [Figure 10B] FIG. 10 shows that NYH001-NYH003 can inhibit cell motility in a dose-dependent manner. [Figure 10C]FIG. 10 shows that NYH001-NYH003 can inhibit cell motility in a dose-dependent manner. [Figure 11] FIG. 11 shows that NYH002 treatment suppresses tumor growth in the HCT116 cell xenograft model of Example 9. Mice were treated with either vehicle control, NYH001 (25 mg / kg), NYH002 (25 mg / kg), or 5-Fu (25 mg / kg). (A) Tumor volume over the entire duration of the experiment. Points indicate the average tumor volume in each experimental group. (B) Representative photographs of tumors isolated at the end of the experiment for each experimental group. Scale bar is 10 mm. (C) Average tumor volume at the end of the experiment. (D) Average tumor weight at the end of the experiment. (E) Mouse body weight over the entire duration of the experiment. Points indicate the average mouse body weight in each treatment group. All error bars indicate SEM, n=5. *P≦0.05, **P≦0.01, comparison between NYH002 and vehicle control. [Figure 12] Figure 12 shows that NYH002 treatment suppresses tumor growth in the DLD-1 cell xenograft model of Example 9. Mice were treated with either vehicle control, NYH002 (25 mg / kg), or 5-Fu (25 mg / kg). (A) Tumor volume over the entire duration of the experiment. Points indicate the average tumor volume in each experimental group. (B) Representative photographs of tumors isolated at the end of the experiment for each experimental group. Scale bar is 10 mm. (C) Average tumor volume at the end of the experiment. (D) Average tumor weight at the end of the experiment. (E) Mouse body weight over the entire duration of the experiment. Points indicate the average mouse body weight in each treatment group. All error bars indicate SEM, n=4. *P≦0.05, **P≦0.01, comparison between NYH002 and vehicle control. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present invention relates to a compound of formula I: [ka] [In the formula, R 1 and R 2are each independently H, -C(O)R 3 , or -C(O)C 1-6 alkyl, where the latter group is unsubstituted or includes halo and R 4 or is substituted by one or more groups selected from Or, R 1 is -C(O)R 3 or -C(O)C 1-6 alkyl, where the latter group is unsubstituted or includes halo and R 4 and R 2 represents -C(O)C(=CH2)CH3, R 3 represents, if present, an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or is selected from the group consisting of NO, particularly halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups; R 4 represents, if present, an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or selected from the group consisting of halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups. or a pharma- ceutically acceptable salt or solvate thereof. to provide.

[0028] Therefore, R 1 is H, -C(O)R 3 , or -C(O)C 1-6 alkyl, where the latter group is unsubstituted or can be selected from halo and R 4 or R2 When represents -C(O)C(=CH2)CH3, R 1 is -C(O)R 3 or -C(O)C 1-6 alkyl, where the latter group is unsubstituted or can be selected from halo and R 4 or is substituted with one or more groups selected from:

[0029] In other words, R 2 When represents -C(O)C(=CH2)CH3, R 1 is not H.

[0030] In some embodiments of the present invention that may be referred to herein, R 1 is -C(O)R 3 or -C(O)C 1-6 alkyl, where the latter group is unsubstituted or can be selected from halo and R 4 or is substituted with one or more groups selected from:

[0031] In some embodiments of the present invention that may be referred to herein, R 2 may represent -C(O)C(=CH2)CH3.

[0032] In some embodiments of the present invention that may be referred to herein, R 1 and R 2 are each independently H, -C(O)R 3 , or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or may include halo and R 4 may be substituted with one or more groups selected from

[0033] In some such embodiments, R 1 and R 2 are each independently -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or may include halo and R4 may be substituted with one or more groups selected from

[0034] In some embodiments of the present invention that may be referred to herein, R 1 is -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or may include halo and R 4 and R 2 may represent -C(O)C(=CH2)CH3.

[0035] In some such embodiments, R 1 is -C(O)R 3 or -C(O)C 1-3 alkyl, where the latter group may be unsubstituted or may include halo and R 4 and R 2 may represent -C(O)C(=CH2)CH3.

[0036] In some embodiments of the present invention that may be referred to herein, R 1 is -C(O)R 3 may be indicated, R 2 is -C(O)R 3 Or it may represent -C(O)C(=CH2)CH3.

[0037] R 3 represents, if present, an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or is selected from the group consisting of NO, particularly halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups.

[0038] In some embodiments of the present invention that may be referred to herein, R 3 may, when present, represent an aryl or heterocyclic ring system, where each of the aryl and heterocyclic ring systems, even if unsubstituted, may be selected from NO, particularly halo and C. 1-3 alkyl, wherein C 1-3 The alkyl can be unsubstituted or substituted with one or more halo groups.

[0039] In some embodiments of the present invention that may be referred to herein, R 3 may, if present, be aryl, where aryl is unsubstituted or selected from NO, particularly halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups.

[0040] In some embodiments of the present invention that may be referred to herein, R 3 When present, may be phenyl, where phenyl may be unsubstituted or substituted by one or more groups selected from NO, in particular F and C alkyl, where C alkyl may be unsubstituted or substituted by one or more halo groups.

[0041] In any of the above embodiments of the present invention, R 3 The substituents present on may be replaced by non-NO2 substituents. In other words, in any of the above embodiments of the invention, R 3 may represent an aryl, cycloalkyl, or heterocyclic ring system (e.g., an aryl or heterocyclic ring system, such as an aryl (e.g., phenyl), etc.), where each of the aryl, cycloalkyl, heterocyclic ring system, and phenyl may be unsubstituted or may be selected from halo (e.g., F) and C. 1-3alkyl (e.g., C alkyl), where C 1-3 An alkyl (or C1 alkyl) is unsubstituted or substituted by one or more halo (eg, F) ​​groups.

[0042] R 4 represents, if present, an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or selected from the group consisting of halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups.

[0043] In some embodiments of the present invention that may be referred to herein, R 4 may, when present, represent an aryl or heterocyclic ring system, where each of the aryl and heterocyclic ring systems may be unsubstituted or selected from halo and C 1-3 alkyl, wherein C 1-3 The alkyl can be unsubstituted or substituted with one or more halo groups.

[0044] In some embodiments of the present invention that may be referred to herein, R 4 When present, it may be aryl, where aryl is unsubstituted or selected from halo and C 1-3 or alkyl, where C 1-3 The alkyl is unsubstituted or substituted with one or more halo groups.

