1 -(piperidinocarbonylmethyl)-2-oxopiperazine derivatives for treating cancer

Abstract

The present invention relates to novel compounds of formula (I) or formula (Ia), pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof, and pharmaceutical compositions of these compounds which are useful for preventive and therapeutic use in human and veterinary medicine.

Description

[0001] 1 -(PIPERIDINOCARBONYLMETHYL)-2-OXOPIPERAZINE DERIVATIVES

[0002] FOR TREATING CANCER

[0003] Cross-Reference to Related Applications

[0004] This application claims priority to, and the benefit of U.S. Application No.

[0005] 62 / 599,336, filed December 15, 2017 and Swiss Application No. 1522018, filed February 8,

[0006] 2018, the entire contents of each of which are incorporated herein by reference.

[0007] Incorporation of the Sequence Listing

[0008] The contents of the text file named“NTHR-OOl-OOlWO_SeqList” which was created on December 12, 2018 and is 32 KB in size are hereby incorporated by reference in their entirety.

[0009] Field of the Invention

[0010] The present invention relates to novel compounds of formula (I) or formula (la):

[0011]

[0012] pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof, and pharmaceutical compositions of these compounds which are useful for preventive and therapeutic use in human and veterinary medicine. Background

[0013] Despite the ever increasing number of cancer therapies in general, and combination cancer therapies in particular, cancer is still the third most common cause of death worldwide after cardiovascular diseases and infectious / parasitic diseases; in absolute numbers, this corresponds to 7.6 million deaths (ca. 13% of all deaths) in any given year. The World Health Organization (WHO) estimates deaths due to cancer to increase to 13.1 million by 2030, while the American Cancer Society expects over 1,685,210 new cancer cases diagnosed and 595,690 cancer deaths in the U.S. in 2016. A 2012 survey by McMillan Cancer Support in the U.K. has revealed that the median survival time of cancer patients overall has increased from 1 year to 6 years since the l970s. However, for many cancers including esophageal-, stomach-, lung-, brain- and pancreatic cancer, median survival has barely improved, remaining less than one year. These statistics illustrate the fact that cancer remains a critical health condition and that there is an urgent need for new anticancer drugs.

[0014] Summary

[0015] The present invention relates to novel compounds of formula (la). The present invention provides novel compounds according to formula (la):

[0016]

[0017] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

[0018] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0019] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0020] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn, or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0021] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0022] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloakenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and wherein R6can form a ring with any part of X; or is imidazolidinone;

[0023] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0024] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R5, R6, or Y, wherein the ring optionally contains a carbonyl group;

[0025] Y is selected from H, C(O)NR10R12, C(0)0R10, R10NC(O)NR10R12, OC(0)R10, OC(O)NR10R12, S (0)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S- heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0026] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)0R8, C1-5 alkyl- C(0)NR8Rn, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, NR8C(0)NR8Rn, 0C(0)NR8Rn, S02NR8Ru, NR8S02R8, OR8, NR8Rn, or S(0)nR8wherein n is 0, 1 or 2;

[0027] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NR8Rn; R13is Ci-5 alkyl substituted by a bi cyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0028] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0029] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0030] In another aspect, the present invention relates to novel compounds of formula (I). The present invention provides novel compounds according to formula (I):

[0031]

[0032] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

[0033] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0034] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0035] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0036] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0037] R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; or C1-3 alkyl substituted by C(0)NR8Rn; Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0038] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0039] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0040] Y is selected from H, C(O)NR10R12, C(0)OR10, R10NC(O)NR10R12, OC(0)R10, OC(O)NR10R12, S (0)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S- heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0041] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C 1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)0R8, C1-5 alkyl- C(0)NR8Rn, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, NR8C(0)NR8Rn, 0C(0)NR8Rn, S02NR8Ru, NR8S02R8, OR8, NR8Rn, or S(0)nR8wherein n is 0, 1 or 2;

[0042] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NR8Rn;

[0043] R13is C1-5 alkyl substituted by a bi cyclic ring optionally containing at least one heteroatom and a carbonyl group; R14is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0044] each R15is independently selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C 1-3 alkyl-OR8.

[0045] The present invention also relates to pharmaceutical compositions useful for preventive and therapeutic use in human and veterinary medicine comprising compounds of the formula (I) and / or formula (la) and pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof. The present invention is useful in methods for preventing and treating cancer.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to hose described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of compounds disclosed herein, the chemical structures will control.

[0047] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.

[0048] Brief Description of the Figures

[0049] FIG. 1 is a graph showing tumor growth inhibition in a patient-derived xenograft model of head and neck cancer. NMRI nude mice bearing HN11873 subcutaneous tumors were treated p.o. BID with either vehicle (control) or 30 mg / kg test Compound 57.

[0050] FIG. 2A - 2F are graphs depicting characteristic 5-day cell proliferation inhibition curves. The figure shows the inhibition curves for the values reported for lymphoma cell lines and Compound 258 (light gray line) in TABLE 5. Concentrations are given in micromol / lt (mM), To=day 0 reading (proliferation reference). The cisplatin (quality control) inhibition curve is shown in dark grey. FIG. 3 is a graph showing the tumor size development in a castration-resistant patient- derived xenograft mouse model of prostate cancer at various concentrations of Compound 258 and Compound 284, compared to standard-of-care treatment (Enzalutamide). The arrow indicates a concentration switch from Compound 258 10 mg / kg to 3 mg / kg at day 51.

[0051] FIG. 4 is a graph showing mice body weight development in a castration-resistant patient-derived xenograft mouse model of prostate cancer at various concentration of Compound 258 and Compound 284, compared to standard-of-care treatment (Enzalutamide). The arrow indicates a concentration switch from Compound 258 10 mg / kg to 3 mg / kg at day 51.

[0052] FIG. 5 is a graph showing tumor size development in a hormone-resistant cell-derived xenograft mouse model of prostate cancer (DU-145 cells) at various concentrations of Compound 258, Compound 279, Compound 253 and Compound 284.

[0053] FIG. 6 is a graph showing mice body weight development in a hormone-resistant cell- derived xenograft mouse model of prostate cancer (DU-145 cells) at various concentrations of Compound 258, Compound 279, Compound 253 and Compound 284.

[0054] FIG. 7 is a graph showing tumor size development in a colorectal cancer cell-derived xenograft mouse model (HCT116 cells) at various concentrations of Compound 258, Compound 279 and Compound 284, compared to standard-of-care treatment (Avastin, also called bevacizumab).

[0055] FIG. 8 is a graph showing mice body weight development in a colorectal cancer cell- derived xenograft mouse model (HCT116 cells) at various concentrations of Compound 258, Compound 279 and Compound 284, compared to standard-of-care treatment (Avastin).

[0056] FIG. 9 is a graph showing the tumor size development in a gastric cancer cell-derived xenograft mouse model (MKN45 cells) at various concentrations of Compound 258, Compound 253 and Compound 284, compared to standard-of-care treatment (Paclitaxel).

[0057] FIG. 10 is a graph showing mice body weight development in a gastric cancer cell- derived xenograft mouse model (MKN45 cells) at various concentrations of Compound 258, Compound 253 and Compound 284, compared to standard-of-care treatment (Paclitaxel).

[0058] FIG. 11 is a graph showing tumor size development in an HPV-positive cervical cancer cell-derived xenograft mouse model (SiHa cells) at various concentrations of

[0059] Compound 248, Compound 273, Compound 318 and Compound 258.

[0060] FIG. 12 is a graph showing mice body weight development in an HPV-positive cervical cancer cell-derived xenograft mouse model (SiHa cells) at various concentrations of Compound 248, Compound 273, Compound 318 and Compound 258. FIG. 13A and 13B are graphs showing luciferase activity in a MOLMl3-Luc mouse model for acute myeloid leukemia tumor spread. (A) Mean in vivo luciferase activity (photons / s) profile (whole body imaging): test compound is Compound 258, administered at 1, 3 and 6 mg / kg, displayed versus the corresponding vehicle control group. Data are displayed as mean values + / - SEM. (B) Luciferase activity (photons / s), measured in vivo on Day 19 (whole body imaging at necropsy): test compound is Compound 258, administered at 1, 3 and 6 mg / kg, displayed versus the corresponding vehicle control group. Data are displayed as individual data points together with their corresponding median values and interquartile ranges. P-values were calculated compared to the corresponding vehicle control group and between the 3mg / kg and 6mg / kg groups, using the Mann Whitney test and the unpaired t-test (in parentheses) as well as the one-way ANOVA with Dunnett's post test. *=p<0.05; **=r<0.01; ***=p<0.00l.

[0061] FIG. 14 is a graph showing the mean animal weight (g) profile in a MOLMl3-Luc mouse model for acute myeloid leukemia tumor spread. The test compound is Compound 258, administered at 1, 3 and 6 mg / kg, displayed versus the corresponding vehicle control group. Data are displayed as mean values + / - SEM.

[0062] FIG. 15 is a graph showing the ex vivo, post-necropsy organ / tissue luciferase activity (Photons / s / mg weight or Photon / s for lymph nodes) in a MOLMl3-Luc mouse model for acute myeloid leukemia tumor spread. Test compound is Compound 258, administered at 1, 3 and 6 mg / kg is displayed versus the corresponding Vehicle Control Group, for femur, lumbar spine, peritoneal carcinomatosis (fat tissue) and lymph nodes (both axillary and inguinal). Data are displayed as means + / - SD. P values were calculated compared to the corresponding Vehicle Control Group using the Mann Whitney test.

[0063] FIG. 16 is a graph showing the tumor volume development in a patient-derived HPV- positive human head-and-neck squamous cell carcinoma xenograft mouse model for Compound 248 and Compound 282 (both 30mg / kg, twice a day, administered orally).

[0064] FIG. 17 is a graph showing mice body weight development in a patient-derived HPV- positive human head-and-neck squamous cell carcinoma xenograft mouse model for Compound 248 and Compound 282 (both 30mg / kg, twice a day, administered orally).

[0065] FIG. 18 is a graph showing the tumor volume development in a patient-derived HPV- positive human head-and-neck squamous cell carcinoma xenograft mouse model for Compound 57, Compound 248, Compound 282 and Compound 273, at variable dosages (TABLE 23). All sixteen mice treated with Compound 248 and Compound 273 were tumor- free at the end of the observation period. FIG. 19 is a graph showing mice body weight development in a patient-derived HPV- positive human head-and-neck squamous cell carcinoma xenograft mouse model for Compound 57, Compound 248, Compound 282 and Compound 273, at variable dosages (TABLE 23).

[0066] FIG. 20 is a graph showing the tumor volume development in a cell-derived syngeneic mouse model for colorectal carcinoma (CT-26 cells) combined with an immuno- oncology treatment (anti-PDl antibodies). Compound 258 was administered as single agent and as a combination. Data after day 21 are mean + / - SEM of mice still in the experiment. Only the combination therapies and anti-PDl have data after day 28 (TABLE 26). Two mice displayed complete regression in the combination groups, hence the huge SEM-values.

[0067] FIG. 21 is a graph showing mice body weight development in a cell-derived syngeneic mouse model for colorectal carcinoma (CT-26 cells) combined with an immuno- oncology treatment (anti-PDl antibodies). Compound 258 was administered as single agent and as a combination. Data after day 21 are mean + / - SEM of mice still in the experiment. Only the combination therapies and anti-PDl have data after day 28 (TABLE 26).

[0068] FIG. 22 is a graph showing gene expression inhibition of three well-characterized androgen receptor (AR)-targets through Compound 258-mediated disruption of p300- CH1 / TAZ1-AR signaling in the castration-resistant prostate cancer cell line LNCaP.

[0069] Prostate-specific antigen (PSA / KLK3); transmembrane serine protease 2 (TMPRSS2); and prostein (SLC45A3) gene expression was measured in 4-hour dihydrotestosterone - stimulated cells (DHT, 100hM) and compared to untreated cells. 300nM Compound 258 was added concomitantly to DHT. Treatment with Compound 258 resulted in complete repression of PSA stimulation, and 85%, respectively 80% repression of TMPRSS2 and SLC45A3 stimulation.

[0070] FIG. 23 is a graph showing serum prostate-specific antigen (PSA) levels in a castration resistant prostate cancer (CRPC) patient-derived xenograft mouse model. Serum levels were determined in five mice that still had detectable tumors at experiment termination (following a 19 day treatment period, blood samples taken 3h after the last dose was applied, FIGURE 3, numbering on the x-axis of FIGURE 23). Two mice were treated daily with 10 and 3 mg / kg and three mice daily with 6mg / kg Compound 258 (FIGURE 3). Minimal relative expected PSA-levels were calculated based on minimal PSA / tumor size ratio of vehicle-treated mice. All five mice had a clear reduction of the expected serum PSA levels.

[0071] FIG. 24 is a graph showing tumor Vascular Endothelial Growth Factor A (VEGF) protein levels in HCT-116 and MKN45 colorectal / gastric cancer cell-derived xenograft mouse model after approximately 4 and 3 weeks, respectively, of treatment with 3mg / kg or 6mg / kg Compound 258 (FIGURES 7 and 9). In accordance with the proposed mode of action of Compound 258, the p300 / CBP-HIFl alpha transcriptional complex was disturbed, resulting in VEGF protein levels which were significantly reduced upon Compound 258-treatment.

[0072] The effect is more evident in the HCT-l 16 than in the MKN45 xenograft, reflecting the higher VEGF-dependence of HCT-l 16 xenograft vascularization (described in Dang et al. Cancer Res 2008;68(6): 1872-80).

[0073] FIG. 25 is a pair of Western blots of Compound 258-treated HPV16-positive cervical cancer CaSki cells. The figure depicts a characteristic rescue of p53 protein expression and p53 lysine 382 acetylation (K382Ac-p53) after Compound 258-mediated inhibition of p300 / CBP-HPVE6-p53 protein-protein-interactions. Cells were treated with the indicated concentrations (nM) for 72h. Induction of p53 protein above baseline is evident at 7nM already, acetylation of p53 lysine 382 is detectable at 20nM. Equivalent amounts of protein were loaded on the blot and the loading quantity assessed by total protein detection of the same blot on a Bio-Rad ChemiDoc Touch imager.

[0074] Detailed Description

[0075] The present invention is directed to a series of compounds having strong activities against a broad variety of tumor types, including, but not limited to, prostate, colon, head- and-neck and cervical cancer as well as hematological malignancies.

[0076] The present invention is directed to a series of compounds having a strong activity as p300 / CBP inhibitors, including stereoisomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds to treat p300 / CBP-related conditions or diseases, such as cancer.

[0077] Exemplary conditions which can be treated with the disclosed compounds include cancer. The cancer types which can be treated include, but are not limited to, prostate cancer, renal cancer, pancreatic cancer, liver cancer, breast cancer, gastric cancer, colorectal cancer, cervical cancer, ovarian cancer, head-and-neck cancer, esophageal cancer, leukemia, lymphoma, lung cancer, brain cancer, cancer of the central nervous system and skin cancer.

[0078] The invention provides pharmaceutical compositions of the described compounds, comprising the described compounds and pharmaceutically acceptable carriers, diluents or excipients.

[0079] The invention provides pharmaceutical compositions of the described compounds, wherein the compounds are administered in combination with one or more anti-cancer treatments or anti-cancer therapeutic agents. In one aspect, the pharmaceutical composition consists of the combination of one of the compounds with an immune checkpoint inhibitor of programmed cell death protein 1 (PD-l).

[0080] Definitions

[0081] The following are definitions of terms used in present application. The initial definition provided for a group or term herein applies to that group or term throughout the description and the claims, individually or as part of another group, unless otherwise indicated.

[0082] The term "alkyl" as used herein refers to a saturated straight or branched chain group of carbon atoms derived from an alkane by the removal of one hydrogen atom. C i-3 alkyl includes, but is not limited to, for example methyl, ethyl, n-propyl, i-propyl. Ci-4 alkyl comprises for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl. C1-5 alkyl comprises for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, Ci-7 alkyl comprises for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl. The alkyl groups of this invention can be optionally substituted.

[0083] The term " C2-5 alkenyl" and "C2-7 alkenyl" as used herein refers to straight or branched chain hydrocarbon groups having 2 to 5 carbon atoms and 2 to 7 carbon atoms, respectively and at least one double bond.

[0084] The term " C2-5 alkynyl" and "C2-7 alkynyl" as used herein refers to straight or branched chain hydrocarbon groups having 2 to 5 carbon atoms and 2 to 7 carbon atoms, respectively and at least one triple bond.

[0085] The term " C3-7 cycloalkyl " and“C3-5 cycloalkyl” as used herein refers to a monovalent saturated cyclic or bicyclic hydrocarbon group of 3-7 or 3-5 carbons, respectively derived from a cycloalkane by the removal of a single hydrogen atom. “C3-5 cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, and cyclopentyl. “C3-7 cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "C3-7 cycloalkyl” and“C3-5 cycloalkyl” as used herein also includes cycloalkyl groups that comprise a C1-3 -alkyl radical. Examples of such "C3-7 cycloalkyf'groups comprise cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl, 2- cyclobutylethyl, cyclopentylmethyl, 2-cyclopentylethyl. Examples of such“C3-5

[0086] cycloalkyf’groups comprise cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl.

[0087] Cycloalkyl groups of this invention can be optionally substituted. Substitutents can be e.g. halogen, C1-4 alkyl or C3-5 cycloalkyl. The term " C4-7 cycloalkenyl " as used herein refers to a monovalent cyclic or bicyclic hydrocarbon group of 4-7 carbons having at least one double bond, derived from a cycloalkene by the removal of a single hydrogen atom. The term " C4-7 cycloalkeny 1” as used herein also includes cycloalkenyl groups that comprise a C1-3 -alkyl radical.

[0088] The term " C1-3 alkanediyl ", “C 1-6 alkanediyl” and“C1-7 alkanediyl” as used herein refers to a diradical of a saturated straight or branched chain hydrocarbon group, having 1 to 3, 1 to 6 carbon and 1 to 7 carbon atoms, respectively. Examples of alkanediyl groups include methane-diyl, ethane- 1,2- diyl, and the like.

[0089] The term " C2-6 alkenediyl "and " C2-7 alkenediyl " as used herein refers to a diradical of a straight or branched chain hydrocarbon groups having 2 to 6 carbon atoms and 2 to 7 carbon atoms, respectively and at least one double bond. Examples of alkenediyl groups include ethene-l,2- diyl and the like.