[0045] In some embodiments of the present invention that may be referred to herein, R 4When present, it may be phenyl, where phenyl is unsubstituted or substituted with one or more groups selected from F and C alkyl, where C alkyl is unsubstituted or substituted with one or more halo groups.

[0046] R 4 In some embodiments of the invention where C is present, it may be present as a substituent on a methyl group. For example, C 1-6 The alkyl moiety and R 4 may together represent a substituted or unsubstituted benzyl group, where the substituents are as defined above.

[0047] Where the above group is referred to as including "one or more" substituents, it may be substituted with one substituent or with two or more substituents, for example it may be substituted with 1 to 6 substituents, such as 1 to 5 substituents, for example 1; 2; or 3 substituents.

[0048] For example, alkyl groups (e.g., C such as methyl) 1-3 When an alkyl group is substituted with one or more substituents (e.g., halo groups), the alkyl group may be substituted with one, two, or three substituents (e.g., halo groups). The halo group may be a fluoro group. An example of an alkyl group substituted with one or more halo (e.g., fluoro) groups is trifluoromethyl.

[0049] As a further example, when an aryl group (e.g., a phenyl group) is substituted with one or more substituents, the aryl group may have from 1 to 5 substituents (e.g., a halo group or a C 1-3 Alkyl group, where C 1-3 The alkyl group itself may be substituted with aryl, which may be substituted or unsubstituted as defined above. The aryl group may be a phenyl group. The halo group may be a fluoro group. 1-3The alkyl group may be as defined above. An example of an aryl group (such as a phenyl group) substituted with one or more halo (such as a fluoro) groups is pentafluorophenyl.

[0050] Specific compounds according to the invention include the following: [Table 5] [Table 6] and pharma- ceutically acceptable salts and solvates thereof.

[0051] In one embodiment of the invention, the compound of formula I is: The above compounds (a) to (f); The above compounds (a) to (e); The above compounds (b) to (f); and The above compounds (b) to (e); and pharma- ceutically acceptable salts and solvates thereof. It may be selected from.

[0052] The present invention provides a pharmaceutical formulation comprising a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, in admixture with a pharma- ceutically acceptable adjuvant, diluent or carrier.

[0053] The compounds of formula I have anticancer activity. Therefore, the present invention relates to the following compounds: - A compound of formula I or a pharma- ceutically acceptable salt or solvate thereof for use in medicine. - Use of a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for treating cancer. A compound of formula I or a pharma- ceutically acceptable salt or solvate thereof for use in the treatment of cancer. A method of treating cancer comprising administering an effective amount of a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof. to provide.

[0054] In each of the above uses, compounds for use, and methods of treatment, the cancer is selected from the group consisting of adrenal gland cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, CNS tumors, breast cancer, Castleman's disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastric cancer, cancer), gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, renal cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g. acute lymphocytic, acute myeloid, chronic lymphocytic, chronic myelogenous, chronic myelomonocytic), liver cancer, lung cancer (e.g. small cell or non-small cell), pulmonary carcinoid tumor, lymphoma (e.g. of the skin), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, gastric cancer The cancer may be selected from one or more of the group selected from: uterine cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, and Wilms' tumor.

[0055] In some embodiments of the invention as may be referred to herein, the cancer may be selected from colorectal cancer and gastric cancer.

[0056] The word "comprising" referred to herein may be interpreted as requiring the recited features but not limiting the presence of other features. Alternatively, the word "comprising" may relate to a situation where only the recited components / features are intended to be present (e.g., the word "comprising" may be replaced with the phrase "consists of" or "consists essentially of"). It is expressly intended that both the broader and narrower interpretations may be applied to all aspects and embodiments of the present invention. In other words, the word "comprising" and its synonyms may be replaced with the phrase "consisting of" or "consist essentially of" or their synonyms, and vice versa.

[0057] The phrase "consisting essentially of" and pseudonyms thereof may be construed herein to refer to a material in which small amounts of impurities may be present. For example, the material may be at least 90% pure, such as at least 95% pure, such as at least 97% pure, such as at least 99% pure, such as at least 99.9% pure, such as at least 99.99% pure, such as at least 99.999% pure, such as at least 100% pure.

[0058] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0059] A reference herein to a compound of formula I (in any aspect or embodiment of the invention) includes a reference to such a compound per se, a tautomer of such a compound, as well as a pharma- ceutically acceptable salt or solvate of such a compound, or a pharma- ceutically functional derivative thereof.

[0060] Pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts.Such salts may be formed by conventional means, for example, by reacting the free acid or free base form of the compound of formula I with one or more equivalents of a suitable acid or base, optionally in a solvent or in a medium in which the salt is insoluble, and then removing said solvent or said medium using standard techniques (for example, under reduced pressure, by lyophilization, or by filtration).Salts may also be prepared by exchanging the counterion of the compound of formula I in the form of a salt with another counterion, for example, by using a suitable ion exchange resin.

[0061] Examples of pharma- ceutically acceptable salts include acid addition salts derived from mineral and organic acids, as well as salts derived from metals, such as sodium, magnesium, and preferably potassium and calcium.

[0062] Examples of acid addition salts include those of acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, arylsulfonic acids (e.g., benzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, and p-toluenesulfonic acid), ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzoic acid, 4-acetamidobenzoic acid, butanoic acid, (+)camphoric acid, camphoric acid, and the like. Sulfonic acids, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid (e.g. D-gluconic acid), glucuronic acid (e.g. D-gluconic acid), glucuronic acid), glutamic acid (e.g. L-glutamic acid), α-oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid (e.g. (+)-L-lactic acid and (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid (e.g. (-)-L-malic acid), malonic acid, (±)-DL-mandelic acid, metaphosphoric acid, methanesulfonic acid, 1-hydroxypropyl 1-methyl ... These include acid addition salts formed with hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, L-pyroglutamic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, tartaric acid (e.g., (+)-L-tartaric acid), thiocyanic acid, undecylenic acid, and valeric acid.

[0063] Particular examples of salts are those derived from mineral acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid; organic acids, such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, arylsulfonic acids, and the like; and metals, such as sodium, magnesium, and preferably potassium and calcium.

[0064] As mentioned above, any solvate of the compound and its salts is also encompassed by formula I. Preferred solvates are those formed by incorporating molecules of non-toxic pharma- ceutically acceptable solvents (hereinafter referred to as solvating solvents) into the solid structure (e.g., crystalline structure) of the compound of the present invention. Examples of such solvents include water, alcohols (e.g., ethanol, isopropanol, and butanol, etc.), and dimethylsulfoxide. Solvates can be prepared by recrystallizing the compound of the present invention with a solvent or a mixture of solvents containing solvating solvents. Whether a solvate is formed in any given case can be determined by subjecting the crystal of the compound to analysis using well-known standard techniques (e.g., thermogravimetry (TGE), differential scanning calorimetry (DSC), and X-ray crystallography, etc.).

[0065] The solvates may be stoichiometric or non-stoichiometric solvates. Particularly preferred solvates are hydrates, examples of which include hemihydrates, monohydrates, and dihydrates.

[0066] For a more detailed discussion of solvates and the methods used to make and characterize them, see Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0067] "Pharmaceutically functional derivatives" of compounds of formula I as defined herein include ester derivatives and / or derivatives that have or provide the same biological function and / or activity as any relevant compound of the invention. Therefore, for purposes of the present invention, the term also includes prodrugs of compounds of formula I.

[0068] The term "prodrug" of related compounds of formula I includes any compound that is metabolized in vivo following oral or parenteral administration to form an experimentally detectable amount of that compound within a predetermined time period, e.g., within a 6-24 hour dosing interval (i.e., once to four times daily).

[0069] Prodrugs of compounds of formula I may be prepared by modifying functional groups present on the compounds such that the modifications are cleaved in vivo when such prodrugs are administered to a mammalian subject.Modification is generally accomplished by synthesizing the parent compound with a prodrug substituent.Prodrugs include compounds of formula I in which a hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group in the compound of formula I is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxyl, or carbonyl group, respectively.

[0070] Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxyl functional groups, ester groups of carboxyl functional groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. "Design of Prodrugs" p. I-92, Elsevier, New York-Oxford (1985).

[0071] The compounds of formula I, as well as the pharma- ceutically acceptable salts, solvates, and pharma- ceutically functional derivatives of such compounds, are hereinafter collectively referred to as "compounds of formula I" for brevity.

[0072] Compounds of formula I may contain double bonds and therefore may exist as E (entgegen) and Z (zusammen) geometric isomers about each double bond, and all such isomers and mixtures thereof are included within the scope of the present invention.

[0073] Compounds of formula I may exist as positional isomers and may exhibit tautomerism, all tautomeric forms and mixtures thereof are included within the scope of the invention.

[0074] Compounds of formula I may contain one or more asymmetric carbon atoms and therefore may exhibit optical and / or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, such as chromatography or fractional crystallization. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques (e.g. fractional crystallization or HPLC). Alternatively, the desired optical isomer may be prepared by reaction of the appropriate optically active starting material under conditions that do not cause racemization or epimerization (i.e., the "chiral pool" method), by reaction of the appropriate starting material with a "chiral auxiliary" which can be removed at a later appropriate stage, by derivatization (i.e., resolution such as kinetic resolution) with, for example, a homochiral acid, followed by separation of the diastereomeric derivatives by conventional means (e.g., chromatography), or by reaction with a suitable chiral reagent or chiral catalyst, all under conditions known to those skilled in the art. All stereoisomers and mixtures thereof are included within the scope of the present invention.

[0075] For the avoidance of doubt, in the context of the present invention, the term "treatment" includes reference to the therapeutic or symptomatic treatment of patients in need of such treatment, as well as to the prophylactic treatment and / or diagnosis of patients susceptible to the relevant pathology.

[0076] The term "patient" includes reference to a mammalian (e.g., human) patient. The terms "subject" or "patient" as used herein are well-recognized in the art and are used interchangeably herein to refer to mammals such as dogs, cats, rats, mice, monkeys, cows, horses, goats, sheep, pigs, camels, and most preferably humans. In some embodiments, the subject is one in need of treatment or one with a disease or disorder. However, in other embodiments, the subject may be healthy. The term does not denote a particular age or sex. Thus, adult and neonatal subjects, whether male or female, are intended to be encompassed.

[0077] The term "effective amount" refers to that amount of a compound that confers a therapeutic effect on the treated patient (e.g., sufficient to treat or prevent a disease). The effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect).

[0078] The term "halo," as used herein, includes references to fluoro, chloro, bromo, and iodo.

[0079] Unless otherwise specified, the term "aryl" as used herein means any of C 6-14 (For example, C 6-10 Such groups may be monocyclic, bicyclic, or tricyclic and may have from 6 to 14 ring carbon atoms, where at least one ring is aromatic. The point of attachment of the aryl group may be through any atom in the ring system. However, when the aryl group is bicyclic or tricyclic, it is attached to the remainder of the molecule through an aromatic ring. C 6-14Aryl groups include phenyl, naphthyl, and the like, such as 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, fluorenyl, etc. Embodiments of the invention that may be mentioned include those in which aryl is phenyl.

[0080] Unless otherwise specified, the term "alkyl" refers to a hydrocarbyl radical that is unbranched or branched, acyclic or cyclic, saturated or unsaturated (e.g., forming an alkenyl or alkynyl), and may be substituted (e.g., with one or more halo atoms) or unsubstituted. When the term "alkyl" refers to an acyclic group, it is preferably a C 1-10 Alkyl, more preferably C 1-6 Alkyl (e.g., ethyl, propyl (e.g., n-propyl or isopropyl), butyl (e.g., branched or unbranched butyl), pentyl, and more preferably methyl). When the term "alkyl" is a cyclic group (which may be the case when the group "cycloalkyl" is specified), it is preferably C 3-12 Cycloalkyl, more preferably C 5-10 (For example, C 5-7 ) cycloalkyl.

[0081] In certain embodiments of the present invention, when the term "alkyl" is used, it may refer to an unbranched or branched, acyclic, saturated hydrocarbyl radical, which may be substituted (e.g., with one or more halo atoms) or unsubstituted. When the term "alkyl" refers to a non-cyclic group, it is preferably a C 1-10 Alkyl, more preferably C 1-6 Alkyl (eg ethyl, propyl (eg n-propyl or isopropyl), butyl (eg branched or unbranched butyl), pentyl, more preferably methyl, etc.).