[0090] The term " C2-6 alkynediyl "and " C2-7 alkynediyl " as used herein refers to a diradical of a straight or branched chain hydrocarbon groups having 2 to 6 carbon atoms and 2 to 7 carbon atoms, respectively and at least one triple bond. Examples of alkynediyl groups include ethine-l,2- diyl and the like.

[0091] The term " C3-6 cycloalkanediyl " as used herein refers to a diradical saturated cyclic or bicyclic hydrocarbon group of 3-6 carbons.

[0092] The term " C3-6 cycloalkenediyl " as used herein refers to a diradical cyclic or bicyclic hydrocarbon group of 3-6 carbons having at least one double bond.

[0093] The term "heteroalkyl" or“heteroalkanediyl” as used herein refers to an alkyl radical or an alkanediyl radical as defined herein wherein one, two, three or four hydrogen atoms have been replaced with a substituent independently selected from the group consisting of OH, Eand halogen. Representative examples include, but are not limited to, 2- hydroxy ethyl, 2-hydroxypropyl, 3 -hydroxy propyl, 2-hydroxy-l-hydroxymethylethyl, 2- hydroxy-l-methylethyl, 2,3-dihydroxypropyl, l-hydroxymethylethyl, 3-hydroxybutyl, 2,3- dihydroxy butyl, l-hydroxy-2-methylpropyl, 3-hydroxy- 1 -(2 -hydroxy ethyl)-propyl, 2- hy droxy-l -methylpropyl, 1,1,1 -trifluoroethyl, 2,2,3,3-tetrafluoropropyl.

[0094] The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings. The aryl group can also be fused to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring or to a cyclohexane, cyclohexene, cyclopentane, or cyclopentene ring comprising a carbonyl group. Thus the aryl group includes e.g. indane or mono-oxo substituted indane rings. The aryl groups of this invention can be optionally substituted as further described below. A preferred aryl group and optionally substituted aryl group, respectively of this invention is a phenyl group or substituted phenyl group. Substitutents can be e.g. halogen, Ci-4 alkyl or C3-5 cycloalkyl.

[0095] The term "heteroaryl" as used herein refers to substituted and unsubstituted aromatic 5-, or 6- membered monocyclic groups and 9- or lO-membered bicyclic groups, which have at least one heteroatom (O, S or N) in at least one of the rings. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and / or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom. Heteroaryl groups must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.

[0096] The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. Heteroaryl groups of this invention can be optionally substituted as further described below. Usually, a heteroaryl group and optionally substituted heteroaryl group, respectively of this invention is selected from the group consisting of substituted and / or unsubstituted aromatic 5- , or 6- membered monocyclic groups, which have at least one heteroatom (O, S or N), preferably one heteroatom (O, S or N), more preferably one O or N in the ring, even more preferably two N in the ring. A preferred heteroaryl group and optionally substituted heteroaryl group, respectively of this invention is selected from the group consisting of a pyridinyl group, a substituted pyridinyl group, a imidazole group, a substituted imidazole group, a pyrazole group, a substituted pyrazole group, a triazole group, a substituted triazole group, a benzimidazole group and a substituted benzimidazole group. More preferably a substituted pyridinyl group, a pyridinyl group, a triazole group, a substituted triazole group, a imidazole group, and / or a substituted imidazole group, is used as heteroaryl group in the present invention.

[0097] Most preferably a substituted pyridinyl group, a pyridinyl group, an imidazole group, and / or a substituted imidazole group, is used as heteroaryl group in the present invention. Substitutents can be e.g. halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0098] The term "S-aryl" as used herein refers to a radical -SR where R is an aryl as defined herein.

[0099] The term "O-aryl" as used herein refers to a radical -OR where R is an aryl as defined herein.

[0100] The term "S-heteroaryl" as used herein refers to a radical -SR where R is an heteroaryl as defined herein.

[0101] The term "O-heteroaryl" as used herein refers to a radical -OR where R is an heteroaryl as defined herein. The term "Ci-3 alkyl-aryl" as used herein refers to a radical of Ci-3 alkyl as defined herein to which an aryl group as defined herein is bonded at any carbon of the alkyl.

[0102] The term "Ci-3 alkyl-heteroaryl" as used herein refers to a radical of Ci-3 alkyl as defined herein to which a heteroaryl group as defined herein is bonded at any carbon of the alkyl.

[0103] The terms "halo" or "halogen" as used herein refers to F, Cl, Br, or I and is preferably F, Cl, or Br .

[0104] Compounds of the Present Disclosure

[0105] In some aspects, the present disclosure relates to a compound of Formula (la):

[0106]

[0107] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

[0108] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0109] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)OR15, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0110] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR". or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0111] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0112] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloakenyl, all optionally substituted by halogen, OR8, NRSR"; C1-3 alkyl substituted by C(0)NR8R11; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and wherein R6can form a ring with any part of X; or is imidazolidinone;

[0113] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0114] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R5, R6, or Y, wherein the ring optionally contains a carbonyl group;

[0115] Y is selected from H, C(O)NR10R12, C(0)0R10, R10NC(O)NR10R12, OC(0)R10, OC(O)NR10R12, S (0)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S- heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring optionally substituted by R9or R14; wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0116] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)0R8, C1-5 alkyl- C(0)NR8R14, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, NR8C(0)NR8Rn, 0C(0)NR8R14, S02NR8R14, NR8S02R8, OR8, NR8Rn, or S(0)nR8wherein n is 0, 1 or 2;

[0117] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NR8Rn; R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0118] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0119] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0120] In some aspects, the present disclosure relates to a compound of Formula (I):

[0121]

[0122] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:

[0123] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0124] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0125] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR". or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0126] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0127] R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloakenyl, all optionally substituted by halogen, OR8, NRSR"; C 1-3 alkyl substituted by C(0)NR8R11; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0128] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0129] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0130] Y is selected from H, C(O)NR10R12, C(0)OR10, R10NC(O)NR10R12, OC(0)R10, OC(O)NR10R12, S (0)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S- heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0131] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)0R8, C 1-5 alkyl- C(0)NR8R14, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NRsR". C(0)0R8, NRsC(0)NRsR". 0C(0)NR8R14, S02NRSR". NR8S02R8, OR8, NRSR". or S(0)nR8wherein n is 0, 1 or 2;

[0132] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0133] R13is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group; R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0134] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0135] It is understood that, for a compound of Formula (I) or Formula (la), R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, X, and Y can each be, where applicable, selected from the groups described herein, and any group described herein for any of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, X, and Y can be combined, where applicable, with any group described herein for one or more of the remainder of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, X, and Y

[0136] In some embodiments, R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl

[0137] In some embodiments, R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0138] In some embodiments, R1is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0139] In some embodiments, R1is selected from C2-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0140] In some embodiments, R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl.

[0141] In some embodiments, R1is H.

[0142] In some embodiments, R1is C3-7 cycloalkyl.

[0143] In some embodiments, R1is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0144] In some embodiments, R1is selected from cyclopropyl or cylcohexyl.

[0145] In some embodiments, R1is cyclopropyl.

[0146] In some embodiments, R1is cyclohexyl.

[0147] In some embodiments, R1is C1-7 alkyl. In some embodiments, R1is C2-7 alkyl.

[0148] In some embodiments, R1is C3-7 alkyl.

[0149] In some embodiments, R1is selected from methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, or tert-butyl.

[0150] In some embodiments, R1is selected from ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0151] In some embodiments, R1is selected from propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0152] In some embodiments, R1is isobutyl.

[0153] In some embodiments, R1is C1-3 alkyl substituted by cycloalkyl.

[0154] In some embodiments, R1is methyl, ethyl, or propyl substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0155] In some embodiments, R1is ethyl or propyl substituted by cyclopropyl or cyclohexyl.

[0156] In some embodiments, R1is C1-3 alkyl substituted by aryl or heteroaryl.

[0157] In some embodiments, R1is methyl, ethyl, or propyl substituted by phenyl, imidazole, pyridine, or triazole.

[0158] In some embodiments, R1is ethyl or propyl substituted by phenyl or pyridine.

[0159] In some embodiments, R1is ethyl substituted by phenyl.

[0160]

[0161]

[0162] In some embodiments,

[0163] In some embodiments, R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, Ci- 7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0164] In some embodiments, R2is selected from H, C(0)R14, C(0)NR15R15, C(0)OR15, Ci- 7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both

[0165] R15 can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0166] In some embodiments, R2is selected from H, C(0)R14, C(0)OR15, C1-7 alkyl, C3-7 cycloalkyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-OR8, C1-5 alkyl- NHCOR13, or Ci-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0167] In some embodiments, R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, Ci- 5 alkyl-OR8, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0168] In some embodiments, R2is selected from H, C(0)R14, wherein R14is C1-7 alkyl; C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl-NHCOR13, wherein R13is pentylamino-5- oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0169] In some embodiments, R2is selected from H, C(0)R14, wherein R14is C1-7 alkyl; C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8, wherein R8is C1-7 alkyl; C1-5 alkyl-NHCOR13, wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0170] In some embodiments, R2is H.

[0171] In some embodiments, R2is C1-7 alkyl.

[0172] In some embodiments, R2is selected from methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, or tert-butyl. In some embodiments, R2is selected from methyl, ethyl, or propyl.

[0173] In some embodiments, R2is C(0)R14, and R14is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0174] In some embodiments, R2is C(0)NR15R15, wherein each R15is independently selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl,

[0175] OR8, or C1-3 alkyl-OR8.

[0176] In some embodiments, R2is C(0)NR15R15, wherein each R15is independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0177] In some embodiments, R2is C(0)NR15R15, wherein each R15is independently selected from methyl or ethyl.

[0178] In some embodiments, R2is C(0)NR15R15, wherein each R15is methyl.

[0179] In some embodiments, R2is C3-7 cycloalkyl.

[0180] In some embodiments, R2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0181] In some embodiments, R2is cyclopropyl.

[0182] In some embodiments, R2is C 1-5 alkyl-OR8, wherein R8is C 1-7 alkyl

[0183] In some embodiments, R2is methyl-OR8, ethyl-OR8, propyl-OR8, or butyl-OR8wherein R8is methyl, ethyl, propyl, or butyl.

[0184] In some embodiments, R2is ethyl-OR8wherein R8is methyl, ethyl, propyl, or butyl.

[0185] In some embodiments, R2is ethyl-OR8wherein R8is methyl.

[0186] In some embodiments, R2is C 1-3 alkyl substituted by cycloalkyl.

[0187] In some embodiments, R2is methyl, ethyl, or propyl substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0188] In some embodiments, R2is ethyl or propyl substituted by cyclopropyl or cyclohexyl.

[0189] In some embodiments, R2is ethyl substituted by cyclopropyl.

[0190] In some embodiments, R2is C 1-3 alkyl substituted by aryl or heteroaryl.

[0191] In some embodiments, R2is methyl, ethyl, or propyl substituted by phenyl, imidazole, pyridine, or triazole.

[0192] In some embodiments, R2is ethyl or propyl substituted by phenyl or pyridine.

[0193] In some embodiments, R2is ethyl substituted by phenyl.

[0194] In some embodiments, R2is C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0195] In some embodiments, R2is methyl, ethyl, or propyl substituted by phenyl, imidazole, pyridine, or triazole substituted by fluoro, iodo, or bromo. In some embodiments, R2is ethyl or propyl substituted by phenyl or pyridine substituted fluoro, iodo, or bromo.

[0196] In some embodiments, R2is ethyl substituted by phenyl substituted fluoro.

[0197] In some embodiments,

[0198] In some embodiments, R2is C 1-5 alkyl-NHCOR13, wherein R13is pentylamino-5- oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one.

[0199] In some embodiments, R2is methyl-NHCOR13, ethyl-NHCOR13, propyl-NHCOR13, butyl-NHCOR13, or pentyl-NHCOR13, wherein R13is pentylamino-5-oxopentyl-7-thia-2.4- diazabicy clo[3.3.0] octan-3-one.

[0200] In some embodiments, R2is pentyl-NHCOR13, wherein R13is pentylamino-5- oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one.

[0201] In some embodiments,

[0202] In some embodiments, R2is C 1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0203] In some em .bod.iments, R2i.s ^ rv, * , ^l ,0X re .

[0204] In some embodiments, R3is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, or C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn, or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C3-5 cycloalkyl.

[0205] In some embodiments, R3is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, or C4-7 cycloalkenyl.

[0206] In some embodiments, R3is C1-7 alkyl.

[0207] In some embodiments, R3is selected from methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, or tert-butyl.

[0208] In some embodiments, R3is C2-7 alkenyl.

[0209] In some embodiments, R3is vinyl.

[0210] In some embodiments, R3is C3-7 cycloalkyl. In some embodiments, R3is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0211] In some embodiments, R3is H.

[0212] In some embodiments, R3and R7are each independently selected from H, Ci-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8R". or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl

[0213] In some embodiments, R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0214] In some embodiments, R3and R7are each independently C1-7 alkyl.

[0215] In some embodiments, R3and R7are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0216] In some embodiments, R3and R7are each independently C2-7 alkenyl.

[0217] In some embodiments, R3and R7are each vinyl.

[0218] In some embodiments, R3and R7are each independently C3-7 cycloalkyl.

[0219] In some embodiments, R3and R7are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0220] In some embodiments, R3and R7are each H.

[0221] In some embodiments, R7is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, or C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR". or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C3-5 cycloalkyl.

[0222] In some embodiments, R7is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, or C4-7 cycloalkenyl.

[0223] In some embodiments, R7is C1-7 alkyl.

[0224] In some embodiments, R7is selected from methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, or tert-butyl.

[0225] In some embodiments, R7is C2-7 alkenyl.

[0226] In some embodiments, R7is vinyl.

[0227] In some embodiments, R7is C3-7 cycloalkyl.

[0228] In some embodiments, R7is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0229] In some embodiments, R7is H.

[0230] In some embodiments, the group R7is in position -5 of the piperidine ring. In some embodiments, the group R7is in position -6 of the piperidine ring.

[0231] In some embodiments, the group R6is in position -2 of the piperidine ring.

[0232] In some embodiments, the group R6is in position -2 of the piperidine ring and / or the group R7is in position -5 of the piperidine ring.

[0233] In some embodiments, the group R6is in position -2 of the piperidine ring and the group R7is in position -5 of the piperidine ring.

[0234] In some embodiments, R4is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C3-5 cycloalkyl

[0235] In some embodiments, R4is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl.

[0236] In some embodiments, R4is selected from C 1-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0237] In some embodiments, R4is selected from C2-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0238] In some embodiments, R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl.

[0239] In some embodiments, R4is H.

[0240] In some embodiments, R4is C3-7 cycloalkyl.

[0241] In some embodiments, R4is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0242] In some embodiments, R4is selected from cyclopropyl or cylcohexyl.

[0243] In some embodiments, R4is cyclopropyl.

[0244] In some embodiments, R4is cyclohexyl.

[0245] In some embodiments, R4is C1-7 alkyl.

[0246] In some embodiments, R4is C2-7 alkyl.

[0247] In some embodiments, R4is C3-7 alkyl.

[0248] In some embodiments, R4is selected from methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, or tert-butyl. In some embodiments, R4is selected from ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0249] In some embodiments, R4is selected from propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0250] In some embodiments, R4is isobutyl.

[0251] In some embodiments, R4is Ci-3 alkyl substituted by cycloalkyl.

[0252] In some embodiments, R4is methyl, ethyl, or propyl substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0253] In some embodiments, R4is ethyl or propyl substituted by cyclopropyl or cyclohexyl.

[0254] In some embodiments, R4is Ci-3 alkyl substituted by aryl or heteroaryl.

[0255] In some embodiments, R4is methyl, ethyl, or propyl substituted by phenyl, imidazole, pyridine, or triazole.

[0256] In some embodiments, R4is ethyl or propyl substituted by phenyl or pyridine.

[0257] In some embodiments, R4is ethyl substituted by phenyl.

[0258]

[0259]

[0260] In some embodiments,

[0261] In some embodiments, the compound is of any one of Formulae (Ila), (lib), or (lie):

[0262] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1,

[0263] R2, R3, R4, R5, R6, R7, X, and Y are as described herein.

[0264] In some embodiments, the compound is of Formula (Ila) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, X, and Y are as described herein.

[0265] In some embodiments, the compound is of Formula (lib) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, X, and Y are as described herein.

[0266] In some embodiments, the compound is of Formula (lie) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, X, and Y are as described herein.

[0267] In some embodiments, the compound is of any one of Formulae (Ilia), (Illb), (IIIc), or

[0268] (Hid):

[0269] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1,

[0270] R4, R5, R6, X, and Y are as described herein.

[0271] In some embodiments, the compound is of Formula (Ilia) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R4, R5, R6, X, and Y are as described herein.

[0272] In some embodiments, the compound is of Formula (Illb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R4, R5, R6, X, and Y are as described herein.

[0273] In some embodiments, the compound is of Formula (IIIc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R4, R5, R6, X, and Y are as described herein.

[0274] In some embodiments, the compound is of Formula (Hid) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R4, R5, R6, X, and Y are as described herein.

[0275] In some embodiments, the group R6is in position -2 of the piperidine ring.

[0276] In some embodiments, the group R6is in position -3 of the piperidine ring.

[0277] In some embodiments, the group R6is in position -2 of the piperidine ring and / or the group R7is in position -5 of the piperidine ring.

[0278] In some embodiments, the group R6is in position -2 of the piperidine ring and the group R7is in position -5 of the piperidine ring.

[0279] In some embodiments, R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloakenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and wherein R6can form a ring with any part of X; or is imidazolidinone.

[0280] In some embodiments, R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloakenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone.

[0281] In some embodiments, R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, or C4-7 cycloalkenyl; or is imidazolidinone.

[0282] In some embodiments, R6is H, C1-7 alkyl, or imidazolidinone.

[0283] In some embodiments, R6is H or C1-7 alkyl. In some embodiments, R6is H.

[0284] In some embodiments, R6is in position -2 of the piperidine ring and is H.

[0285] In some embodiments, R6is in position -3 of the piperidine ring and is H.

[0286] In some embodiments, R6is imidazolidinone.

[0287] In some embodiments,

[0288] In some embodiments, R6is C1-7 alkyl.