[0082] The term "heteroaryl," as used herein, refers to an aromatic group that contains one or more heteroatoms (e.g., 1-4 heteroatoms) preferably selected from N, O, and S (e.g., forming a mono-, bi-, or tricyclic heteroaromatic group). Heteroaryl groups include 5-14 (e.g., 10) membered heteroaryl groups and may be monocyclic, bicyclic, or tricyclic, but at least one of the rings is aromatic. However, when a heteroaryl group is bicyclic or tricyclic, it is attached to the remainder of the molecule via an aromatic ring.Heterocyclic groups which may be mentioned include benzothiadiazolyl (such as 2,1,3-benzothiadiazolyl), isothiochromanyl, more preferably acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (such as 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (such as 2,1,3-benzoxadiazolyl), benzoxazinyl (such as 3,4-dihydro-2H-1,4-benzoxazinyl), benzo Oxazolyl, benzomorpholinyl, benzoselenadiazolyl (such as 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (1,6-naphthyridinyl, preferably 1,5-naphthyridinyl), lysinyl and 1,8-naphthyridinyl), oxadiazolyl (such as 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (such as 1,2,3,4-tetrahydroisoquinolinyl and 5,6 Examples of heteroaryl groups include 1,2,3-, 1,2,4-, 1,3,4-triazolyl, 5,6,7,8-tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl, tetrazolyl, thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl, thiazolyl, thiochromanyl, thiophenethyl, thienyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl, and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including the heteroatom.The attachment point of the heteroaryl group may be through any atom in the ring system, including (where appropriate) a heteroatom (such as a nitrogen atom), or through an atom on any fused carbocyclic ring that may be present as part of the ring system. The heteroaryl group may be in N- or S-oxidized form. Particularly preferred heteroaryl groups include pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl, indazolyl, pyrimidinyl, thiophenethyl, thiophenyl, pyranyl, carbazolyl, acridinyl, quinolinyl, benzimidazolyl, benzthiazolyl, purinyl, cinnolinyl, and pterdinyl. Particularly preferred heteroaryl groups include monocyclic heteroaryl groups.

[0083] Unless otherwise stated in this specification, a "heterocyclic ring system" may be a 4-14 membered, such as 5-10 membered, e.g. 6-10 membered, heterocyclic group containing one or more heteroatoms selected from O, S, and N, which may be aromatic, fully saturated, or partially unsaturated, and the heterocyclic group may contain one or two rings. Examples of heterocyclic ring systems that may be mentioned herein include azetidinyl, dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydropyranyl (e.g., 3,4-dihydropyranyl, 3,6-dihydropyranyl), 4,5-dihydro-1H-maleimido, dioxanyl, dioxolanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, isothiaziolyl, isoxazolidinyl, isoxazolyl, morpholinyl, 1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl, piperazinyl, pyranyl, pyrazinyl, Examples include, but are not limited to, pyridazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolinyl (e.g., 3-pyrrolinyl), pyrrolyl, pyrrolidinyl, pyrrolidinonyl, 3-sulfolenyl, sulfolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl (e.g., 3,4,5,6-tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylene sulfoxide, tetrazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, thiophenethyl, triazolyl, and triazinanyl.

[0084] Unless otherwise specified herein, a "carbocyclic ring system" may be a 4-14 membered, e.g., 5-10 membered (e.g., 6-10 membered, e.g., 6 or 10 membered, etc.) carbocyclic group that may be aromatic, fully saturated, or partially unsaturated, and the carbocyclic group may contain one or two rings. Examples of carbocyclic ring systems that may be mentioned herein include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, naphthyl, decalinyl, tetralinyl, bicyclo[4.2.0]octanyl, and 2,3,3a,4,5,6,7,7a-octahydro-1H-indanyl. Particularly preferred carbocyclic groups include phenyl, cyclohexyl, and naphthyl.

[0085] Further embodiments of the invention that may be mentioned include those in which the compound of formula I is isotopically labeled. However, other specific embodiments of the invention that may be mentioned include those in which the compound of formula I is not isotopically labeled.

[0086] The term "isotopically labeled," as used herein, includes reference to a compound of formula I having a non-natural isotope (or a non-natural distribution of isotopes) at one or more positions in the compound. References herein to "one or more positions in a compound" will be understood by those of skill in the art to refer to one or more of the atoms of a compound of formula I. Thus, the term "isotopically labeled" includes reference to a compound of formula I that is isotopically enriched at one or more positions in the compound.

[0087] The compounds of formula I may be isotopically labeled or enriched with any of the following isotopes: hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine, and / or iodine, either radioactive or non-radioactive. Specific isotopes that may be mentioned in this regard include: 2 H, 3 H, 11 C. 13 C. 14 C. 13N, 15 N, 15 O. 17 O. 18 O. 35 S, 18 F, 37 Cl, 77 Br, 82 Br, and 125 I can be mentioned.

[0088] Where a compound of formula I is labelled or enriched with a radioactive or non-radioactive isotope, reference may be made to compounds of formula I that exhibit an isotopic distribution in which at least one atom in the compound is present at a level of the radioactive or non-radioactive isotope of the atom in question that is at least 10% (e.g. 10% to 5000%, particularly 50% to 1000%, more particularly 100% to 500%) higher than the natural level of that radioactive or non-radioactive isotope.

[0089] The compounds of formula I may be administered by any suitable route, in particular orally, intravenously, intramuscularly, cutaneously, subcutaneously, mucosally (e.g. sublingually or buccally), rectally, transdermally, intranasally, pulmonary (e.g. tracheal or bronchial), topically or any other parenteral route, in the form of a pharmaceutical preparation containing the compound in a pharma- ceutically acceptable dosage form. Specific administration methods that may be mentioned include oral, intravenous, cutaneous, subcutaneous, intranasal, intramuscular or intraperitoneal administration.

[0090] The compounds of formula I are generally administered as pharmaceutical preparations in a mixture with pharma- ceutically acceptable adjuvants, diluents, or carriers, which may be selected with due consideration of the intended route of administration and standard pharmaceutical practice. Such pharma-ceutically acceptable carriers may be chemically inert to the active compounds and may have no adverse side effects or toxicity under the conditions of use. Suitable pharmaceutical preparations are described, for example, in Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). For parenteral administration, parenterally acceptable aqueous solutions may be utilized, which are pyrogen-free and have the required pH, isotonicity, and stability. Suitable solutions are well known to those skilled in the art, and numerous methods are described in the literature. Brief reviews of methods of drug delivery are also described, for example, in Langer, Science (1990) 249, 1527.

[0091] Otherwise, preparation of suitable formulations may be routinely accomplished by one skilled in the art using routine techniques and / or in accordance with standard and / or accepted pharmaceutical practice.