[0289] In some embodiments, R6is selected from methyl, ethyl, propyl, isopropyl, butyl, sec- butyl, isobutyl, or tert-butyl.

[0290] In some embodiments, R6is methyl.

[0291] In some embodiments, R6is in position -2 of the piperidine ring and is C1-7 alkyl.

[0292] In some embodiments, R6is in position -2 of the piperidine ring and is selected from methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl.

[0293] In some embodiments, R6is in position -2 of the piperidine ring and is methyl.

[0294] In some embodiments, R6is selected from the group consisting of H, , and

[0295] In some embodiments, R6is in position -2 of the piperidine ring and is selected from the group consisting

[0296] In some embodiments,

[0297] In some embodiments, R6is in position -2 of the piperidine ring and is ^

[0298] In some embodiments, R6is Ci-3 alkyl substituted by C(0)NR8Rn.

[0299] In some embodiments, R6is Ci-3 alkyl substituted by C(0)NR8Rn, wherein R8is H. In some embodiments, R6is Ci-3 alkyl substituted by C(0)NR8Rn, wherein R11is H. In some embodiments, R6is Ci-3 alkyl substituted by C(0)NR8Rn, wherein R8and

[0300] R11is H.

[0301] In some embodiments, R6is C 1-3 alkyl substituted by C(0)NH2.

[0302] In some embodiments, R6is methyl, ethyl, or propyl substituted by C(0)NH2.

[0303] In some embodiments, R6is ethyl substituted by C(0)NH2.

[0304] In some embodiments, R6is propyl substituted by C(0)NH2.

[0305] In some embodiments, R6is selected from the group consisting of NH2and

[0306] In some embodiments, R6is in position -3 of the piperidine ring and is selected from the group consisting

[0307] In some embodiments, R6forms a ring with any part of X.

[0308] In some embodiments, R6is in position -3 of the piperidine ring and forms a ring with any part of X.

[0309] In some embodiments, R6is in position -3 of the piperidine ring and forms a 3- membered, a 4-membered, 5-membered, or 6-membered ring with any part of X.

[0310] In some embodiments, R6is in position -3 of the piperidine ring and forms a 4- membered or 6-membered ring with any part of X.

[0311] In some embodiments, R6is in position -3 of the piperidine ring and forms a 4- membered or ring with any part of X.

[0312] In some embodiments, R6is in position -3 of the piperidine ring and forms a 6- membered ring with any part of X.

[0313] In some embodiments, the compound is of any one of Formulae (IV a), (IVb), (IV c) or

[0314] (IVd):

[0315]

[0316] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R4, R5, R6, X, and Y are as described herein. In some embodiments, the compound is of Formula (IV a) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R4, R5, R6, X, and Y are as described herein.

[0317] In some embodiments, the compound is of Formula (IVb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R4, R5, R6, X, and Y are as described herein.

[0318] In some embodiments, the compound is of Formula (IV c) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R4, R5, R6, X, and Y are as described herein.

[0319] In some embodiments, the compound is of Formula (IV d) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R4, R5, R6, X, and Y are as described herein.

[0320] In some embodiments, R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0321] In some embodiments, R5is selected from H, C 1-7 alkyl, OR8, or SR8; and wherein Ci- 7 alkyl, OR8or SR8of R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group.

[0322] In some embodiments, R5is selected from H, C 1-7 alkyl, OR8, or SR8; and wherein Ci-7 alkyl, OR8or SR8of R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, Ci-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group.

[0323] In some embodiments, R5is selected from H, C 1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group.

[0324] In some embodiments, R5is selected from H, C 1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, Ci-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group.

[0325] In some embodiments, R5is selected from C 1-7 alkyl, OR8, or SR8; wherein C1-7 alkyl, OR8or SR8can form a ring with any part of X.

[0326] In some embodiments, R5is OR8, wherein R8of OR8is C 1-7 alkyl, and wherein OR8can form a ring with any part of X. In some embodiments, R5is selected from H and C1-7 alkyl; and wherein C1-7 alkyl can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group.

[0327] In some embodiments, R5is selected from H and C1-7 alkyl; and wherein C1-7 alkyl of R5can form a ring with any part of X or, when Y is is C(O)NR10R12or NR10R12, C1-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group.

[0328] In some embodiments, R5is selected from H and C1-7 alkyl.

[0329] In some embodiments, R5is selected from H, methyl, and ethyl.

[0330] In some embodiments, R5is H.

[0331] In some embodiments, R5is methyl.

[0332] In some embodiments, R5is ethyl.

[0333] In some embodiments, R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0334] In some embodiments, R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl.

[0335] In some embodiments, R8is C 1-7 alkyl and / or R11is selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl.

[0336] In some embodiments, R8is C 1-7 alkyl and / or R11is C 1-7 alkyl.

[0337] In some embodiments, R9is selected from H, halogen, C 1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl- C(0)0R8, C1-5 alkyl-C(0)NR8Rn, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, NR8C(0)NR8Rn, 0C(0)NR8Rn, S02NRSR". NR8S02R8, OR8, NRSR". or S(0)nR8wherein n is 0, 1 or 2.

[0338] In some embodiments, R9is selected from H, C 1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)OR8, C1-5 alkyl-C(0)NR8Rn, CN, C(0)R8, C(0)NR8Rn, C(0)OR8, and OR8.

[0339] In some embodiments, R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NR8Rn.

[0340] In some embodiments, R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci- 3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen or OR8. In some embodiments, R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, or C1-3 alkyl-aryl, all these groups optionally substituted by halogen.

[0341] In some embodiments, Y is C(O)NR10R12or NR10R12, and R10and R12can form a ring optionally substituted by R9or R14; wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0342] In some embodiments, R13is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group.

[0343] In some embodiments, R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0344] In some embodiments, R14is selected from C1-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

[0345] In some embodiments, R14is selected from C1-7 alkyl and C3-7 cycloalkyl.

[0346] In some embodiments, R14is C1-7 alkyl.

[0347] In some embodiments, each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0348] In some embodiments, each R15is independently selected from H, C1-7 alkyl, and C3-7 cycloalkyl.

[0349] In some embodiments, each R15is independently selected from H and C1-7 alkyl.

[0350] In some embodiments, X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R5, R6, or Y, wherein the ring optionally contains a carbonyl group.

[0351] In some embodiments, X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group.

[0352] In some embodiments, X is selected from a bond, C1-7 alkanediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-Ci-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group.

[0353] In some embodiments, X is selected from a bond, C1-7 alkanediyl, -0-, C1-3 alkanediyl-O, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-Ci-7 alkanediyl; and wherein X can form a ring with any part of R5or, when Y is

[0354] C(O)NR10R12or NR10R12, X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group.

[0355] In some embodiments, X is selected from a bond, -O-C1-7 alkanediyl, -S-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-C1-7 alkanediyl, S-C1-7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group.

[0356] In some embodiments, X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-C1-7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, C1-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group.

[0357] In some embodiments, X is selected from a bond, -O-C1-7 alkanediyl, S-C1-7 alkanediyl and C1-7 alkanediyl, and wherein -O-C1-7 alkanediyl, S-C1-7 alkanediyl or C1-7 alkanediyl can form a ring with any part of R5, wherein the ring optionally contains a carbonyl group.

[0358] In some embodiments, X is selected from a bond and C1-7 alkanediyl, wherein C1-7 alkanediyl can form a ring with any part of R5or Y.

[0359] In some embodiments, X is selected from a bond and C1-7 alkanediyl, wherein C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, Ci-7 alkanediyl of X can form a ring with any part of Y.

[0360] In some embodiments, X is selected from a bond and C1-7 alkanediyl, wherein C1-7 alkanediyl can form a ring with any part of Y.

[0361] In some embodiments, X is selected from a bond and C1-7 alkanediyl, wherein C1-7 alkanediyl of X can form a ring with any part of Y when Y is C(O)NR10R12or NR10R12.

[0362] In some embodiments, the ring which can be formed by R5and any part of X or Y, the ring which can be formed by X and any part of R5or Y, and / or the ring which can be formed by Y and any part of X or R5is a non-aromatic ring, preferably a non-aromatic ring containing between four and six atoms e.g. between four and six carbon and heteroatoms, more preferably a non-aromatic ring containing between three and five carbon and one nitrogen atom or a non-aromatic ring containing between two and four carbon and one or two, preferably two, oxygen or sulfur, preferably oxygen, atoms.

[0363] In some embodiments, Y is C(O)NR10R12or NR10R12and R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8, wherein the ring, R10and R12can form is a non-aromatic ring, preferably a non aromatic ring containing between four and seven atoms e.g. between three and six carbon atoms and the N of NR10R12, or between three and five carbon atoms and the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0364] In some embodiments, R2is C(0)NR15R15and both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8, wherein the ring, both R15can form is a non-aromatic ring, preferably a non-aromatic ring containing between four and seven atoms e.g. between three and six carbon atoms and the N of NR15R15, or between three and five carbon atoms and the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0365] In some embodiments, the integer n of S(0)nR8is 1 or 2.

[0366] In some embodiments, Y is selected from H, C(O)NR10R12, C(0)OR10,

[0367] R10NC(O)NR10R12, OC(0)R10, OC(O)NR10R12, S(0)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O- heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0368] In some embodiments, Y is selected from NR10R12and C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; and wherein Y can form a ring with any part of X or R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0369] In some embodiments, R5is selected from H and C1-7 alkyl; wherein C 1-7 alkyl of R5can form a ring with any part of Y;

[0370] X is selected from a bond and C1-7 alkanediyl, and wherein C1-7 alkanediyl of X can form a ring with any part of Y;

[0371] Y is selected from NR10R12and C3-7-cycloalkyl optionally containing a hetero atom in the ring wherein the heteroatom is N and is optionally substituted by R8wherein R8is C1-7 alkyl;

[0372] wherein Y can form a ring with any part of C1-7 alkanediyl of X or with any part of C1-7 alkyl of R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8; and

[0373] R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, or Ci- 3 alkyl-aryl, all these groups optionally substituted by halogen.

[0374] In some embodiments, R5is selected from C 1-7 alkyl, OR8, or SR8; wherein C1-7 alkyl, OR8or SR8of R5can form a ring with any part of X;

[0375] X is selected from -O-C1-7 alkanediyl, -S-C1-7 alkanediyl, or C1-7 alkanediyl, and wherein -O-C1-7 alkanediyl, -S-C1-7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5; and

[0376] Y is NR10R12, wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0377] In some embodiments, R5is OR8, wherein R8of OR8is C 1-7 alkyl, wherein OR8of R5can form a ring with any part of X;

[0378] X is -O-C1-7 alkanediyl and wherein -O-C1-7 alkanediyl of X can form a ring with any part of R5; and

[0379] Y is NR10R12wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and four or five carbon atoms.

[0380] In some embodiments, Y is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14. In some embodiments, Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14.

[0381] In some embodiments, R5is selected from H and C1-7 alkyl;

[0382] X is selected from a bond and C1-7 alkanediyl; and

[0383] Y is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl wherein the S-heteroaryl is optionally substituted by one or more R14.

[0384] In some embodiments, R5is selected from H and C1-7 alkyl;

[0385] X is selected from a bond and C1-7 alkanediyl; and

[0386] Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl wherein the S-heteroaryl is optionally substituted by one or more R14.

[0387] In some embodiments, R5is selected from H and C1-7 alkyl;

[0388] X is selected from a bond and C1-7 alkanediyl; and

[0389] Y is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by one of R8wherein R8is selected from C1-7 alkyl, C2-7 alkenyl, or C3-7 cycloalkyl; or S- heteroaryl wherein the S-heteroaryl is optionally substituted by one of R14wherein R14is selected from C1-7 alkyl, C2-7 alkenyl, or C3-7 cycloalkyl.

[0390] In some embodiments, R5is selected from H and C1-7 alkyl;

[0391] X is selected from a bond and C1-7 alkanediyl; and

[0392] Y is heteroaryl, wherein the heteroaryl is optionally substituted by one of R8wherein R8is selected from C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalky; or S-heteroaryl wherein the S- heteroaryl is optionally substituted by one of R14wherein R14is selected from C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl.

[0393] In some embodiments, the compound is of any one of Formulae (Va), (Vb), (Vc), or

[0394] (Vd):

[0395]

[0396] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0397] In some embodiments, the compound is of Formula (Va) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0398] In some embodiments, the compound is of Formula (Vb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0399] In some embodiments, the compound is of Formula (Vc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0400] In some embodiments, the compound is of Formula (Vd) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0401] In some embodiments,

[0402] In some embodiments, the compound is of any one of Formulae (Via), (VIb), (Vic), or (VId):

[0403]

[0404] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0405] In some embodiments, the compound is of Formula (Via) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0406] In some embodiments, the compound is of Formula (VIb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0407] In some embodiments, the compound is of Formula (Vic) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0408] In some embodiments, the compound is of Formula (VId) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

[0409] In some embodiments, Y is C(O)NR10R12, wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8. In some embodiments,

[0410] In some embodiments, R5is selected from H and C1-7 alkyl;

[0411] X is selected from a bond and C1-7 alkanediyl;

[0412] Y is C(O)NR10R12, wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8; and

[0413] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, or C1-3 alkyl-aryl. In some embodiments, Y is selected from S-aryl, O-aryl, S-heteroaryl, or O- heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl are optionally substituted by one or more R9or R14.

[0414] In some embodiments, Y is selected from O-aryl and O-heteroaryl, wherein the O-aryl and O-heteroaryl are optionally substituted by one or more R9or R14.

[0415] In some embodiments, Y is selected from S-aryl, O-aryl, S-heteroaryl, or O- heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl are optionally substituted by one or more R9; wherein R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C1-5 alkyl- C(0)0R8, C1-5 alkyl-C(0)NR8R14, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, and OR8.

[0416] In some embodiments, R5is selected from H and C1-7 alkyl;

[0417] X is selected from a bond and C1-7 alkanediyl; and

[0418] Y is selected from O-aryl and O-heteroaryl, wherein the O-aryl and O-heteroaryl is optionally substituted by one or more R9; wherein R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8R41, C1-5 alkyl-C(0)NR8Rn, C1-5 alkyl- C(0)0R8, CN, C(0)R8, C(0)NR8R14, C(0)0R8, and OR8.

[0419] In some embodiments, Y is C(0)0R10.

[0420] In some embodiments, R5is selected from H and C1-7 alkyl;

[0421] X is selected from a bond and C1-7 alkanediyl;

[0422] Y is C(0)OR10; and

[0423] R10is selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by OR8.

[0424] In some embodiments, Y is H.

[0425] In some embodiments, R5is C1-7 alkyl; X is a bond; and Y is H.

[0426] In some embodiments, Y is CN.

[0427] In some embodiments, R5is H; X is C1-7 alkanediyl; and Y is CN.

[0428] In some embodiments, Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, CN, C3-7-cycloalkyl optionally containing a hetero atom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0429] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0430] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0431] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)OR15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0432] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0433] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0434] R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0435] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0436] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0437] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0438] Y is selected from H, C(O)NR10R12, C(0)0R10, NR10R12, CN, C3-7-cycloalkyl optionally containing a hetero atom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0439] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, halogen, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl- C(0)0R8, C1-5 alkyl- C(0)NR8R11, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NRsR". C(0)0R8, NRsC(0)NRsR". 0C(0)NR8R14, S02NRSR". NR8S02R8, OR8, NRSR". or S(0)nR8wherein n is 0, 1 or 2;

[0440] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0441] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0442] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0443] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0444] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0445] In some embodiments, Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O- heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12,Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0446] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0447] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0448] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0449] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0450] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0451] R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0452] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0453] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0454] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0455] Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0456] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl- C(0)0R8, C1-5 alkyl- C(0)NR8R11, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NRsR". C(0)0R8, NRsC(0)NRsR". 0C(0)NR8R14, S02NRSR". NR8S02R8, OR8, NRSR". or S(0)nR8wherein n is 0, 1 or 2;

[0457] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0458] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0459] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0460] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0461] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0462] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0463] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0464] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or Ci-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0465] R3and R7are H;

[0466] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0467] R5is selected from H, C1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, C1-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0468] R6is H, Ci-7 alkyl, or imidazolidinone;

[0469] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0470] X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-Ci- 7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, Ci-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0471] Y is selected from H, C(O)NR10R12, C(0)0R10, NR10R12, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or the O-heteroaryl are optionally substituted by one or more R9and wherein the S-heteroaryl is optionally substituted by one or more R14; or aryl, heteroaryl wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of C1-7 alkanediyl of X or any part of Ci-7 alkyl of R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0472] R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)0R8, Ci- 5 alkyl-C(0)NR8Rn, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, and OR8;

[0473] R10and R12are each independently selected selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen or OR8; and

[0474] R14is C1-7 alkyl. In some embodiments, Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, C3- 7-cycloalkyl optionally containing a hetero atom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O- heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0475] In some embodiments, Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, C3- 7-cycloalkyl optionally containing a hetero atom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O- heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0476] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0477] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0478] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0479] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8R"; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0480] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0481] R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0482] R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; C1-3 alkyl substituted by C(0)NR8Rn; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0483] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0484] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0485] Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O- aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0486] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, halogen, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C 1-5 alkyl-NR8Rn, C 1-5 alkyl-C(0)NR8R41, C1-5 alkyl- C(0)0R8, C 1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8R14, C(0)0R8,

[0487] NR8C(0)NR8Rn, 0C(0)NR8Rn, S02NR8R14, NR8S02R8, OR8, NR8R41, or S(0)nR8wherein n is 0, 1 or 2; R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NR8Rn;

[0488] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0489] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0490] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0491] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0492] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0493] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0494] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0495] R3and R7are H;

[0496] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0497] R5is selected from H, C1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, C1-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0498] R6is H, C1-7 alkyl, or imidazolidinone;

[0499] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0500] X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-Ci- 7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, C1-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0501] Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or the O- heteroaryl are optionally substituted by one or more R9and wherein the S-heteroaryl is optionally substituted by one or more R14; or aryl, heteroaryl wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is

[0502] C(O)NR10R12or NR10R12, Y can form a ring with any part of C1-7 alkanediyl of X or any part of Ci-7 alkyl of R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0503] R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)NR8Rn, C1-5 alkyl- C(0)0R8, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, and OR8;

[0504] R10and R12are each independently selected selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen or OR8; and

[0505] R14is Ci-7 alkyl.

[0506] In some embodiments, Y is selected from C(O)NR10R12, C(0)0R10, NR10R12, C3-7- cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O- heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0507] In some embodiments, Y is selected from C(O)NR10R12, C(0)OR10, NR10R12, C3-7- cycloalkyl optionally containing a hetero atom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O- heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0508] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0509] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0510] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0511] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0512] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0513] R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0514] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0515] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0516] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group; Y is selected from C(O)NR10R12, C(0)OR10, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O- aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0517] R9is selected from H, halogen, Ci-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl- C(0)OR8, C1-5 alkyl- C(0)NR8R11, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NRsR". C(0)OR8, NRsC(0)NRsR". OC(0)NR8R11, S02NRSR". NR8S02R8, OR8, NRSR". or S(0)nR8wherein n is 0, 1 or 2;

[0518] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0519] R13is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0520] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0521] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl; and

[0522] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0523] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0524] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0525] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0526] R3and R7are H; R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0527] R5is selected from H, C1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, C1-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0528] R6is H or Ci-7 alkyl;

[0529] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0530] X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-Ci- 7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, Ci-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0531] Y is selected from C(O)NR10R12, C(0)OR10, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or the O- heteroaryl are optionally substituted by one or more R9and wherein the S-heteroaryl is optionally substituted by one or more R14; or aryl, heteroaryl wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is

[0532] C(O)NR10R12or NR10R12, Y can form a ring with any part of C1-7 alkanediyl of X or any part of Ci-7 alkyl of R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0533] R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C1-5 alkyl- C(0)0R8, C1-5 alkyl-C(0)NR8Rn, CN, C(0)R8, C(0)NR8R14, C(0)0R8, and OR8;

[0534] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl- aryl, or Ci-3 alkyl-heteroaryl, all these groups optionally substituted by halogen or OR8; and

[0535] R14is Ci-7 alkyl.

[0536] In some embodiments, Y is selected from C(O)NR10R12, C(0)OR10, NR10R12, C3-7- cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O- heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0537] In some embodiments, Y is selected from C(O)NR10R12, C(0)OR10, NR10R12, C3-7- cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O- heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0538] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0539] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0540] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0541] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0542] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0543] R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; C1-3 alkyl substituted by C(0)NR8R11; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0544] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0545] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0546] Y is selected from C(O)NR10R12, C(0)OR10, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O- aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0547] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)NR8Rn, C1-5 alkyl- C(0)0R8, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, NR8C(0)NR8R14, 0C(0)NR8R14, S02NRSR". NR8S02R8, OR8, NRSR". or S(0)nR8wherein n is 0, 1 or 2; wherein R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0548] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group; R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0549] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0550] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0551] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0552] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0553] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0554] R3and R7are H;

[0555] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0556] R5is selected from H, C 1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, C 1-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0557] R6is H or Ci-7 alkyl;

[0558] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0559] X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-Ci- 7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, C1-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0560] Y is selected from C(O)NR10R12, C(0)OR10, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or the O- heteroaryl are optionally substituted by one or more R9and wherein the S-heteroaryl is optionally substituted by one or more R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of C1-7 alkanediyl of X or any part of C1-7 alkyl of R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0561] R9is selected from H, Ci-5 alkyl, halogen, Ci-5 alkyl-NR8Rn, Ci-5 alkyl-C(0)NR8Rn, Ci-5 alkyl-C(0)0R8, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, and OR8;

[0562] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl- aryl, or Ci-3 alkyl-heteroaryl, all these groups optionally substituted by halogen or OR8; and

[0563] R14is Ci-7 alkyl.

[0564] In some embodiments, Y is selected from C(O)NR10R12, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0565] In some embodiments, Y is selected from C(O)NR10R12, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0566] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0567] R1is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, Ci-v alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0568] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0569] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0570] R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0571] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0572] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl;

[0573] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0574] Y is selected from C(O)NR10R12, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S- heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0575] R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl- C(0)0R8, C1-5 alkyl- C(0)NR8R11, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NRsR". C(0)0R8, NRsC(0)NRsR". 0C(0)NR8R11, S02NRSR". NR8S02R8, OR8, NR8Rn, or S(0)nR8wherein n is 0, 1 or 2;

[0576] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0577] R13is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0578] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0579] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl; and

[0580] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8.

[0581] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0582] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, C1-3 alkyl substituted by aryl or heteroaryl;

[0583] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0584] R3and R7are H;

[0585] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0586] R5is selected from H, C1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is C(O)NR10R12or NR10R12, C1-7 alkyl of R5can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0587] R6is H or Ci-7 alkyl;

[0588] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl; X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-Ci- 7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is C(O)NR10R12or NR10R12, C1-7 alkanediyl of X can form a ring with any part of Y, wherein the ring optionally contains a carbonyl group;

[0589] Y is selected from C(O)NR10R12, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; O-aryl, S-heteroaryl, O-heteroaryl wherein the O-aryl or the O-heteroaryl are optionally substituted by one or more R9and wherein the S-heteroaryl is optionally substituted by one or more R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of C1-7 alkanediyl of X or any part of C1-7 alkyl of R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0590] R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)NR8Rn, C1-5 alkyl- C(0)0R8, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, and OR8;

[0591] R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, C1-3 alkyl-aryl, all these groups optionally substituted by halogen; and

[0592] R14is Ci-7 alkyl.

[0593] In some embodiments, Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14; aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0594] In some embodiments, Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14; aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0595] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0596] R1is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0597] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C 1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C i-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0598] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0599] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0600] R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0601] R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C 1-3 alkyl substituted by C(0)NR8Rn; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0602] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0603] X is selected from a bond, C 1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C 1-3 alkanediyl-O-, -O-C 1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C 1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0604] Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or R14; aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0605] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0606] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0607] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0608] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0609] R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0610] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0611] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0612] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0613] R3and R7are H;

[0614] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl; R5is selected from H, C 1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is NR10R12, C1-7 alkyl of R5can form a ring with any part of Y;

[0615] R6is H;

[0616] R8is selected from H, C 1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0617] X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-Ci- 7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is NR10R12, Ci-7 alkanediyl of X can form a ring with any part of Y;

[0618] Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8, wherein R8is C 1-7 alkyl; S-heteroaryl wherein the S-heteroaryl is optionally substituted by one or more R14; aryl, or heteroaryl wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is NR10R12, Y can form a ring with any part of Ci-7 alkanediyl of X or any part of C 1-7 alkyl of R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0619] R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, or Ci- 3 alkyl-aryl, all these groups optionally substituted by halogen; and

[0620] R14is Ci-7 alkyl.

[0621] In some embodiments, the aryl, the heteroaryl or the S-heteroaryl group of any of the compounds of the present disclosure are preferably selected from the group consisting of phenyl, imidazole, pyridine and triazole, more preferably selected from the group consisting of phenyl, imidazole and pyridine.

[0622] In some embodiments, Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8. In some embodiments, Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0623] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0624] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0625] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0626] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0627] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0628] R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0629] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8R11; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0630] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0631] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0632] Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0633] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0634] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0635] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0636] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0637] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0638] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0639] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0640] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or Ci-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0641] R3and R7are H;

[0642] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0643] R5is selected from H, C 1-7 alkyl, or OR8; and wherein C1-7 alkyl or OR8of R5can form a ring with any part of X or, when Y is NR10R12, C 1-7 alkyl of R5can form a ring with any part of Y;

[0644] R6is H;

[0645] R8is selected from H, C 1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0646] X is selected from a bond, -O-C1-7 alkanediyl and C1-7 alkanediyl; and wherein -O-Ci- 7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5or, when Y is NR10R12, Ci-7 alkanediyl of X can form a ring with any part of Y;

[0647] Y is selected from NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8, wherein R8is C 1-7 alkyl; S-heteroaryl wherein the S-heteroaryl is optionally substituted by one or more R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein, when Y is NR10R12, Y can form a ring with any part of C1-7 alkanediyl of X or any part of C 1-7 alkyl of R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8; and

[0648] R14is Ci-7 alkyl.

[0649] In some embodiments, the aryl, the heteroaryl or the S-heteroaryl group of the compounds of the present disclosure are preferably selected from the group consisting of phenyl, imidazole, pyridine and triazole, more preferably selected from the group consisting of phenyl, imidazole and pyridine.

[0650] In some embodiments, Y is selected from NR10R12and C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; and wherein Y can form a ring with any part of X or R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8. In some embodiments, Y is selected from NR10R12and C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; and wherein, when Y is NR10R12, Y can form a ring with any part of X or R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0651] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0652] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0653] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0654] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0655] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0656] R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;

[0657] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0658] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl; X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;

[0659] Y is selected from NR10R12and C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; and wherein Y can form a ring with any part of X or R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0660] R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NRSR'

[0661] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0662] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0663] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0664] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0665] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0666] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, C1-3 alkyl substituted by aryl or heteroaryl;

[0667] R2is selected from H, C(0)R14, wherein R14is C1-7 alkyl; C1-7 alkyl, C3-7 cycloalkyl, Ci-5 alkyl-OR8; C1-5 alkyl-NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4- diazabicyclo[3.3.0]octan-3-one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0668] R3and R7are H;

[0669] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0670] R5is selected from H and C1-7 alkyl; and wherein C1-7 alkyl of R5can form a ring with any part of Y; R6is H;

[0671] R8is selected from H, C 1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0672] X is selected from a bond and C1-7 alkanediyl, and wherein C1-7 alkanediyl of X can form a ring with any part of Y;

[0673] Y is selected from NR10R12or C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8, wherein R8is C 1-7 alkyl; and wherein, when Y is NR10R12, Y can form a ring with any part of Ci-7 alkanediyl of X or any part of C1-7 alkyl of R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8; and

[0674] R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, C1-3 alkyl-aryl, all these groups optionally substituted by halogen.

[0675] In some embodiments, the aryl or the heteroaryl group of the compounds of the present disclosure are preferably selected from the group consisting of phenyl, imidazole, pyridine and triazole, more preferably selected from the group consisting of phenyl, imidazole and pyridine.

[0676] In some embodiments, the compound is of any one of Formulae (Vila), (Vllb), (Vile), (Vlld), (Vile), or (Vllf):

[0677]

[0678] or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein.

[0679] In some embodiments, the compound is of Formula (Vila) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein.

[0680] In some embodiments, the compound is of Formula (Viib) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein.

[0681] In some embodiments, the compound is of Formula (Vile) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein.

[0682] In some embodiments, the compound is of Formula (Vlld) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein. In some embodiments, the compound is of Formula (Vile) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein.

[0683] In some embodiments, the compound is of Formula (Vllf) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein.

[0684]

[0685] In some embodiments, Y is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14.

[0686] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0687] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0688] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C 1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0689] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0690] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0691] R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8;

[0692] R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; C 1-3 alkyl substituted by C(0)NRsR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0693] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0694] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl;

[0695] Y is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14;

[0696] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0697] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0698] C4-7 cycloalkenyl, C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0699] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8. In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0700] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0701] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0702] R3and R7are H;

[0703] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0704] R5is selected from H and C1-7 alkyl;

[0705] R6is H;

[0706] R8is selected from H, C 1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0707] X is selected from a bond and C1-7 alkanediyl;

[0708] Y is aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14; and

[0709] R14is C1-7 alkyl.

[0710] In some embodiments, the aryl, the heteroaryl or the S-heteroaryl group of any of the compounds of the present disclosure are preferably selected from the group consisting of phenyl, imidazole, pyridine and triazole, more preferably selected from the group consisting of phenyl, imidazole and pyridine.

[0711] In some embodiments, Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14.

[0712] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0713] R1is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0714] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C 1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0715] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0716] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0717] R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8;

[0718] R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NRSR"; C1-3 alkyl substituted by C(0)NRsR"; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0719] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;

[0720] X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl;

[0721] Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14;

[0722] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0723] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0724] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0725] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0726] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein: R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0727] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0728] R3and R7are H;

[0729] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0730] R5is selected from H and C1-7 alkyl;

[0731] R6is H;

[0732] R8is selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0733] X is selected from a bond and C1-7 alkanediyl;

[0734] Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14; and

[0735] R14is Ci-7 alkyl.

[0736] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0737] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0738] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0739] R3and R7are H;

[0740] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0741] R5is selected from H, C1-7 alkyl, OR8, and O-C1-7 alkyl;

[0742] R6is H;

[0743] R8is selected from H, C1-7 alkyl, C2-7 alkenyl, and C3-7 cycloalkyl;

[0744] X is selected from a bond, C1-7 alkanediyl, -0-, and -O-C1-7 alkanediyl;

[0745] Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14; and

[0746] R14is Ci-7 alkyl. In some embodiments, the aryl, the heteroaryl or the S-heteroaryl group of any of the compounds of the present disclosure are preferably selected from the group consisting of phenyl, imidazole, pyridine and triazole, more preferably selected from the group consisting of phenyl, imidazole and pyridine.

[0747] In some embodiments, R5, X and Y form a spirane or spiro compound at the -4 position of the piperidine ring.

[0748] In some embodiments, R5, X and Y form a spirane or spiro compound at the -4

[0749] position of the piperidine ring and R5, X and Y form

[0750]

[0751] indicates the -4 position of the piperidine ring, the common atom of the spirane

[0752] In some embodiments, the compound is of any one of Formulae (Villa), (VUIb), (VIIIc), (Vllld), (Vllle), (VUIf), (VHIg), (Vlllh), (Villi), (VUIj), (VUIk), (VIII1):

[0753] or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0754] In some embodiments, the compound is of Formula (Villa) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0755] In some embodiments, the compound is of Formula (VUIb) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0756] In some embodiments, the compound is of Formula (VIIIc) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0757] In some embodiments, the compound is of Formula (VIII d) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0758] In some embodiments, the compound is of Formula (VUIe) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0759] In some embodiments, the compound is of Formula (Vlllf) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0760] In some embodiments, the compound is of Formula (VHIg) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0761] In some embodiments, the compound is of Formula (VHIh) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0762] In some embodiments, the compound is of Formula (Villi) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0763] In some embodiments, the compound is of Formula (VUIj) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0764] In some embodiments, the compound is of Formula (VUIk) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0765] In some embodiments, the compound is of Formula (VIII1) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0766] In some embodiments, the compound is of any one of Formulae (VUIal), (VUIbl), (Vlllcl), (VUIdl), (VUIel), (VUIfl), (VUIgl), (VHIhl), (Vlllil), (VHIjl), (VUIkl), (VIII11):

[0767] ); R1

[0768]

[0769] or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0770] In some embodiments, the compound is of Formula (VUIal) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0771] In some embodiments, the compound is of Formula (VUIbl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0772] In some embodiments, the compound is of Formula (Vlllcl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0773] In some embodiments, the compound is of Formula (VUIdl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0774] In some embodiments, the compound is of Formula (VUIel) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0775] In some embodiments, the compound is of Formula (VUIfl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0776] In some embodiments, the compound is of Formula (VUIgl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0777] In some embodiments, the compound is of Formula (VHIhl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0778] In some embodiments, the compound is of Formula (VHIil) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0779] In some embodiments, the compound is of Formula (VUIj 1) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein. In some embodiments, the compound is of Formula (VUIkl) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2 are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0780] In some embodiments, the compound is of Formula (VIII11) or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein Qi and Q2 are each independently O, S, NR8, or CR8, n8a is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

[0781] In some embodiments, Y is NR10R12, wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0782] In some embodiments, the compound is of any one of Formulae (IXa), (IXb), (IXc), or (IXd):

[0783]

[0784] or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein.

[0785] In some embodiments, the compound is of Formula (IXa) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein.

[0786] In some embodiments, the compound is of Formula (IXb) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein. In some embodiments, the compound is of Formula (IXc) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein.

[0787] In some embodiments, the compound is of Formula (IXd) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein.

[0788] In some embodiments, the compound is of any one of Formulae (IXal), (IXbl), (IXcl), or (IXdl):

[0789]

[0790] or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein, and * indicates the Z-isomer of the spiro compound.

[0791] In some embodiments, the compound is of Formula (IXal) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein, and * indicates the Z-isomer of the spiro compound.

[0792] In some embodiments, the compound is of Formula (IXbl) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein, and * indicates the Z-isomer of the spiro compound.

[0793] In some embodiments, the compound is of Formula (IXcl) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein, and * indicates the Z-isomer of the spiro compound.

[0794] In some embodiments, the compound is of Formula (IXdl) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein, and * indicates the Z-isomer of the spiro compound.

[0795] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0796] R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0797] R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0798] R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0799] R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;

[0800] R5is selected from C1-7 alkyl, OR8, or SR8; wherein C1-7 alkyl, OR8or SR8of R5can form a ring with any part of X;

[0801] R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;

[0802] R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl; X is selected from -O-C1-7 alkanediyl, -S-C1-7 alkanediyl, or C1-7 alkanediyl, and wherein -O-C1-7 alkanediyl, -S-C1-7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5;

[0803] Y is NR10R12, wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;

[0804] R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;

[0805] R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl,

[0806] C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and

[0807] each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

[0808] In some embodiments, the compound is a compound of Formula (I) or Formula (la), wherein:

[0809] R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl;

[0810] R2is selected from H, C(0)R14, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8; C1-5 alkyl- NHCOR13wherein R13is pentylamino-5-oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3- one; or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;

[0811] R3and R7are H;

[0812] R4is selected from C3-7 alkyl, C3-7 cycloalkyl, C1-3 alkyl substituted by aryl or heteroaryl;

[0813] R5is OR8, and OR8of R5can form a ring with any part of X;

[0814] R6is H;

[0815] R8and R11are C1-7 alkyl;

[0816] X is -O-C1-7 alkanediyl and wherein -O-C1-7 alkanediyl of X can form a ring with any part of R5; and

[0817] Y is NR10R12, wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

[0818] Some preferred embodiments of the present application relate to the compounds having one of the following structures or being one of the following compounds, pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:

[0819]

[0820] Some preferred embodiments of the present application relate to the compounds having one of the following structures or being one of the following compounds, pharmaceutically-acceptable salts, hydrates, solvates, or stereoisomers thereof:

[0821]

[0822] Some embodiments of the present application relate to the compounds having one of the following structures or being one of the following compounds, pharmaceutically - acceptable salts, hydrates, solvates, or stereoisomers thereof:

[0823] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds formed by the process of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are

[0824] commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences , 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the application, or separately by reacting the free base or acid function with a suitable acid or base.