[0092] The amount of the compound of formula I in any pharmaceutical formulation used in accordance with the present invention will depend on a variety of factors, such as the severity of the condition being treated, the particular patient being treated, as well as the compound being utilized, etc. In any case, the amount of the compound of formula I in the formulation may be routinely determined by one of ordinary skill in the art.

[0093] For example, a solid oral composition (such as a tablet or capsule) may comprise 1-99% (w / w) active ingredient; 0-99% (w / w) diluent or filler; 0-20% (w / w) disintegrant; 0-5% (w / w) lubricant; 0-5% (w / w) flow aid; 0-50% (w / w) granulating or binding agent; 0-5% (w / w) antioxidant; and 0-5% (w / w) colorant. Extended release tablets may further comprise 0-90% (w / w) release controlling polymer.

[0094] Parenteral formulations (e.g., solutions or suspensions for injection, or solutions for infusion) may contain 1-50% (w / w) active ingredient; and 50% (w / w) to 99% (w / w) liquid or semisolid carrier or vehicle (e.g., a solvent such as water); and 0-20% (w / w) of one or more other additives (e.g., buffers, antioxidants, suspension stabilizers, osmolality adjusting agents, and preservatives).

[0095] Depending on the disorder and the patient to be treated, as well as the route of administration, the compounds of formula I may be administered in different therapeutically effective amounts to a patient in need of treatment.

[0096] However, in the context of the present invention, the dosage administered to a mammal, particularly a human, should be sufficient to produce a therapeutic response in the mammal over a reasonable period of time.Those skilled in the art will recognize that the selection of the exact dosage and composition and the most appropriate delivery regimen will also be influenced by, among other things, the pharmacological properties of the formulation, the nature and severity of the pathology being treated, and the health and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, weight, sex, and response of the patient to be treated, and the stage / severity of the disease.

[0097] Administration may be continuous or intermittent (by bolus injection). The dosage may be determined by the timing and frequency of administration. For oral or parenteral administration, the dosage may vary from about 0.01 mg to about 1000 mg of the compound of formula I per day.

[0098] In any event, a physician or other skilled artisan can routinely determine the actual dosage which will be most appropriate for an individual patient. The above dosages are representative of the average case, and there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

[0099] Aspects of the invention described herein (e.g., the compounds, combinations, methods, and uses described above) may have advantages in that they may be more convenient for the physician and / or patient, more effective, less toxic, more selective, have a broader spectrum of activity, are more potent, have fewer side effects, or have other useful pharmacological properties in treating the conditions described herein compared to similar compounds, combinations, methods (treatments), or uses known in the art for use in treating the conditions described herein or otherwise.

[0100] The present invention is illustrated by the following examples, which should not be construed as limiting the scope of the claims. EXAMPLES

[0101] Preparation Example 1: Extraction and purification of molefantin from E. tomentosus L. E. tomentosus L. leaves were used for the extraction and purification of molephantin. Briefly, both water and methanol were used as solvents to obtain the crude extract using powdered freeze-dried leaves or freshly harvested leaves. Insoluble residues were removed from the crude extract by centrifugation and filtration. The solvent was then removed to produce a concentrated extract, which was then purified using flash column chromatography with silica gel as described below.

[0102] A crude water extract was prepared by adding 50 g of freeze-dried powder to 1 L distilled water. The powder-water mixture was sonicated for 10 min at 75% amplitude (10 sec on / off) using a Vibra-Cell, VCX130 sonicator. This was followed by centrifugation and filtration to remove insoluble residues. Methanol (MeOH) was then added to the filtered extract in a 1:1 (v / v) ratio. The solvent was removed from the extract using a vacuum concentrator to obtain the concentrated extract.

[0103] The extracted material (2.47 g) was resuspended in MeOH. Silica gel (4 g) was added to the suspended material, and the mixture was evaporated to prepare the mixture for dry-packing onto a flash column chromatography. The extracted material was purified by flash column chromatography (silica gel; CH2Cl2:MeOH=90:10-80:20). The resulting purified material (138 mg) was further purified by GPC (model: LaboACE LC-5060; column used: JAIGEL-2HR; injection concentration: 13.8 mg / mL; injection volume: 10 mL; flow rate: 10 mL / min) to give molefantin (21.8 mg, 0.0629 mmol) as a brown solid.

[0104] Molefantin may also be synthesized by the following improved method, which has higher yields.

[0105] A crude extract was obtained using powdered freeze-dried leaves with ethyl acetate as the solvent. Briefly, 40 g of freeze-dried powder was added to 250 mL of ethyl acetate and the suspension was sonicated for 30 min (Fisherbrand® FB15051). The residue in the mixture was allowed to settle and the green solution was decanted. The residue was then suspended in another 250 mL of ethyl acetate and sonicated for 30 min. This was repeated a total of five times until the solution turned a pale greenish yellow color. The combined organic extracts were filtered through Celite® and concentrated under reduced pressure. The crude residue was purified by flash column silica gel chromatography (n-hexane / ethyl acetate=4:1 to 1:1). Charcoal (200 mg) was then added to the purified product in ethyl acetate (15 mL) and the mixture was allowed to stand for 30 min before being filtered through Celite®. After evaporating the solvent under reduced pressure, gel permeation chromatography (model: LaboAce LC-5060; column used: JAIGEL-2HR-40; injection volume: 10 mL; flow rate: 30 mL / min) afforded two distinct fractions: an inseparable mixture of molephantinin and molephantin, and pure molephantin (120 mg, 0.289 mmol) as a white solid.

[0106] Molefantin is hereinafter referred to as NYH001. [ka]

[0107] Example 2: Synthesis of molefantin derivatives NYH002-NYH007 Derivatives of molefantin were produced by esterification reactions. Synthesis of NYH002 [ka]

[0108] To a solution of molefantin (NYH001) (3.4 mg, 9.82 μmol, 1 equiv) in CHCl (1 mL), BzCl (6 μL, 52.07 μmol, 5 equiv), EtN (14 μL, 100.44 μmol, 10 equiv), and DMAP (100 μL, 1.0 mg / mL, 0.82 μmol, 8 mol%) in CHCl was added at 0 °C under nitrogen, and the reaction mixture was stirred at 24 °C for 14 h. Volatiles were then concentrated in vacuo. The resulting crude material was purified by flash column chromatography (silica gel, n-hexane:EtOAc = 70:30) to give NYH002 in 18% yield (0.8 mg, 1.8 μmol) as a yellow oil and NYH001 in 71% yield (2.4 mg, 1.8 μmol) as a brown solid.