[0825] Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other

[0826] pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate,

[0827] camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate,

[0828] ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

[0829] As used herein, the term "pharmaceutically acceptable ester" refers to esters of the compounds formed by the process of the present application which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

[0830] The term "pharmaceutically acceptable prodrugs" as used herein, refers to those prodrugs of the compounds formed by the process of the present application which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like,

[0831] commensurate with a reasonable benefit / risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present application.

[0832] "Prodrug", as used herein, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to afford any compound delineated by the formulae of the instant application. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al, (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8: 1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & Joachim Mayer, "Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology," John Wiley and Sons, Ltd. (2002).

[0833] This application also encompasses pharmaceutical compositions containing, and methods of treating disorders through administering, pharmaceutically acceptable prodrugs of compounds of the application. For example, compounds of the application having free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the application. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes 4-hydroxy proline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma- aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free hydroxy groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem. 1996, 39, 10. Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.

[0834] The application also provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound of the application, or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a

[0835] pharmaceutically acceptable carrier.

[0836] In another aspect, the application provides a method of synthesizing a compound disclosed herein.

[0837] The synthesis of the compounds of the application can be found herein and in the Examples below.

[0838] Other embodiments are a method of making a compound of any of the formulae herein using any one, or combination of, reactions delineated herein. The method can include the use of one or more intermediates or chemical reagents delineated herein.

[0839] Another aspect is an isotopically labeled compound of any of the formulae delineated herein. Such compounds have one or more isotope atoms which may or may not be radioactive (e.g., ¾,2H,14C,13C,18F,35S,32P,125I, and131I) introduced into the compound. Such compounds are useful for drug metabolism studies and diagnostics, as well as therapeutic applications.

[0840] A compound of the application can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the application can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.

[0841] Alternatively, the salt forms of the compounds of the application can be prepared using salts of the starting materials or intermediates.

[0842] The free acid or free base forms of the compounds of the application can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example, a compound of the application in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the application in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0843] The compounds of the present invention may be used in the form of

[0844] pharmaceutically-acceptable salts derived from inorganic or organic acids. By

[0845] "pharmaceutically-acceptable salt" is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically-acceptable salts are well-known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid.

[0846] Representative acid addition salts include, but are not limited to trifluoroacetic acid (TFA), formate, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p- toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides ; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil- soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

[0847] Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically-acceptable basic addition salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

[0848] Prodrugs of the compounds of the application can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al, (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the application with a suitable carbamylating agent (e.g., l,l-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, or the like).

[0849] Protected derivatives of the compounds of the application can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal include, but are not limited to, those illustrated in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.

[0850] Compounds of the present application can be conveniently prepared or formed during the process of the application, as solvates (e.g., hydrates). Hydrates of compounds of the present application can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0851] Acids and bases useful in the methods herein are known in the art. Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions. Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.

[0852] Combinations of substituents and variables envisioned by this application are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). When any variable (e.g., R14) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with one or more R14 moieties, then R14 at each occurrence is selected independently from the definition of R14. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds within a designated atom’s normal valency.

[0853] In addition, some of the compounds of this application have one or more double bonds, or one or more asymmetric centers. Such compounds can occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry or even E or Z isomerism across several bonds and / or rings, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion. All such isomeric forms of such compounds are expressly included in the present application.

[0854] Optical isomers may be prepared from their respective optically active precursors by the procedures described herein, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al. , Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981).

[0855] “Isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed“stereoisomers”.

[0856] Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a“racemic mixture”.

[0857] A carbon atom bonded to four non-identical substituents is termed a“chiral center”. “Chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed“diastereomeric mixture”. When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0858] “Geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds and / or other rigid structures such as a ring or polycyclic system. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond and / or other rigid structures such as a ring or a polycyclic system in the molecule according to the Cahn-Ingold-Prelog rules.

[0859] Furthermore, the structures and other compounds discussed in this application include all atropic isomers thereof. “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques; it has been possible to separate mixtures of two atropic isomers in select cases.

[0860] “Tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.

[0861] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring- chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring- shaped) form as exhibited by glucose. Common tautomeric pairs are: ketone-enol, amide- nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-enamine. The compounds of this application may also be represented in multiple tautomeric forms, in such instances, the application expressly includes all tautomeric forms of the compounds described herein (e.g., alkylation of a ring system may result in alkylation at multiple sites, the application expressly includes all such reaction products).

[0862] In the present application, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present application includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like. In the present specification, the structural formula of the compound represents a certain isomer for convenience in some cases, but the present application includes all isomers, such as geometrical isomers, optical isomers based on an asymmetrical carbon, stereoisomers, tautomers, and the like.

[0863] Compounds of the present invention can exist as stereoisomers wherein asymmetric or chiral centers are present. These compounds are designated by the symbols"R"or"S", depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

[0864] Geometric isomers can also exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic or heterocyclic ring.

[0865] Compounds of the present invention can also exist as racemates which is given the descriptor“rac” The term racemate, as used herein, means an equimolar mixture of a pair of enantiomers. A racemate is usually formed when synthesis results in the generation of a stereocenter. As used herein, the term racemic mixture means racemate. Compounds of the present invention can also exist as diastereomeric meso forms which is given the descriptor “re / ”. The term diastereomeric meso form as used herein means achiral forms with a pseudostereogenic C-atom, which is given the descriptor“r” or“ s respectively.

[0866] Additionally, the compounds of the present application, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0867] “Solvate” means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0868] It should be appreciated that solvates and hydrates of the compound according to formula (I) or formula (la) are also within the scope of the present application. Methods of solvation are generally known in the art.

[0869] A further embodiment of the present invention may also include compounds which are identical to the compounds of formula (I) or formula (la) except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in2H (D),3H,13C,127I, etc. These isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in therapy and / or diagnosis, for example, but not limited to, where a fine-tuning of in vivo half-life time could lead to an optimized dosage regimen.

[0870] The synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. In addition, the solvents, temperatures, reaction durations, etc. delineated herein are for purposes of illustration only and one of ordinary skill in the art will recognize that variation of the reaction conditions can produce the desired bridged macrocyclic products of the present application. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.

[0871] The compounds of this application may be modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0872] The compounds of the application are defined herein by their chemical structures and / or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0873] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. Methods of Synthesizing the Compounds

[0874] The compounds of the invention may be prepared by the exemplary processes described in the following reaction schemes or by the processes described in the examples below. Exemplary reagents and procedures for these reactions appear hereinafter. Starting materials can be purchased or readily prepared by one of ordinary skill in the art.

[0875] Compounds of the present application can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999, incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present application. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt, ester or prodrug thereof. Suitable synthetic routes are depicted in the schemes below.

[0876] Those skilled in the art will recognize if a stereocenter exists in the compounds disclosed herein. Accordingly, the present application includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0877] The compounds of the present application can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present application can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.

[0878] Compounds of the present application can be synthesized by following the steps outlined in General Scheme 1 (Method A), General Scheme 2 (Method Bl and Method B2) and General Scheme 3 (Method C) which comprise different sequences of assembling intermediates. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated.

[0879] General Scheme 1 (Method A)

[0880] Method A: Using I where P is a suitable protecting group such as tBoc or nosyl, I and II are coupled using a dehydrating agent such as DCC or HATU in a suitable solvent such as DMF or NMP. The compounds where R2is H are obtained by deprotection under standard conditions. The compounds where is R2is C(0)R14, C(0)NR15R15or C(0)0R15are obtained by acylation of the secondary amine. The compounds where is R2 not the above are obtained by reductive animation of the secondary amine with the appropriate aldehyde or ketone. General Scheme 2 (Method Bl and B2)

[0881]

[0882] Method Bl: Using the appropriate precursor Ilia and Illb, III is prepared by amide coupling using a dehydrating agent such as DCC or HATU in a suitable solvent such as DMF or NMP.

[0883] Method B2: Z can be elaborated into the desired functional group using reaction sequences described in Table X. In cases where compound of the invention has R2= H, the starting material of Method B will have P as a protecting group, such as t-Boc or Nosyl. The compounds of the invention are then obtained by deprotection under standard conditions.

[0884] The compounds where is R2is C(0)R14, C(0)NR15R15or C(0)0R15are obtained by acylation of the secondary amine at this point. The compounds where is R2is not the above are obtained by reductive amination of the secondary amine with the appropriate aldehyde or ketone.

[0885] General Scheme 3 (Method C)

[0886]

[0887] Method C: I may be prepared following the sequence described in Method C. Using the appropriate la bearing a protecting group P and lb bearing a short alkyl group R, the coupling is performed by using a dehydrating agent such as DCC or HATU in a suitable solvent such as DMF or NMP. The resulting dipeptide ester is reacted with Ic. When P2 is Br, Ic is reacted in a suitable solvent such as DMF or DMSO in the presence of a base such as potassium carbonate or cesium carbonate to yield a short-chain ester derivative of f When P2 is a protected alcohol such as OTHP or OTBDMS, the short chain ester of I is obtained by first reacting Ic with the dipeptide ester in a suitable solvent such as DMF or DMSO in the presence of a base such as potassium carbonate or cesium carbonate, followed by alcohol deprotection, followed by alcohol activation and coupling using methods like the Mitsunobu reaction or the formation of a mesylate and base-catalyzed cyclization. I is finally obtained by hydrolysis using a base such as sodium hydroxide or potassium carbonate, in a suitable solvent such as water or a water-THF mixture.

[0888] Pharmaceutical Compositions

[0889] In a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (la) according to the invention and a pharmaceutically acceptable diluent, excipient or carrier.

[0890] In one embodiment the pharmaceutical composition further comprises another pharmaceutical active agent.

[0891] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (la) according to the invention and a pharmaceutically acceptable diluent, excipient or carrier, wherein said compound of formula (I) or formula (la) is present in a therapeutically effective amount.

[0892] The expression“effective amount” or“therapeutically effective amount” as used herein refers to an amount capable of invoking one or more of the following effects in a subject receiving the combination of the present invention: (i) inhibition or arrest of tumor growth, including, reducing the rate of tumor growth or causing complete growth arrest; (ii) reduction in the number of tumor cells; (iii) reduction in tumor size; (iv) reduction in tumor number; (v) inhibition of metastasis (i.e., reduction, slowing down or complete stopping) of tumor cell infiltration into peripheral organs; (vi) enhancement of antitumor immune response, which may, but does not have to, result in the regression or elimination of the tumor; (vii) relief, to some extent, of one or more symptoms associated with cancer; (viii) increase in progression-free survival (PFS) and / or; overall survival (OS) of the subject receiving the combination.

[0893] The compounds of the present invention may, in accordance with the invention, be administered in single or divided doses by oral, parenteral, inhalatory, rectal or topical administration including cutaneous, ophthalmic, mucosal scalp, sublingual, buccal and intranasal routes of administration; further, the compounds provided by the invention may be formulated to be used for the treatment of leukocyte populations in vivo, ex vivo and in vitro.

[0894] When the compounds of the present invention are to be administered e.g. by the oral route, they may be administered as medicaments in the form of pharmaceutical compositions which contain them in association with a pharmaceutically acceptable diluent, excipient or carrier material. Thus the present invention also provides a pharmaceutical composition comprising the compounds according to the invention as described supra and one or more pharmaceutically acceptable diluent, excipient or carrier. The pharmaceutical compositions can be prepared in a conventional manner and finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules, and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like. Pharmaceutically acceptable diluent, excipient or carrier include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art.

[0895] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or formula (la) according to the invention and at least one pharmaceutically acceptable diluent, excipient or carrier, wherein the composition is a tablet or a capsule, preferably a tablet. The amount of the compounds of the invention to be administered will vary depending upon factors such as the particular compound, disease condition and its severity, according to the particular circumstances surrounding the case, including, e.g., the specific compound being administered, the route of administration, the condition being treated, the target area being treated, and the subject or host being treated

[0896] In another aspect, the application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present application or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0897] Compounds of the application can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, or topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present application in free form or in a pharmaceutically acceptable salt form in association with at least one

[0898] pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and / or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth,

[0899] methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and / or buffers. In addition, they may also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present application with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[0900] The pharmaceutical compositions of the present application comprise a

[0901] therapeutically effective amount of a compound of the present application formulated together with one or more pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylenepolyoxy propylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water, isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0902] The pharmaceutical compositions of this application can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally,

[0903] intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol,

[0904] tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0905] Injectable preparations, for example, sterile injectable aqueous, or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0906] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0907] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this application with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0908] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0909] Dosage forms for topical or transdermal administration of a compound of this application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this application.

[0910] The ointments, pastes, creams and gels may contain, in addition to an active compound of this application, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0911] Powders and sprays can contain, in addition to the compounds of this application, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0912] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0913] Compounds and compositions of the application can be administered in

[0914] therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., an anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory agent. Where the compounds of the application are administered in conjunction with other therapies, dosages of the co-administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth. Compounds and compositions of the application can be administered in therapeutically effective amounts in a combinational therapy with one or more therapeutic agents (pharmaceutical combinations) or modalities, e.g., anti-proliferative, anti-cancer, immunomodulatory or anti-inflammatory agent, and / or non-drug therapies, etc. For example, synergistic effects can occur with anti -proliferative, anti-cancer, immunomodulatory or anti-inflammatory substances. Where the compounds of the application are administered in conjunction with other therapies, dosages of the co administered compounds will of course vary depending on the type of co-drug employed, on the specific drug employed, on the condition being treated and so forth.

[0915] Combination therapy includes the administration of the subject compounds in further combination with one or more other biologically active ingredients. For instance, the compounds of the application can be used in combination with other pharmaceutically active compounds, preferably compounds that are able to enhance the effect of the compounds of the application. The compounds of the application can be administered simultaneously (as a single preparation or separate preparation), in temporal proximity, or sequentially to the other drug therapy or treatment modality. In general, a combination therapy envisions

[0916] administration of two or more drugs during a single cycle or course of therapy.

[0917] In another aspect of the application, the compounds may be administered in combination with one or more separate pharmaceutical agents, e.g., a chemotherapeutic agent, an immunotherapeutic agent, or an adjunctive therapeutic agent.

[0918] Methods of Treatment

[0919] The compounds according to the invention as described supra have preventive and therapeutic utility in human and veterinary diseases.

[0920] Thus, in a further aspect the present invention provides the use of the compounds as described herein and the use of the pharmaceutical composition described herein for preventive and / or therapeutic purposes.

[0921] In one embodiment of the present invention, the compounds according to the invention as described herein or the pharmaceutical composition as described herein may be used as a medicament, preferably for use in human medicine and / or veterinarian medicine. Accordingly the present invention provides the compounds according to the invention as described herein or a pharmaceutical composition as described herein, for use as a medicament.

[0922] In another embodiment, the compounds according to the invention as described herein or the pharmaceutical composition as described herein may be used in a method for preventing or treating cancer in a subject.

[0923] Also provided is the use of the compounds according to the invention as described herein or the pharmaceutical composition as described herein for the manufacture of a medicament for the prevention or treatment of cancer in a subject.

[0924] Also provided is the use of the compounds according to the invention as described herein or the pharmaceutical composition as described herein for the prevention or treatment of cancer in a subject.

[0925] Also provided is a method for the prevention or treatment of cancer in a subject, comprising administering to said subject a therapeutically effective amount of the compounds according to the invention as described herein or the pharmaceutical composition as described herein.

[0926] The terms“treatment’’ / ’’treating” as used herein includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in an animal, particularly a mammal and especially a human, that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (3) relieving the condition (i.e. causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

[0927] Preventive treatments comprise prophylactic treatments. In preventive applications, the pharmaceutical combination of the invention is administered to a subject suspected of having, or at risk for developing cancer. In therapeutic applications, the pharmaceutical combination is administered to a subject such as a patient already suffering from cancer, in an amount sufficient to cure or at least partially arrest the symptoms of the disease. Amounts effective for this use will depend on the severity and course of the disease, previous therapy, the subject's health status and response to the drugs, and the judgment of the treating physician.

[0928] In the case wherein the subject's condition does not improve, the pharmaceutical combination of the invention may be administered chronically, which is, for an extended period of time, including throughout the duration of the subject's life in order to ameliorate or otherwise control or limit the symptoms of the subject's disease or condition.

[0929] In the case wherein the subject's status does improve, the pharmaceutical combination may be administered continuously; alternatively, the dose of drugs being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”). Once improvement of the patient's condition has occurred, a maintenance dose of the pharmaceutical combination of the invention is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at which the improved disease is retained.

[0930] When provided preventively, the compound(s) are provided in advance of established disease. The preventive administration of a compound of the present invention serves to prevent or attenuate the evolution of disease. The therapeutic administration of a compound of the present invention serves to attenuate established disease. Thus, in accordance with the invention, a compound of the present invention can be administered either prior to the onset of disease or during the course of disease.

[0931] In one embodiment of the invention, there is provided the compounds according to the invention as described supra or the pharmaceutical composition as described supra, for use in a method for the prevention or treatment of cancer in a subject. Preferably the cancer is selected from the group consisting of head cancer and neck cancer. P300

[0932] Dysregulation of the cellular transcription machinery is a fundamental feature of cancer. El A binding protein (p300) and CREB binding protein (CBP) are two closely related paralog transcriptional co-activators involved in the expression of oncogenic drivers in cancer cells (Attar and Kurdistani in Cold Spring Harbor Perspectives in Medicine 7:a026534 (2017)).

[0933] P300 / CBP interact through their conserved domains with hundreds of proteins; can act synergistically or antagonistically; and modulate downstream biological processes in a highly context-dependent manner to promote either apoptosis or cell proliferation (Bedford and co-workers in Epigenetics 5(1): 9 (2010); Goodman and Smolik in Genes & Development 14(13): 1553 (2000); Dancy and Cole in Chemical Reviews 115(6):2419 (2015)). These domains include the nuclear receptor interaction domain (RID), the cysteine / histidine regions CH1 (TAZ1) and CH3 (TAZ2), the CREB and MYB interaction domain (KIX), Bromodomain, the plant homeodomain (PHD), the histone acetyltransferase and / or lysine acetyltransferase domain (KAT / HAT), the ZZ type zinc finger domain (ZZ), and the interferon response binding domain (IBiD (NCBD)).

[0934] The following examples (from Dancy and Cole in Chemical Reviews 115(6):2419 (2015)) demonstrate the context-dependency of gene expression regulation by p300 / CBP. For instance, Hottiger and co-workers (in EMBO Journal 17, 3124 (1998)) showed that HIV gene expression could be upregulated by tumor-necrosis factor alpha through binding of the RelA subunit of NFKB to p300 / CBP-CHl but was repressed through interferon-alpha-mediated binding of STAT2 to the same motif. In other studies, p300 / CBP mediated both induction and repression of antioxidant response genes, via AP-l binding to the C-terminal region, respectively by p53-binding to CH1 / CH3 and glucocorticoid receptor-binding to the NRID domain (Avantaggiati and co-workers in Cell 89: 1175 (1997); Kamei and co-workers in Cell 85:403 (1996)). P53 binding to p300 / CBP / CH3 and consequent induction of p53-dependent genes results in cell cycle arrest (e.g., as a consequence of genotoxic insults), but apoptosis is induced when overexpressed E2F-1 (a central protein in cell cycle regulation that can act through p53 as well) is bound to p300 / CBP / CH3 (Goodman and Smolik in Genes &

[0935] Development 14:1553 (2000); Lee and co-workers in Oncogene 16:2695 (1998)). Cyclic- AMP response is both induced and repressed by p300 / CBP via CREB binding to the KIX domain, respectively S6 kinase pp90RSK binding to the CH3 domain (Nakajima and co workers in Cell 86:465 (1996)).

[0936] Modulation of cancer-relevant pathways by p300 / CBP include hormone-dependent androgen receptor signaling in prostate cancer (Culig in Journal of Cell Physiology

[0937] 231(2): 270 (2016)); the HIF-l alpha / VEGF pathway in hypoxia-dependent tumor growth (Masoud and Li in Acta Pharmacologica Sinica B 5(5):378 (2015)); and the interaction with tumor suppressor p53 and HPV-E6 oncoprotein in HPV-positive carcinomas (Tomesello and co-workers in Cancers (Basel) 10(7)rϋ:E213 (2018)).

[0938] P300 and CBP also play an important role in hematopoiesis and control processes whose disruption can lead to the development of leukemias and lymphomas (Blobel in Blood 95(3):745 (2000); Dutta and co-workers in Molecular Genetics and Metabolism 1 l9(l-2):37 (2016)). Taken together, these studies highlight how indispensable p300 / CBP is to many cellular signaling pathways and how p300 and CBP utilize their protein-protein interactions to determine how the cell responds to environmental stimuli. This makes CBP / p300 an ideal target for the development of novel cancer therapies (Di Martile and co-workers in

[0939] Oncotarget 7(34):55789 (2016); Ali and co-workers in Chemical Reviews 118(3): 1216 (2018)).

[0940] Exploitation of CBP / p300 protein-protein interactions for drug discovery has nonetheless proven difficult because of the inherent highly disordered nature of the protein structure (Wright and Dyson in Nature Reviews in Molecular and Cell Biology 16(1): 18-29 (2015)). Yet specific inhibitors have been developed against highly conserved, more ordered domains such as the HAT / KAT catalytic site, KIX and bromodomain (Breen and Mapp in Current Opinion in Chemical Biology 45: 195-203 (2018); Dancy and Cole in Chemical Reviews H5(6):24l 9-2452 (2015)).

[0941] Without being bound by any particular theory, an extremely well-conserved p300 / CBP domain that can be a suitable drug target is the transcriptional adaptor and zinc finger 1 CH1 / TAZ1 domain, as highlighted by several publications showing e.g. that the interaction between p300 / CBP-CHl / TAZl and HIFl-alpha as well as the interaction between HPV-E6 / E7 and p300 / CBP-CHl / TAZl in HPV-positive Cervical and Head-and-Neck cancer can potentially be exploited for the development of anti cancer therapies (Wuchano Yuan and Giordano in Oncogene 21 :2253-2260(2002); Breen and Mapp in Current Opinion in

[0942] Chemical Biology 45: 195-203 (2018); Lao and co-workers in PNAS l l l(2l):753 l (2014); Kushal and co-workers in PNAS 110(39): 15602 (2013); Masoud and Li in Acta

[0943] Pharmacologica Sinica B 5(5):378 (2015); Burslem and co-workers in Chemical Science 8(6):4l 88 (2017); Fera and co-workers in Biochemistry 51 (47):9524 (2012); Xie and co- workers in Oncogene 33(8): 1037 (2014); Patel and co-workers in The EMBO Journal 18(18):5061 (1999); Bemat and co-workers in Oncogene 22(39):787l (2003)).

[0944] In summary, reprogramming the transcriptional profile of cancer cells by modulation of p300 / CBP activity - for example by targeting the CH1 / TAZ1 domain - represents a novel and broadly applicable approach for the treatment of cancer.

[0945] Without being bound by any particular theory, compounds of the disclosure can inhibit or modify the activity of p300 by inhibiting or modifying the activity of any p300 domain. For example, compounds of the disclosure can inhibit or modify the activity of the CH1 / TAZ1, CH2 / TAZ2, RID, KIX, KAT / HAT, PHD, Bromodomain, ZZ or IBiD domains. Compounds of the disclosure can inhibit or modify the interaction of p300 with any one of its protein interaction partners, or combination of protein interaction partners, through the CH1 / TAZ1, CH2 / TAZ2, RID, KIX, IBiD or any other p300 protein-protein interaction domain. A non-limiting list of p300 interaction partners whose interaction with p300 can be affected by compounds of the disclosure includes transcription coactivator BCL3 (BCL3), beta-catenin, breast cancer 1, early onset (BRCA1), caudal type homeobox 2 (CDX2), CCAAT enhancer binding protein beta (CEBPB) and CCAAT enhancer binding protein epsilon (CEBPE), Cbp / p300 interacting transactivator with Glu / Asp rich carboxy -terminal domain 1 (CITED1), Cbp / p300 interacting transactivator with Glu / Asp rich carboxy -terminal domain 2 (CITED2), DEAD-box helicase 5 (DDX5), deltex E3 ubiquitin ligase 1 (DTX1), EP300 interacting inhibitor of differentiation 1 (EID1), ELK1, ETS transcription factor

[0946] (ELK1), estrogen receptor 1 (ESR1), flap structure-specific endonuclease 1 (FEN1), G protein pathway suppressor 2 (GPS2), hypoxia inducible factor 1 subunit alpha (HIF1A), HNF1 homeobox A (HNF1A), heterogeneous nuclear ribonucleoprotein U (HNRPU), inhibitor of growth family member 4 (ING4), inhibitor of growth family member 5 (ING5), interferon regulatory factor 2 (IRF2), lymphoid enhancer binding factor 1 (LEF1), MAF bZIP transcription factor (MAF), mastermind like transcriptional coactivator 1 (MAML1), myocyte enhancer factor 2C (MEF2C), myocyte enhancer factor 2D (MEF2D), MYB proto oncogene like 2 (MYBL2), MDM2 proto-oncogene (Mdm2), myogenic differentiation 1 (MyoD), myocyte enhancer factor 2A (MEF2A), nuclear receptor coactivator 6 (NCOA6), nuclear factor of activated T cells 2 (NFATC2), neuronal PAS domain protein 2 (NPAS2), tumor protein p53 (P53), paired box 6 (PAX6), proliferating cell nuclear antigen (PCNA), prospero homeobox 1 (PROX1), prothymosin alpha (PTMA), peroxisome proliferator activated receptor alpha (PPARA), peroxisome proliferator activated receptor gamma (PPARG), RAR related orphan receptor A (RORA), RELA proto-oncogene, NF-kB subunit (RELA), SMAD family member 1 (SMAD1), SMAD family member 2 (SMAD2), MAD family member 7 (SMAD7), Smad nuclear interacting protein 1 (SNIP1), SS 18, nBAF chromatin remodeling complex subunit (SS 18), signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 6 (STAT6), TAL bHLH transcription factor 1, erythroid differentiation factor (TAL1), transcription factor 3 (TCF3), transcription factor AP-2 alpha (TFAP2A), trimethylguanosine synthase 1 (TGS1), transcriptional regulating factor 1 (TRERF1), tumor susceptibility 101 (TSG101), twist family bHLH transcription factor 1 (TWIST1), YY1 transcription factor (YY1) and early growth response 1 (Zif-268). Without wishing to be bound by any particular theory, inhibiting or modifying the ability of p300 to interact with protein-protein interaction partners can inhibit or modify the ability of p300 or protein complexes comprising p300 to bind to DNA. For example, a compound of the disclosure can prevent p300 or a protein complex comprising p300 from binding to a target promoter, thereby preventing transcription of a target gene. A compound of the disclosure can prevent p300 or protein complexes comprising p300 from binding to a subset of all p300 target promoters, thereby altering the transcriptional profile of a cell, for example a cancer cell. Alternatively, or in addition, a compound of the disclosure can inhibit or modify the ability of p300 or a p300 protein complex to recruit one or more additional transcription factors, for example, transcription co-activators, to a promoter. Without limiting the possible pathways affected, a compound of the disclosure can alter the expression of genes involved in cell cycle progression, Wnt, Notch and Hedgehog signaling, DNA damage response, apoptosis, antioxidant response, Cyclic-AMP response, hormone-dependent androgen receptor signaling, hypoxia-dependent tumor growth, hematopoiesis or a combination thereof, thereby reducing the proliferation of or otherwise reducing the viability of cancer cells. For example, compounds of the disclosure can inhibit p300 interaction with CBP-HPVE6-p53, thereby rescuing p53 protein expression and acetylation and restoring the DNA damage response pathway in cervical cancer cells. Alternatively, or in addition, compounds of the disclosure can inhibit the formation of the p300 / CBP-HIFlalpha protein complex, and reducing the transcription of growth factors and pro-proliferation genes such as vascular endothelial growth factor A (VEGF) in cancer cells. Alternatively, or in addition, compounds of the disclosure can disrupt p300-CHl / TAZl androgen receptor (AR) in castration resistant prostate cancers inhibiting the expression of AR target genes.

[0947] Without wishing to be bound by any particular theory, compounds of the disclosure can inhibit the activity of p300 in its regulation of oncogenic transcription factors that contribute to cancer progression.

[0948] Without wishing to be bound by any particular theory, compounds of the disclosure can act by inhibiting or modifying the acetyltransferase activity of the KAT / HAT domain.

[0949] An exemplary human p300 protein sequence can be found in NCBI NP_00l420.2, the contents of which are hereby incorporated by reference in their entirety. An exemplary human p300 protein comprises a sequence of:

[0950] 1 maenvvepgp psakrpklss palsasasdg tdfgslfdle hdlpdelins telgltnggd

[0951] 61 inqlqtslgm vqdaas khkq lsellrsgss pnlnmgvggp gqvmasqaqq s spglglins

[0952] 121 mvkspmtqag ltspnmgmgt sgpnqgptqs tgirannspvnq pamgmntgmn agmnpgmlaa

[0953] 181 gngqgimpnq wingsigagr grqnmqypnp gmgsagnllt eplqqgspqm ggqtgirgpq 241 plkmgmmnnp npygspytqn pgqqigasgl glqiqtktvl snnlspfamd kkavpgggmp

[0954] 301 nmgqqpapqv qqpglvtpva qgmgsgahta dpekrkliqq qlvlllhahk cqrreqange

[0955] 361 vrqcnlphcr tmknvlnhmt hcqsgkscqv ahcassrqii shwknctrhd cpvclplkna

[0956] 421 gdkrnqqpil tgapvglgnp sslgvgqqsa pnlstvsqid pssierayaa lglpyqvnqm

[0957] 481 ptqpqvqakn qqnqqpgqsp qgmrpmsnms aspmgvnggv gvqtpsllsd smlhsainsq

[0958] 541 npmmsenasv pslgpmptaa qpsttgirkq wheditqdlr nhlvhklvqa i fptpdpaal

[0959] 601 kdrrmenlva yarkvegdmy esannraeyy hllaekiyki qkeleekrrt rlqkqnmlpn

[0960] 661 aagmvpvsmn pgpnmgqpqp gmtsngplpd psmirgsvpn qmmpritpqs glnqfgqmsm

[0961] 721 aqppivprqt pplqhhgqla qpgalnppmg ygprmqqpsn qgqfipqtqf psqgmnvtni

[0962] 781 plaps sgqap vsqaqmssss cpvnspimpp gsqgshihcp qlpqpalhqn spspvpsrtp

[0963] 841 tphhtppsig aqqppattip apvptppamp pgpqsqalhp pprqtptppt tqlpqqvqps

[0964] 901 lpaapsadqp qqqprsqqst aasvptptap llppqpatpl sqpavsiegq vsnppstsst

[0965] 961 evnsqaiaek qpsqevkmea kmevdqpepa dtqpedises kvedckmest eteerstelk

[0966] 1021 teikeeedqp stsatqsspa pgqs kkki fk peelrqalmp tlealyrqdp eslpfrqpvd

[0967] 1081 pqllgipdyf divkspmdls tikrkldtgq yqepwqyvdd iwlmfnnawl ynrkts rvyk

[0968] 1141 ycsklsevfe qeidpvmqsl gyccgrklef spqtlccygk qlctiprdat yysyqnryhf

[0969] 1201 cekcfneiqg esvslgddps qpqttinkeq fskrkndtld pel fvectec grkmhqicvl

[0970] 1261 hheiiwpagf vcdgclkksa rtrkenkfsa krlpstrlgt flenrvndf1 rrqnhpesge

[0971] 1321 vtvrvvhasd ktvevkpgmk arfvdsgema es fpyrtkal fafeeidgvd lcffgmhvqe

[0972] 1381 ygsdcpppnq rrvyisylds vhffrpkclr tavyheilig yleyvkklgy ttghiwacpp

[0973] 1441 segddyifhc hppdqkipkp krlqewykkm ldkavseriv hdykdifkqa tedrltsake

[0974] 1501 lpyfegdfwp nvleesikel eqeeeerkre entsnestdv tkgds knakk knnkktsknk

[0975] 1561 sslsrgnkkk pgmpnvsndl sqklyatmek hkevffvirl iagpaanslp pivdpdplip

[0976] 1621 cdlmdgrdaf ltlardkhle fsslrraqws tmcmlvelht qsqdrfvytc neckhhvetr

[0977] 1681 whctvcedyd lcitcyntkn hdhkmeklgl glddesnnqq aaatqspgds rrlsiqrciq

[0978] 1741 slvhacqcrn ancslpscqk mkrvvqhtkg ckrktnggcp ickqlialcc yhakhcqenk

[0979] 1801 cpvpfclnik qklrqqqlqh rlqqaqmlrr rmasmqrtgv vgqqqglpsp tpatpttptg

[0980] 1861 qqpttpqtpq ptsqpqptpp nsmppylprt qaagpvsqgk aagqvtpptp pqtaqpplpg

[0981] 1921 pppaavemam qiqraaetqr qmahvqifqr piqhqmppmt pmapmgmnpp pmtrgpsghl

[0982] 1981 epgmgptgmq qqppwsqggl pqpqqlqsgm prpammsvaq hgqplnmapq pglgqvgisp

[0983] 2041 lkpgtvsqqa lqnllrtlrs ps splqqqqv lsilhanpql laafikqraa kyansnpqpi

[0984] 2101 pgqpgmpqgq pglqpptmpg qqgvhsnpam qnmnpmqagv qraglpqqqp qqqlqppmgg

[0985] 2161 mspqaqqmnm nhntmpsqfr dilrrqq mq qqqqqgagpg igpgmanhnq fqqpqgvgyp

[0986] 2221 pqqqqrmqhh mqqmqqgnmg qigqlpqalg aeagaslqay qqrllqqqmgspvqpnpmsp

[0987] 2281 qqhmlpnqaq sphlqgqqip nslsnqvrsp qpvpsprpqs qpphs spspr mqpqpsphhv

[0988] 2341 spqts sphpg lvaaqanpme qghfaspdqn smlsqlasnp gmanlhgasa tdlglstdns

[0989] 2401 dlnsnlsqst ldih (SEQ D NO: 1) .

[0990] In some embodiments, a p300 protein comprises a protein having at least 85% identity to SEQ ID NO: 1, at least 90% identity to SEQ ID NO: 1, at least 95% identity to SEQ ID NO: 1, at least 96% identity to SEQ ID NO: 1, at least 97% identity to SEQ ID NO: 1, at least 98% identity to SEQ ID NO: 1, at least 99% identity to SEQ ID NO: 1 or at least 99.8% identity to SEQ ID NO: 1. In some embodiments, a p300 protein is identical to a protein of SEQ ID NO: 1.

[0991] The CH1 / TAZ domain corresponds approximately to amino acids 347-414 of SEQ ID NO: 1. The KIX domain corresponds approximately to amino acids 566-646 of SEQ ID NO: 1. The bromodomain corresponds approximately to amino acids 1051-1158 of SEQ ID NO: 1. The PHD domain corresponds approximately to amino acids 1243-1277 of SEQ ID NO: 1. The HAT / KAT domain corresponds approximately to amino acids 1306-1612 of SEQ ID NO: 1. The ZZ domain ccorresponds approximately to amino acids 1668-1708 of SEQ ID NO: 1. The TAZ2 domain ccorresponds approximately to amino acids 1729-1807 of SEQ ID NO: 1.

[0992] As used herein in the context of polypeptides, nucleic acids, and chemical compounds, the term "corresponding to", designates the position / identity of a structural element, e.g., of an amino acid residue, a nucleotide residue, or a chemical moiety, in a compound or composition through comparison with an appropriate reference compound or composition. For example, in some embodiments, a monomeric residue in a polymer (e.g., an amino acid residue in a polypeptide or a nucleic acid residue in a polynucleotide) may be identified as "corresponding to" a residue in an appropriate reference polymer. For example, those of ordinary skill will appreciate that, for purposes of simplicity, residues in a polypeptide are often designated using a canonical numbering system based on a reference related polypeptide, so that an amino acid "corresponding to" a residue at position 190, for example, need not actually be the l90th amino acid in a particular amino acid chain but rather corresponds to the residue found at position 190 in the reference polypeptide; those of ordinary skill in the art readily appreciate how to identify "corresponding" amino acids (see. e.g., Benson et al. Nucl. Acids Res. (1 January 2013) 41 (Dl): D36-D42; Pearson et al.