[0109] NYH002 may also be synthesized by the following improved method, which has higher yields. [ka]

[0110] To a mixture of NYH001 (190.1 mg, 0.55 mmol, 1.0 equiv), DMAP (6.7 mg, 0.05 mmol, 10 mol%), and triethylamine (459 μL, 3.29 mmol, 6.0 equiv) in anhydrous dichloromethane (2 mL) was added benzoyl chloride (127 μL, 1.10 mmol, 2.0 equiv) slowly at 0 °C under argon. The reaction was then warmed to room temperature and stirred for 1 h. The mixture was then concentrated under reduced pressure. The crude residue was washed with saturated NaHCO3 (10 mL) followed by extraction with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated under reduced pressure. The resulting crude material was purified using flash column silica gel chromatography (n-hexane:EtOAc = 75:25) to give NYH002 (228 mg, 92%) as a white solid.

[0111] Synthesis of NYH003 [ka] To a solution of NYH001 (4.5 mg, 12.99 μmol, 1 equiv) in CHCl (1 mL), pentafluorobenzoyl chloride (19 μL, 131.96 μmol, 10 equiv), EtN (18 μL, 129.14 μmol, 10 equiv), and DMAP (140 μL, 1.1 mg / mL in CHCl, 1.26 μmol, 10 mol%) were added at 0 °C under nitrogen, and the reaction mixture was stirred at 24 °C for 1 h. Volatiles were then concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (silica gel, n-hexane:EtOAc = 70:30) to give NYH003 in 24% yield (1.7 mg, 3.1 μmol) as a colorless oil.

[0112] NYH003 may also be synthesized by the following improved method, which has higher yields. [ka]

[0113] To a mixture of NYH001 (35.8 mg, 0.10 mmol, 1.0 equiv), DMAP (1.2 mg, 0.01 mmol, 10 mol%), and triethylamine (86 μL, 0.62 mmol, 6.0 equiv) in anhydrous dichloromethane (1 mL) was slowly added pentafluorobenzoyl chloride (30 μL, 0.21 mmol, 2.0 equiv) at 0 °C under argon. The reaction was then warmed to room temperature and stirred for 1 h. The mixture was then concentrated in vacuo. The crude residue was washed with saturated NaHCO3 (5 mL) followed by extraction with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated in vacuo. The crude material was purified using flash column silica gel chromatography (n-hexane: EtOAc = 75:25) to give NYH003 (31.8 mg, 57%) as a white solid.

[0114] Synthesis of NYH004 [ka] To a solution of NYH001 (7.3 mg, 21.08 μmol, 1 equiv) in CHCl (1 mL), 4-(trifluoromethyl)benzoyl chloride (31 μL, 208.69 μmol, 10 equiv), EtN (29 μL, 208.06 μmol, 10 equiv), and DMAP (1.3 mg, 10.64 μmol, 50 mol%) were added at 0 °C under nitrogen, and the reaction mixture was stirred at 24 °C for 16 h. The volatiles were then concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography (silica gel, n-hexane:EtOAc = 80:20) to give NYH004 in 55% yield (6.0 mg, 11.68 μmol) as a pale yellow solid.

[0115] NYH004 may also be synthesized by the following improved method, which has higher yields. [ka]

[0116] To a mixture of NYH001 (32.8 mg, 0.09 mmol, 1.0 equiv), DMAP (1.1 mg, 9.5 μmol, 10 mol%), and triethylamine (79 μL, 0.57 mmol, 6.0 equiv) in anhydrous dichloromethane (1 mL) was added 4-(trifluoromethyl)benzoyl chloride (28 μL, 0.19 mmol, 2.0 equiv) slowly at 0 °C under argon. The reaction was then warmed to room temperature and stirred for 1 h. The mixture was then concentrated in vacuo. The crude residue was washed with saturated NaHCO3 (5 mL) followed by extraction with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated in vacuo. The crude material was purified using flash column silica gel chromatography (n-hexane: EtOAc = 75:25) to give NYH004 (47.6 mg, 97%) as a white solid.

[0117] Synthesis of NYH005 [ka] To a mixture of NYH001 (13.8 mg, 0.04 mmol, 1.0 equiv), DMAP (0.5 mg, 4.0 μmol, 10 mol%), and triethylamine (33 μL, 0.24 mmol, 6.0 equiv) in anhydrous dichloromethane (1 mL) was added 3,5-bis(trifluoromethyl)benzoyl chloride (14 μL, 0.08 mmol, 2.0 equiv) slowly at 0 °C under argon. The reaction was then warmed to room temperature and stirred for 1 h. The mixture was then concentrated in vacuo. The crude residue was washed with saturated NaHCO3 (5 mL) followed by extraction with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated in vacuo. The crude material was purified using flash column silica gel chromatography (n-hexane: EtOAc = 75:25) to give NYH005 (21.1 mg, 90%) as a white solid.

[0118] Synthesis of NYH007 [ka] To a mixture of NYH001 (25.0 mg, 0.07 mmol, 1.0 equiv), DMAP (0.8 mg, 7.2 μL, 10 mol%), and triethylamine (60 μL, 0.43 mmol, 6.0 equiv) in anhydrous dichloromethane (1 mL) was added 4-nitrobenzoyl chloride (27 mg, 0.14 mmol, 2.0 equiv) slowly at 0 °C under argon. The reaction was then warmed to room temperature and stirred for 1 h. The mixture was then concentrated in vacuo. The crude residue was washed with saturated NaHCO3 (5 mL) followed by extraction with dichloromethane (3 x 10 mL). The organic layers were combined, washed with brine (10 mL), dried over MgSO4, filtered, and carefully concentrated in vacuo. The crude material was purified using flash column silica gel chromatography (n-hexane: EtOAc = 75:25) to give NYH007 (31.2 mg, 87%) as a white solid.

[0119] Example 3: Cytotoxicity Assay To test the cytotoxic effect of compounds NYH001-NYH005 in various cancer cell types, different cancer cells were treated with the compounds for 48 hours and analyzed using the MTT assay. For all the compounds tested, the cell proliferation was found to be inhibited in a dose-dependent manner. The absolute IC 50 The IC values ​​were calculated (Table 1, Figure 1A-C). Notably, the inhibitory effects of the novel compounds NYH002-NYH005 were greater than that of the natural compound NYH001 (molefantin), indicating their higher activity in inhibiting cancer cell viability. The cytotoxic effect of NYH007 was tested in DLD-1 cells, and the IC 50 was found to be 0.35 μM. Table 1: IC of NYH001-NYH005 against different cancer cell lines 50 [Table 7]

[0120] To further confirm the growth inhibitory effect of the compounds on cancer cells, colony formation assays were performed. Cells were treated with various doses of compounds and grown for 7–10 days until colonies formed. Colonies were fixed and stained with 0.5% w / v crystal violet containing methanol. Cell culture plates were rinsed with distilled water and then scanned for quantification. Colony numbers were quantified using Image J software.