[0993] PNAS Vol.85, pp. 2444-2448, April 1988). Those skilled in the art will be aware of various sequence alignment strategies, including software programs such as, for example, BLAST, CS-BLAST, CUSASW++, DIAMOND, FASTA, GGSEARCH / GLSEARCH, Genoogle, HMMER, HHpred / HHs earch, IDF, Infernal, KLAST, USEARCH, parasail, PSI-BLAST, PSI-Search, ScalaBLAST, Sequilab, SAM, S SEARCH, SWAPHI, SWAPHI-LS, SWIMM, or SWIPE that can be utilized, for example, to identify "corresponding" residues in polypeptides and / or nucleic acids in accordance with the present disclosure.

[0994] As used herein the term "domain" refers to a section or portion of a polypeptide. In some embodiments, a "domain" is associated with a particular structural and / or functional feature of the polypeptide so that, when the domain is physically separated from the rest of its parent polypeptide, it substantially or entirely retains the particular structural and / or functional feature. In some embodiments, a domain may include a portion of a polypeptide that, when separated from that (parent) polypeptide and linked with a different (recipient) polypeptide, substantially retains and / or imparts on the recipient polypeptide one or more structural and / or functional features that characterized it in the parent polypeptide. In some embodiments, a domain is a section of a polypeptide. In some such embodiments, a domain is characterized by a particular structural element (e.g., a particular amino acid sequence or sequence motif, oc-helix character, b-sheet character, coiled-coil character, random coil character), and / or by a particular functional feature (e.g., binding activity, enzymatic activity, folding activity, signaling activity). One of ordinary skill will appreciate that domain boundaries are typically determined experimentally or via sequence alignment, and may be approximate. In some embodiments, domain boundaries may vary by at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 10, at least 15 or at least 20 amino acids without affecting the in vivo function of the domain.

[0995] An exemplary nucleic acid sequence encoding a p300 protein comprises a sequence of:

[0996] 1 gagaaggagg aggacagcgc cgaggaggaa gaggttgatg gcggcggcgg agctccgaga

[0997] 61 gacctcggct gggcaggggc cggccgtggc gggccgggga ctgcgcctct agagccgcga

[0998] 121 gttctcggga attcgccgca gcggacgcgc tcggcgaatt tgtgctcttg tgccctcctc

[0999] 181 cgggcttggg cccaggcccg gcccctcgca cttgccctta ccttttctat cgagtccgca

[1000] 241 tccctctcca gccactgcga cccggcgaag agaaaaagga acttccccca ccccctcggg

[1001] 301 tgccgtcgga gccccccagc ccacccctgg gtgcggcgcg gggaccccgg gccgaagaag

[1002] 361 agatttcctg aggattctgg ttttcctcgc ttgtatctcc gaaagaatta aaaatggccg

[1003] 421 agaatgtggt ggaaccgggg ccgccttcag ccaagcggcc taaactctca tctccggccc

[1004] 481 tctcggcgtc cgccagcgat ggcacagatt ttggctctct atttgacttg gagcacgact

[1005] 541 taccagatga attaatcaac tctacagaat tgggactaac caatggtggt gatattaatc

[1006] 601 agcttcagac aagtcttggc atggtacaag atgcagcttc taaacataaa cagctgtcag

[1007] 661 aattgctgcg atctggtagt tcccctaacc tcaatatggg agttggtggc ccaggtcaag

[1008] 721 tcatggccag ccaggcccaa cagagcagtc ctggattagg tttgataaat agcatggtca

[1009] 781 aaagcccaat gacacaggca ggcttgactt ctcccaacat ggggatgggc actagtggac

[1010] 841 caaatcaggg tcctacgcag tcaacaggta tgatgaacag tccagtaaat cagcctgcca

[1011] 901 tgggaatgaa cacagggatg aatgcgggca tgaatcctgg aatgttggct gcaggcaatg

[1012] 961 gacaagggat aatgcctaat caagtcatga acggttcaat tggagcaggc cgagggcgac

[1013] 1021 agaatatgca gtacccaaac ccaggcatgg gaagtgctgg caacttactg actgagcctc

[1014] 1081 ttcagcaggg ctctccccag atgggaggac aaacaggatt gagaggcccc cagcctctta

[1015] 1141 agatgggaat gatgaacaac cccaatcctt atggttcacc atatactcag aatcctggac

[1016] 1201 agcagattgg agccagtggc cttggtctcc agattcagac aaaaactgta ctatcaaata

[1017] 1261 acttatctcc atttgctatg gacaaaaagg cagttcctgg tggaggaatg cccaacatgg

[1018] 1321 gtcaacagcc agccccgcag gtccagcagc caggcctggt gactccagtt gcccaaggga

[1019] 1381 tgggttctgg agcacataca gctgatccag agaagcgcaa gctcatccag cagcagcttg

[1020] 1441 ttctcctttt gcatgctcac aagtgccagc gccgggaaca ggccaatggg gaagtgaggc

[1021] 1501 agtgcaacct tccccactgt cgcacaatga agaatgtcct aaaccacatg acacactgcc

[1022] 1561 agtcaggcaa gtcttgccaa gtggcacact gtgcatcttc tcgacaaatc atttcacact

[1023] 1621 ggaagaattg tacaagacat gattgtcctg tgtgtctccc cctcaaaaat gctggtgata

[1024] 1681 agagaaatca acagccaatt ttgactggag cacccgttgg acttggaaat cctagctctc

[1025] 1741 taggggtggg tcaacagtct gcccccaacc taagcactgt tagtcagatt gatcccagct

[1026] 1801 ccatagaaag agcctatgca gctcttggac taccctatca agtaaatcag atgccgacac

[1027] 1861 aaccccaggt gcaagcaaag aaccagcaga atcagcagcc tgggcagtct ccccaaggca

[1028] 1921 tgcggcccat gagcaacatg agtgctagtc ctatgggagt aaatggaggt gtaggagttc

[1029] 1981 aaacgccgag tcttctttct gactcaatgt tgcattcagc cataaattct caaaacccaa

[1030] 2041 tgatgagtga aaatgccagt gtgccctccc tgggtcctat gccaacagca gctcaaccat

[1031] 2101 ccactactgg aattcggaaa cagtggcacg aagatattac tcaggatctt cgaaatcatc

[1032] 2161 ttgttcacaa actcgtccaa gccatatttc ctacgccgga tcctgctgct ttaaaagaca

[1033] 2221 gacggatgga aaacctagtt gcatatgctc ggaaagttga aggggacatg tatgaatctg

[1034] 2281 caaacaatcg agcggaatac taccaccttc tagctgagaa aatctataag atccagaaag

[1035] 2341 aactagaaga aaaacgaagg accagactac agaagcagaa catgctacca aatgctgcag

[1036] 2401 gcatggttcc agtttccatg aatccagggc ctaacatggg acagccgcaa ccaggaatga

[1037] 2461 cttctaatgg ccctctacct gacccaagta tgatccgtgg cagtgtgcca aaccagatga

[1038] 2521 tgcctcgaat aactccacaa tctggtttga atcaatttgg ccagatgagc atggcccagc

[1039] 2581 cccctattgt accccggcaa acccctcctc ttcagcacca tggacagttg gctcaacctg

[1040] 2641 gagctctcaa cccgcctatg ggctatgggc ctcgtatgca acagccttcc aaccagggcc

[1041] 2701 agttccttcc tcagactcag ttcccatcac agggaatgaa tgtaacaaat atccctttgg 2761 ctccgtccag cggtcaagct ccagtgtctc aagcacaaat gtctagttct tcctgcccgg

[1042] 2821 tgaactctcc tataatgcct ccagggtctc aggggagcca cattcactgt ccccagcttc

[1043] 2881 ctcaaccagc tcttcatcag aattcaccct cgcctgtacc tagtcgtacc cccacccctc

[1044] 2941 accatactcc cccaagcata ggggctcagc agccaccagc aacaacaatt ccagcccctg

[1045] 3001 ttcctacacc tcctgccatg ccacctgggc cacagtccca ggctctacat ccccctccaa

[1046] 3061 ggcagacacc tacaccacca acaacacaac ttccccaaca agtgcagcct tcacttcctg

[1047] 3121 ctgcaccttc tgctgaccag ccccagcagc agcctcgctc acagcagagc acagcagcgt

[1048] 3181 ctgttcctac cccaacagca ccgctgcttc ctccgcagcc tgcaactcca ctttcccagc

[1049] 3241 cagctgtaag cattgaagga caggtatcaa atcctccatc tactagtagc acagaagtga

[1050] 3301 attctcaggc cattgctgag aagcagcctt cccaggaagt gaagatggag gccaaaatgg

[1051] 3361 aagtggatca accagaacca gcagatactc agccggagga tatttcagag tctaaagtgg

[1052] 3421 aagactgtaa aatggaatct accgaaacag aagagagaag cactgagtta aaaactgaaa

[1053] 3481 taaaagagga ggaagaccag ccaagtactt cagctaccca gtcatctccg gctccaggac

[1054] 3541 agtcaaagaa aaagattttc aaaccagaag aactacgaca ggcactgatg ccaactttgg

[1055] 3601 aggcacttta ccgtcaggat ccagaatccc ttccctttcg tcaacctgtg gaccctcagc

[1056] 3661 ttttaggaat ccctgattac tttgatattg tgaagagccc catggatctt tctaccatta

[1057] 3721 agaggaagtt agacactgga cagtatcagg agccctggca gtatgtcgat gatatttggc

[1058] 3781 ttatgttcaa taatgcctgg ttatataacc ggaaaacatc acgggtatac aaatactgct

[1059] 3841 ccaagctctc tgaggtcttt gaacaagaaa ttgacccagt gatgcaaagc cttggatact

[1060] 3901 gttgtggcag aaagttggag ttctctccac agacactgtg ttgctacggc aaacagttgt

[1061] 3961 gcacaatacc tcgtgatgcc acttattaca gttaccagaa caggtatcat ttctgtgaga

[1062] 4021 agtgtttcaa tgagatccaa ggggagagcg tttctttggg ggatgaccct tcccagcctc

[1063] 4081 aaactacaat aaataaagaa caattttcca agagaaaaaa tgacacactg gatcctgaac

[1064] 4141 tgtttgttga atgtacagag tgcggaagaa agatgcatca gatctgtgtc cttcaccatg

[1065] 4201 agatcatctg gcctgctgga ttcgtctgtg atggctgttt aaagaaaagt gcacgaacta

[1066] 4261 ggaaagaaaa taagttttct gctaaaaggt tgccatctac cagacttggc acctttctag

[1067] 4321 agaatcgtgt gaatgacttt ctgaggcgac agaatcaccc tgagtcagga gaggtcactg

[1068] 4381 ttagagtagt tcatgcttct gacaaaaccg tggaagtaaa accaggcatg aaagcaaggt

[1069] 4441 ttgtggacag tggagagatg gcagaatcct ttccataccg aaccaaagcc ctctttgcct

[1070] 4501 ttgaagaaat tgatggtgtt gacctgtgct tctttggcat gcatgttcaa gagtatggct

[1071] 4561 ctgactgccc tccacccaac cagaggagag tatacatatc ttacctcgat agtgttcatt

[1072] 4621 tcttccgtcc taaatgcttg aggactgcag tctatcatga aatcctaatt ggatatttag

[1073] 4681 aatatgtcaa gaaattaggt tacacaacag ggcatatttg ggcatgtcca ccaagtgagg

[1074] 4741 gagatgatta tatcttccat tgccatcctc ctgaccagaa gatacccaag cccaagcgac

[1075] 4801 tgcaggaatg gtacaaaaaa atgcttgaca aggctgtatc agagcgtatt gtccatgact

[1076] 4861 acaaggatat ttttaaacaa gctactgaag atagattaac aagtgcaaag gaattgcctt

[1077] 4921 atttcgaggg tgatttctgg cccaatgttc tggaagaaag cattaaggaa ctggaacagg

[1078] 4981 aggaagaaga gagaaaacga gaggaaaaca ccagcaatga aagcacagat gtgaccaagg

[1079] 5041 gagacagcaa aaatgctaaa aagaagaata ataagaaaac cagcaaaaat aagagcagcc

[1080] 5101 tgagtagggg caacaagaag aaacccggga tgcccaatgt atctaacgac ctctcacaga

[1081] 5161 aactatatgc caccatggag aagcataaag aggtcttctt tgtgatccgc ctcattgctg

[1082] 5221 gccctgctgc caactccctg cctcccattg ttgatcctga tcctctcatc ccctgcgatc

[1083] 5281 tgatggatgg tcgggatgcg tttctcacgc tggcaaggga caagcacctg gagttctctt

[1084] 5341 cactccgaag agcccagtgg tccaccatgt gcatgctggt ggagctgcac acgcagagcc

[1085] 5401 aggaccgctt tgtctacacc tgcaatgaat gcaagcacca tgtggagaca cgctggcact

[1086] 5461 gtactgtctg tgaggattat gacttgtgta tcacctgcta taacactaaa aaccatgacc

[1087] 5521 acaaaatgga gaaactaggc cttggcttag atgatgagag caacaaccag caggctgcag

[1088] 5581 ccacccagag cccaggcgat tctcgccgcc tgagtatcca gcgctgcatc cagtctctgg

[1089] 5641 tccatgcttg ccagtgtcgg aatgccaatt gctcactgcc atcctgccag aagatgaagc

[1090] 5701 gggttgtgca gcataccaag ggttgcaaac ggaaaaccaa tggcgggtgc cccatctgca

[1091] 5761 agcagctcat tgccctctgc tgctaccatg ccaagcactg ccaggagaac aaatgcccgg

[1092] 5821 tgccgttctg cctaaacatc aagcagaagc tccggcagca acagctgcag caccgactac

[1093] 5881 agcaggccca aatgcttcgc aggaggatgg ccagcatgca gcggactggt gtggttgggc

[1094] 5941 agcaacaggg cctcccttcc cccactcctg ccactccaac gacaccaact ggccaacagc

[1095] 6001 caaccacccc gcagacgccc cagcccactt ctcagcctca gcctacccct cccaatagca

[1096] 6061 tgccacccta cttgcccagg actcaagctg ctggccctgt gtcccagggt aaggcagcag

[1097] 6121 gccaggtgac ccctccaacc cctcctcaga ctgctcagcc accccttcca gggcccccac

[1098] 6181 ctgcagcagt ggaaatggca atgcagattc agagagcagc ggagacgcag cgccagatgg

[1099] 6241 cccacgtgca aatttttcaa aggccaatcc aacaccagat gcccccgatg actcccatgg

[1100] 6301 cccccatggg tatgaaccca cctcccatga ccagaggtcc cagtgggcat ttggagccag

[1101] 6361 ggatgggacc gacagggatg cagcaacagc caccctggag ccaaggagga ttgcctcagc 6421 cccagcaact acagtctggg atgccaaggc cagccatgat gtcagtggcc cagcatggtc

[1102] 6481 aacctttgaa catggctcca caaccaggat tgggccaggt aggtatcagc ccactcaaac

[1103] 6541 caggcactgt gtctcaacaa gccttacaaa accttttgcg gactctcagg tctcccagct

[1104] 6601 ctcccctgca gcagcaacag gtgcttagta tccttcacgc caacccccag ctgttggctg

[1105] 6661 cattcatcaa gcagcgggct gccaagtatg ccaactctaa tccacaaccc atccctgggc

[1106] 6721 agcctggcat gccccagggg cagccagggc tacagccacc taccatgcca ggtcagcagg

[1107] 6781 gggtccactc caatccagcc atgcagaaca tgaatccaat gcaggcgggc gttcagaggg

[1108] 6841 ctggcctgcc ccagcagcaa ccacagcagc aactccagcc acccatggga gggatgagcc

[1109] 6901 cccaggctca gcagatgaac atgaaccaca acaccatgcc ttcacaattc cgagacatct

[1110] 6961 tgagacgaca gcaaatgatg caacagcagc agcaacaggg agcagggcca ggaataggcc

[1111] 7021 ctggaatggc caaccataac cagttccagc aaccccaagg agttggctac ccaccacagc

[1112] 7081 agcagcagcg gatgcagcat cacatgcaac agatgcaaca aggaaatatg ggacagatag

[1113] 7141 gccagcttcc ccaggccttg ggagcagagg caggtgccag tctacaggcc tatcagcagc

[1114] 7201 gactccttca gcaacagatg gggtcccctg ttcagcccaa ccccatgagc ccccagcagc

[1115] 7261 atatgctccc aaatcaggcc cagtccccac acctacaagg ccagcagatc cctaattctc

[1116] 7321 tctccaatca agtgcgctct ccccagcctg tcccttctcc acggccacag tcccagcccc

[1117] 7381 cccactccag tccttcccca aggatgcagc ctcagccttc tccacaccac gtttccccac

[1118] 7441 agacaagttc cccacatcct ggactggtag ctgcccaggc caaccccatg gaacaagggc

[1119] 7501 attttgccag cccggaccag aattcaatgc tttctcagct tgctagcaat ccaggcatgg

[1120] 7561 caaacctcca tggtgcaagc gccacggacc tgggactcag caccgataac tcagacttga

[1121] 7621 attcaaacct ctcacagagt acactagaca tacactagag acaccttgta gtattttggg

[1122] 7681 agcaaaaaaa ttattttctc ttaacaagac tttttgtact gaaaacaatt tttttgaatc

[1123] 7741 tttcgtagcc taaaagacaa ttttccttgg aacacataag aactgtgcag tagccgtttg

[1124] 7801 tggtttaaag caaacatgca agatgaacct gagggatgat agaatacaaa gaatatattt

[1125] 7861 ttgttatggc tggttaccac cagcctttct tcccctttgt gtgtgtggtt caagtgtgca

[1126] 7921 ctgggaggag gctgaggcct gtgaagccaa acaatatgct cctgccttgc acctccaata

[1127] 7981 ggttttatta ttttttttaa attaatgaac atatgtaata ttaatagtta ttatttactg

[1128] 8041 gtgcagatgg ttgacatttt tccctatttt cctcacttta tggaagagtt aaaacatttc

[1129] 8101 taaaccagag gacaaaaggg gttaatgtta ctttaaaatt acattctata tatatataaa

[1130] 8161 tatatataaa tatatattaa aataccagtt ttttttctct gggtgcaaag atgttcattc

[1131] 8221 ttttaaaaaa tgtttaaaaa aaaaaaaaaa ctgcctttct tcccctcaag tcaacttttg

[1132] 8281 tgctccagaa aattttctat tctgtaagtc tgagcgtaaa acttcaagta ttaaaataat

[1133] 8341 ttgtacatgt agagagaaaa atgacttttt caaaaatata caggggcagc tgccaaattg

[1134] 8401 atgtattata tattgtggtt tctgtttctt gaaagaattt ttttcgttat ttttacatct

[1135] 8461 aacaaagtaa aaaaattaaa aagagggtaa gaaacgattc cggtgggatg attttaacat

[1136] 8521 gcaaaatgtc cctgggggtt tcttctttgc ttgctttctt cctccttacc ctacccccca

[1137] 8581 ctcacacaca cacacacaca cacacacaca cacacacaca cacactttct ataaaacttg

[1138] 8641 aaaatagcaa aaaccctcaa ctgttgtaaa tcatgcaatt aaagttgatt acttataaat

[1139] 8701 atgaactttg gatcactgta tagactgtta aatttgattt cttattacct attgttaaat

[1140] 8761 aaactgtgtg agacagaca (SEQ ID NO: 2).