[0121] The results showed that the compounds could significantly reduce the clonogenic activity of cells in a dose-dependent manner. Similar to the MTT cell viability assay, the novel compounds NYH002-NYH005 caused a greater effect on cell survival compared to NYH001. Notably, NYH002 and NYH003 did not result in any colony formation at concentrations as low as 1 μM in some cell lines (Figure 2A-E).

[0122] Example 4: Morphological changes by live cell imaging To examine cell morphological changes and cell fate, cells were seeded in 12-well tissue culture plates, treated with different concentrations of compounds, and placed on the thermo-controlled stage of a Zeiss Axiovert 200M microscope. Temperature was maintained at 37°C and CO2 concentration was maintained at 5%. Phase contrast images were acquired at 15 min intervals for 72 h.

[0123] While untreated cells were able to grow and proliferate healthily during live cell imaging, cancer cells treated with compounds NYH001-NYH003 underwent growth inhibition and cell death in a dose-dependent manner. Cancer cells were observed to exhibit cell rounding and delayed mitosis, which eventually led to cell shrinkage, membrane blebbing, and apoptosis-like cell death (Figure 3).

[0124] Example 5: Cell migration and invasion assays Cell migration and invasion are major factors that promote cancer cell metastasis. To examine the effect of compounds on cell motility and invasiveness, transwell migration and invasion assays were performed. Transwell assays were performed using 8 μm pore size transwell inserts (Corning Costar). For migration assays, 7.5×10 4 ~1.5x10 5 Cells were added to the upper chamber in serum-free medium. In the invasion assay, transwell inserts were first coated with Matrigel prior to cell seeding. For both assays, the lower chamber was filled with cell medium containing 10% FBS. After 24 h of incubation at 37°C, cells that had not migrated or invaded were removed from the upper chamber. Cells that had migrated or invaded into the lower chamber were fixed with 4% paraformaldehyde, stained with crystal violet, and imaged under a microscope. Bound crystal violet was eluted with 33% acetic acid, and the eluate was transferred to a 96-well plate for measuring absorbance at 590 nm using a plate reader.

[0125] Transwell assays showed that treatment with single compounds dose-dependently inhibited cancer cell migration (Figures 4A-D), with NYH002-NYH005 exhibiting stronger inhibitory effects compared with NYH001.

[0126] Furthermore, the compounds also reduce cell invasiveness in the cell lines tested (FIGS. 5A-B).

[0127] Example 6: Induction of cell cycle arrest and apoptosis The cell cycle distribution of compound-treated DLD-1 cells was further investigated by flow cytometry. Briefly, cells were harvested 24 hours after treatment with NYH001-NYH005 and fixed with 70% ethanol. Cells were washed and suspended in PBS containing propidium iodide and RNase for 30 minutes. A flow cytometer equipped with Cell Quest Pro Software was used to determine the cell cycle distribution. The cytometry results were analyzed using FlowJo software.

[0128] The percentage of cells in G1, S, or G2 / M phase after exposure to the compounds was evaluated. The percentage of compound-treated DLD-1 cells in G2 / M phase was found to be significantly higher than that of the control DMSO group, suggesting that the compounds induced cell cycle arrest in G2 / M phase. The population of cells in S phase was also slightly increased, indicating that the compounds may also delay the cell cycle in S phase (Figure 6).

[0129] To determine the mode of cell death induced by NYH001-NYH003 in cancer cells, the expression of proapoptotic markers (such as cleaved PARP and cleaved caspases 3 and 7) and autophagy markers LC3B and ATG7 were quantified by Western blotting. Compounds NYH001-NYH003 were found to induce the production of both proapoptotic and autophagy markers in a dose-dependent manner in DLD-1 cells. Western blot results suggest that compound-induced cell death is somewhat involved in apoptosis and autophagy (Figure 7).

[0130] Example 7: Tumor spheroid proliferation assay The tumor spheroid growth assay was established to create a more physiologically relevant tumor microenvironment and is therefore considered more representative for in vitro drug screening. In this assay, small tumor spheroids containing DLD-1 cells were created by seeding 8000 cells on an agarose-coated 96-well tissue culture plate, followed by centrifugation at 800g for 5 min. This method allows the creation of small spheroids with similar morphology and dimensions. The spheroids were then grown for 15 days under normal conditions or under treatment with NYH001-003. A 50% medium change with or without compound was performed every 3 days.

[0131] The area of ​​the spheroids was measured using Fiji. It was clear that the growth of spheroids treated with NYH001-NYH003 was inhibited in a dose-dependent manner (FIGS. 8 and 9).

[0132] Example 8: Wound closure assay Wound closure assays were performed to determine the effect of NYH001-003 on cell motility. AGS cells were grown in wells of 4-well silicon inserts (Ibidi) to 100% confluence. The wells were separated by 500 μm walls, and removing the inserts would leave a gap of approximately 500 μm. Before treatment with different concentrations of NYH001-003 or DMSO, cells were washed with PBS to remove dead and floating cells. Cell migration into the gap was monitored for 24 h by live cell imaging. Wound closure was analyzed by Fiji. The data showed that NYH001-003 could efficiently inhibit cell motility in a dose-dependent manner, and thus potentially reduce cancer cell metastasis (Figures 10A-10C).

[0133] Example 9: Inhibition of Tumor Growth in HCT116 and DLD-1 Subcutaneous Tumor Xenograft Mouse Models 1×10 in 1:1 Hanks Balanced Salt Solution / Matrigel 6 HCT116 or DLD-1 cells were injected subcutaneously into the right flank of female J:Nu outbred nude mice (5–6 weeks old). Tumor volumes were 50–100 mm3 Mice were assigned to treatment groups (4–5 mice per group) when they reached 100%. Vehicle control (ethanol: Kolliphor EL: saline = 1:1:8), NYH001 (25 mg / kg), NYH002 (25 mg / kg), or 5-fluorouracil (5-FU, 25 mg / kg) were administered by intraperitoneal injection once every 2 days for 3 weeks. Mice were weighed daily and tumor size was measured twice a week. The formula, volume = (long side × short side) 2 ) / 2mm 3 Tumor size was calculated using the ELISA kit. At the end of the 3-week treatment period, mice were sacrificed and tumors were excised. All procedures were approved by the NTU Institutional Animal Care and Use Committee (IACUC) and performed in accordance with IACUC protocol A20001.

[0134] The results showed that mice treated with NYH002 significantly suppressed tumor growth (Figures 11 and 12). After 21 days of treatment, the average tumor volume was reduced by 46.5% and 51.9% for HCT116 and DLD-1 xenografted mice, respectively, compared to mice administered vehicle control (Figures 11C and 12C). The average tumor weight was also reduced by 49.3% and 57.3% in HCT116 and DLD-1 xenografted mice (Figures 11D and 12D). The reduction in tumor size was more pronounced than in mice treated with 5-FU, a common chemotherapy drug used for the treatment of colon cancer. 5-FU treatment resulted in a 10.4% and 32.3% reduction in tumor volume and a 21.9% and 38.7% reduction in tumor weight compared to controls in HCT116 and DLD-1 xenografted mice, respectively.

[0135] The efficacy of NYH001 treatment in HCT116 xenografted mice was also evaluated. NYH001 treatment was more able to suppress tumor growth than 5-FU treatment, but less effective than NYH002. The mean tumor volume and weight were reduced by 35.4% and 41.7% in HCT116 xenografted mice (Figures 11C and 12D). All treatments did not cause adverse changes in body weight throughout the experiment (Figures 11E and 12E).

[0136] Overall, the results demonstrated that NYH002 treatment had excellent anticancer efficacy and minimal toxicity in vivo, providing improved anticancer efficacy compared to molefantin (NYH001) and 5-FU.

Claims

1. Formula I: 【Chemical 1】 [wherein, R １ and R ２ are each independently H, -C(O)R ３ , or -C(O)C １－６ alkyl, where the latter group is unsubstituted or substituted by one or more groups selected from halo and R ４ and Alternatively, R １ represents -C(O)R ３ or -C(O)C １－６ alkyl, where the latter group is unsubstituted or substituted by one or more groups selected from halo and R ４ and R ２ represents -C(O)C(=CH ２ )CH ３ as shown. R ３ represents, when present, an aryl, cycloalkyl, or heterocyclic ring system, where each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or substituted by one or more groups selected from halo, C １－３ alkyl, and NO ２ wherein C １－３ alkyl is unsubstituted or substituted by one or more halo groups, R ４ represents, when present, an aryl, cycloalkyl, or heterocyclic ring system, wherein each of the aryl, cycloalkyl, and heterocyclic ring systems is unsubstituted or substituted by one or more groups selected from halo and C １－３ alkyl, where C １－３ alkyl is unsubstituted or substituted by one or more halo groups] a compound of, or a pharmaceutically acceptable salt or solvate thereof.

2. R １ and R ２ are each independently H, -C(O)R ３ or -C(O)C １－３ alkyl, where the latter group is unsubstituted or substituted by one or more groups selected from halo and R ４ and Alternatively, R １ is -C(O)R ３ or -C(O)C １－３ alkyl, where the latter group is unsubstituted or substituted by one or more groups selected from halo and R ４ and R ２ is -C(O)C(=CH ２ )CH ３ is shown, and optionally, R １ and R ２ each independently represents -C(O)R ３ or -C(O)C １－３ alkyl, where the latter group is unsubstituted or substituted by one or more groups selected from halo and R ４ is the case, Alternatively, R １ is -C(O)R ３ or -C(O)C １－３ alkyl, where the latter group is unsubstituted or substituted by one or more groups selected from halo and R ４ and R ２ is -C(O)C(=CH ２ )CH ３ as shown. The compound of Formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof.

3. R ３ which, when present, represents an aryl or heteroaromatic ring system, wherein each of the aryl and heteroaromatic ring systems is unsubstituted or substituted by one or more groups selected from halo, C １－３ alkyl, and NO ２ wherein C １－３ alkyl is unsubstituted or substituted by one or more halo groups, The compound of Formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof.

4. R ３ When present, is aryl, where aryl is unsubstituted or substituted by one or more groups selected from halo, C １－３ alkyl, and NO ２ wherein C １－３ alkyl is unsubstituted or substituted by one or more halo groups, The compound of Formula I according to Claim 3, or a pharmaceutically acceptable salt or solvate thereof.

5. R ３ which, when present, is phenyl, where phenyl is unsubstituted or substituted by one or more groups selected from F, C １ alkyl, and NO ２ wherein C １ alkyl is unsubstituted or substituted by one or more halo groups, The compound of Formula I according to Claim 4, or a pharmaceutically acceptable salt or solvate thereof.

6. R ２ is -C(O)C(=CH ２ )CH ３ as shown The compound of Formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof.

7. R １ is -C(O)R ３ and R ２ is -C(O)R ３ or -C(O)C(=CH ２ )CH ３ as shown. The compound of Formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof.

8. The following compounds: 【Table 1】 【Table 2】 selected from the list consisting of The compound of Formula I according to Claim 1, or a pharmaceutically acceptable salt or solvate thereof.

9. The following compounds: 【Table 3】 【Table 4】 selected from the list consisting of The compound of Formula I according to Claim 8, or a pharmaceutically acceptable salt or solvate thereof.

10. A pharmaceutical preparation comprising the compound of Formula I defined in any one of Claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, in a mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier.

11. Use of the compound of Formula I defined in any one of Claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a drug for treating cancer.

12. A therapeutic agent for cancer comprising the compound of Formula I defined in any one of Claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof.

13. The therapeutic agent according to claim 12, wherein the cancer is selected from one or more of the group consisting of adrenal cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain tumor, CNS tumor, breast cancer, Castleman's disease, cervical cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, gastric cancer, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, kidney cancer, laryngeal cancer, hypopharyngeal cancer, leukemia (e.g., acute lymphoblastic, acute myeloid, chronic lymphocytic, chronic myeloid, chronic myelomonocytic), liver cancer, lung cancer (e.g., small cell or non-small cell), lung carcinoid tumor, lymphoma (e.g., of the skin), malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, skin cancer (basal and squamous cell, melanoma, Merkel cell), small intestine cancer, stomach cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

14. The therapeutic agent according to claim 13, wherein the cancer is selected from colorectal cancer and gastric cancer.

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