[1141] In some embodiments, a nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence encoding a protein having at least 85% identity to SEQ ID NO: 1, at least 90% identity to SEQ ID NO: 1, at least 95% identity to SEQ ID NO: 1, at least 96% identity to SEQ ID NO: 1, at least 97% identity to SEQ ID NO: 1, at least 98% identity to SEQ ID NO: 1, at least 99% identity to SEQ ID NO: 1 or at least 99.8% identity to SEQ ID NO: 1. In some embodiments, nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence encoding a protein identical to SEQ ID NO: 1. In some embodiments, a nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence e having at least 85% identity to SEQ ID NO: 2, at least 90% identity to SEQ ID NO: 2, at least 95% identity to SEQ ID NO: 2, at least 96% identity to SEQ ID NO: 2, at least 97% identity to SEQ ID NO: 2, at least 98% identity to SEQ ID NO: 2, at least 99% identity to SEQ ID NO: 2 or at least 99.8% identity to SEQ ID NO: 2. In some embodiments, a nucleic acid sequence encoding a p300 protein comprises a nucleic acid sequence identical to SEQ ID NO: 2 or a portion or subsequence thereof.

[1142] As used herein, the term "expression" of a nucleic acid sequence refers to the generation of any gene product from the nucleic acid sequence. In some embodiments, a gene product can be a transcript. In some embodiments, a gene product can be a polypeptide. In some embodiments, expression of a nucleic acid sequence involves one or more of the following: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5' cap formation, and / or 3' end formation); (3) translation of an RNA into a polypeptide or protein; and / or (4) post- translational modification of a polypeptide or protein.

[1143] As used herein, the term "nucleic acid" refers to a polymer of at least three nucleotides. In some embodiments, a nucleic acid comprises DNA. In some embodiments comprises RNA. In some embodiments, a nucleic acid is single stranded. In some embodiments, a nucleic acid is double stranded. In some embodiments, a nucleic acid comprises both single and double stranded portions. In some embodiments, a nucleic acid comprises a backbone that comprises one or more phosphodiester linkages. In some embodiments, a nucleic acid comprises a backbone that comprises both phosphodiester and non-phosphodi ester linkages. In some embodiments, a nucleic acid comprises one or more, or all, natural residues (e.g, adenine, cytosine, deoxyadenosine, deoxycytidine,

[1144] deoxyguanosine, deoxythymidine, guanine, thymine, uracil). In some embodiments, a nucleic acid comprises on or more, or all, non-natural residues. In some embodiments, a non-natural residue comprises a nucleoside analog. In some embodiments, a nucleic acid has a nucleotide sequence that encodes a functional gene product such as an RNA or polypeptide. In some embodiments, a nucleic acid has a nucleotide sequence that comprises one or more introns. In some embodiments, a nucleic acid may be prepared by isolation from a natural source, enzymatic synthesis (e.g., by polymerization based on a complementary template, e.g., in vivo or in vitro, reproduction in a recombinant cell or system, or chemical synthesis).

[1145] Methods of Treating Cancer

[1146] Cancer is a disease caused by the uncontrolled division of cells in the body.

[1147] Abnormally dividing cancer cells can form a primary tumor, which can then invade nearby tissues, and spread throughout the body through the blood and lymphatic systems (metastatic cancers). Cancer can arise from many organs and cell types in the body, including but not limited to, cells of the lymphatic system, bone marrow, blood, brain and nervous system tissue, breast, cervix, ovary, colorectal cells, stomach and gastric cells, head and neck, kidney, liver, lung, oesophagus, pancreas, prostate and skin.

[1148] As used herein, the term“tumor” refers to an abnormal growth of cells or tissue. In some embodiments, a tumor may comprise cells that are precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and / or non-metastatic. In some embodiments, a tumor is associated with, or is a manifestation of, a cancer.

[1149] In some embodiments, a tumor may be a disperse tumor or a liquid tumor. Liquid tumors can affect bone marrow, blood cells and the lymphatic system. Exemplary liquid tumors include leukemias and lymphomas. Types of lymphomas include, but are not limited to, Hodgkin lymphomas, non-Hodgkin lymphomas, B cell lymphomas, T-cell lymphomas, Burkitt’s lymphomas, mantle cell lymphomas, small lymphocytic lymphomas, histiocytic lymphomas and primary mediastinal B cell lymphomas. Types of leukemias include, but are not limited to, acute myeloid leukemia, T cell leukemias, acute lymphoblastic leukemias and chronic myelogenous leukemias.

[1150] In some embodiments, a tumor may be a solid tumor. Exemplary solid tumors include, but are not limited to Carcinomas, Sarcomas, Myelomas, germ cell tumors, carcinoid tumors, neuroendocrine tumors and tumors of mixed type (a tumor which comprises multiple types of cancer cells). Carcinomas arise from epithelial tissues, either internal or external, such as cells of the gastrointestinal tract. Exemplary carcinomas include adenocarcinoma, which develops in an organ or gland, and squamous cell carcinoma, which originates in the squamous epithelium. Sarcomas are cancers that originate in supportive or connective tissues such as bones, tendons, cartilage, muscle and fat. Exemplary sarcomas include osteosarcoma, chondrosarcoma, leiomyosarcoma, rhabdomyosarcoma, mesothelial sarcoma, fibrosarcoma, angiosarcoma, liposarcoma, glioma or astrocytoma, myxosarcoma and mesenchymous or mixed mesodermal tumors.

[1151] Tumors can arise from most organs and tissue in the body, including, but not limited to, brain and nervous tissue, breast, cervix, ovary, uterus, colorectal, stomach and gastric tissue, kidney, liver, lung oesophagus, pancreas, prostate, skin, bone, head and neck, and lung. Exemplary brain and nervous system cancers include neurogliomas and glioblastomas. Exemplary breast cancers include human breast carcinomas, breast adenocarcinomas and invasive ductal carcinomas. Exemplary cervical cancers include epidermoid carcinomas, cervical carcinomas and HPV positive cervical cancers. Exemplary ovarian cancers include ovarian carcinomas. Exemplary colorectal cancers include colorectal carcinomas and colon colorectal adenocarcinomas. Exemplary stomach and gastric cancers include gastric adenocarcinomas, stomach adenocarcinomas and gastric carcinomas. Exemplary kidney cancers include renal cell adenocarcinomas and kidney clear cell carcinomas. Exemplary liver cancers include hepatocellular carcinomas and hepatomas. Exemplary lung cancers include small cell lung cancers, non-small cell lung cancers, lung carcinomas, lung adenocarcinomas, squamous cell carcinomas and large cell carcinomas. Exemplary esophageal cancers include esophageal squamous cell carcinoma. Exemplary pancreatic cancers include pancreatic carcinoma and pancreatic ductal adenocarcinoma. Exemplary prostate cancers include prostate carcinomas, prostate adenocarcinomas and castrate resistant prostate cancers. Exemplary skin cancers include melanomas, squamous cell carcinomas and basal cell carcinomas. Exemplary head and neck cancers include squamous cell carcinomas.

[1152] As used herein, the term "subject" refers to an organism, for example, a mammal (e.g., a human, a non-human mammal, a non-human primate, a primate, a laboratory animal, a mouse, a rat, a hamster, a gerbil, a cat, a dog). In some embodiments a human subject is an adult, adolescent, or pediatric subject (a child). In some embodiments, a subject is suffering from a disease, disorder or condition, e.g., a disease, disorder or condition that can be treated as provided herein, e.g., a cancer or a tumor listed herein. In some embodiments, a subject displays one or more symptoms of a disease, disorder or condition. In some embodiments, a subject does not display a particular symptom (e.g., clinical manifestation of disease) or characteristic of a disease, disorder, or condition. In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition. In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[1153] A cancer that is to be treated can be staged according to the American Joint

[1154] Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, Tl, Tlmic, Tla, Tib, Tic, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, NO, Nl, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, MO, or Ml. A cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA,

[1155] Stage IIIB, Stage IIIC, or Stage IV. A cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pNO, PNO (I-), PNO (I+), PNO (mol-), PNO (mol+), PN1, PNl(mi), PNla, PNlb, PNlc, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[1156] A cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry. A cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division). A cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction.

[1157] As used herein, a "normal cell" is a cell that cannot be classified as part of a "cell proliferative disorder". A normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease. Preferably, a normal cell possesses normally functioning cell cycle checkpoint control mechanisms.

[1158] As used herein, "contacting a cell" refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell.

[1159] As used herein, "monotherapy" refers to the administration of a single active or therapeutic compound to a subject in need thereof. Preferably, monotherapy will involve administration of a therapeutically effective amount of an active compound. For example, cancer monotherapy with one of the compound of the present invention, or a

[1160] pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof, to a subject in need of treatment of cancer. Monotherapy may be contrasted with combination therapy, in which a combination of multiple active compounds is administered, preferably with each component of the combination present in a therapeutically effective amount. In one aspect, monotherapy with a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, is more effective than combination therapy in inducing a desired biological effect.

[1161] As used herein, "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate one or more symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term "treat" can also include treatment of a cell in vitro or an animal model.

[1162] A compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can also be used to prevent a disease, condition or disorder, or used to identify suitable candidates for such purposes. As used herein, "preventing" or "prevent" describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.

[1163] As used herein, the term "alleviate" is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased. Importantly, a sign or symptom can be alleviated without being eliminated. In a preferred embodiment, the administration of pharmaceutical compositions of the invention leads to the elimination of a sign or symptom, however, elimination is not required. Effective dosages are expected to decrease the severity of a sign or symptom. For instance, a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.

[1164] As used herein, the term "severity" is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state. Alternatively, or in addition, severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other art-recognized methods. Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes). Alternatively, or in addition, severity is meant to describe the tumor grade by art- recognized methods (see, National Cancer Institute, www.cancer.gov). Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute,

[1165] www.cancer.gov). Furthermore, severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing (see, National Cancer Institute, www.cancer.gov).

[1166] In another aspect of the invention, severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized. Moreover, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and immunological tumors), and those which are the most resistant to traditional treatments are considered most severe. In these situations, prolonging the life expectancy of the subject and / or reducing pain, decreasing the proportion of cancerous cells or restricting cells to one system, and improving cancer stage / tumor grade / histological grade / nuclear grade are considered alleviating a sign or symptom of the cancer.

[1167] As used herein the term "symptom" is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others. Others are defined as non- health-care professionals.

[1168] As used herein the term "sign" is also defined as an indication that something is not right in the body. But signs are defined as things that can be seen by a doctor, nurse, or other health care professional.

[1169] Cancer is a group of diseases that may cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, the size of the cancer, and how much it affects the nearby organs or structures. If a cancer spreads (metastasizes), then symptoms may appear in different parts of the body.

[1170] Treating cancer can result in a reduction in size of a tumor. A reduction in size of a tumor may also be referred to as "tumor regression". Preferably, after treatment, tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.

[1171] Treating cancer can result in a reduction in tumor volume. Preferably, after treatment, tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater. Tumor volume may be measured by any reproducible means of measurement.

[1172] Treating cancer results in a decrease in number of tumors. Preferably, after treatment, tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.

[1173] Treating cancer can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%. The number of metastatic lesions may be measured by any reproducible means of measurement. The number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified

[1174] magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.

[1175] Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[1176] Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[1177] Treating cancer can result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof. Preferably, the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days. An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.

[1178] Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof. Preferably, the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%. A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means. A decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.

[1179] Treating cancer can result in a decrease in tumor growth rate. Preferably, after treatment, tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%. Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate can be measured according to a change in tumor diameter per unit time.

[1180] Treating cancer can result in a decrease in tumor regrowth. Preferably, after treatment, tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less ...

Claims

CLAIMS1. A compound of formula (la)or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:R1is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C 1-5 alkyl-NHCOR13, or C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;R3and R7are each independently selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn, or Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C 1-3 alkyl substituted by cycloalkyl, aryl or heteroaryl, wherein the cycloalkyl, aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl;R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloakenyl, all optionally substituted by halogen, OR8, NR8Rn; C1-3 alkyl substituted by C(0)NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; and wherein R6can form a ring with any part of X; or is imidazolidinone;R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R5, R6, or Y, wherein the ring optionally contains a carbonyl group;Y is selected from H, C(O)NR10R12, C(0)OR10, R10NC(O)NR10R12, OC(0)R10, OC(O)NR10R12, S (0)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S- heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)0R8, C1-5 alkyl- C(0)NR8Rn, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, NR8C(0)NR8Rn, 0C(0)NR8Rn, S02NR8Ru, NR8S02R8, OR8, NR8Rn, or S(0)nR8wherein n is 0, 1 or 2;R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NR8Rn;R13is Ci-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; andeach R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C1-3 alkyl-OR8.

2. A compound of formula (I)or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein:R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;R2is selected from H, C(0)R14, C(0)NR15R15, C(0)0R15, C1-7 alkyl, C2-7 alkenyl, C2- 7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; with the proviso that when R2is C(0)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;R5is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, all optionally substituted by halogen, OR8, NR8Rn; or C1-3 alkyl substituted by C(0)NR8Rn; Ci-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; or is imidazolidinone;R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-6 cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, or -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group;Y is selected from H, C(O)NR10R12, C(0)OR10, R10NC(O)NR10R12, OC(0)R10, OC(O)NR10R12, S (0)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S- heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8;R9is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR8, C1-5 alkyl-SR8, C 1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)0R8, C1-5 alkyl- C(0)NR8Rn, C1-5 alkyl-C(0)R10, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, NR8C(0)NR8Rn, 0C(0)NR8Rn, S02NR8Ru, NR8S02R8, OR8, NR8Rn, or S(0)nR8wherein n is 0, 1 or 2;R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen, OR8, or NR8Rn;R13is C1-5 alkyl substituted by a bi cyclic ring optionally containing at least one heteroatom and a carbonyl group;R14is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C 1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl; andeach R15is independently selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, or C 1-3 alkyl-OR8.

3. The compound according to any one of the previous claims, wherein R1is selected from Ci-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Ci-4 alkyl or C3-5 cycloalkyl.

4. The compound according to any one of the previous claims, wherein R1is selected from C2-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

5. The compound according to any one of the previous claims, wherein R1is selected from C3-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl.

6. The compound according to any one of the previous claims, wherein R2is selected from H, C(0)R14, C(0)0R15, C1-7 alkyl, C3-7 cycloalkyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O- Ci-3 alkanediyl, C1-5 alkyl-OR8, C1-5 alkyl-NHCOR13, or C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

7. The compound according to any one of the previous claims, wherein R2is selected from H, C(0)R14, wherein R14is C1-7 alkyl; C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8, C 1-5 alkyl-NHCOR13, wherein R13is pentylamino-5-oxopentyl-7-thia-2.4- diazabicyclo[3.3.0]octan-3-one; or C 1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

8. The compound according to any one of the previous claims, wherein R3and R7are each independently selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

9. The compound according to any one of the previous claims, wherein R3and R7are H.

10. The compound according to any one of the previous claims, wherein R4is selected from Ci-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C 1-4 alkyl or C3-5 cycloalkyl.

11. The compound according to any one of the previous claims, wherein R4is selected from C2-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

12. The compound according to any one of the previous claims, wherein R4is selected fromC3-7 alkyl, C3-7 cycloalkyl, or C 1-3 alkyl substituted by aryl or heteroaryl.

13. The compound according to any one of the previous claims, wherein the compound is of any one of Formulae (Ila), (lib), or (lie):or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, X, and Y are as described herein.

14. The compound according to any one of the previous claims, wherein the compound is of any one o(Illb);or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R4, R5, R6, X, and Y are as described herein.

15. The compound according to any one of the previous claims, wherein R5is selected from H, Ci-7 alkyl, OR8, or SR8; and wherein Ci-7 alkyl, OR8or SR8of R5can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group.

16. The compound according to any one of the previous claims, wherein R6is selected from H, C 1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl; or is imidazolidinone.

17. The compound according to any one of the previous claims, wherein R6is H, C1-7 alkyl, or imidazolidinone.

18. The compound according to any one of the previous claims, wherein the compound is of any one of Formulae (IVa), (IVb), (IV c) or (IVd):or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein R1, R2, R4, R5, R6, X, and Y are as described herein.

19. The compound according to any one of the previous claims, wherein R8and R11are each independently selected from H, C 1-7 alkyl, C2-7 alkenyl, or C3-7 cycloalkyl.

20. The compound according to any one of the previous claims, wherein R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(0)OR8, C1-5 alkyl-C(0)NR8Ru, CN, C(0)R8, C(0)NR8Rn, C(0)OR8, or OR8.

21. The compound according to any one of the previous claims, wherein R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C1-3 alkyl-heteroaryl, all these groups optionally substituted by halogen or OR8.

22. The compound according to any one of the previous claims, wherein R14is selected from Ci-7 alkyl, C3-7 cycloalkyl, or C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl.

23. The compound according to any one of the previous claims, wherein R14is selected from Ci-7 alkyl or C3-7 cycloalkyl.

24. The compound according to any one of the previous claims, wherein R14is C1-7 alkyl.

25. The compound according to any one of the previous claims, wherein each R15is independently selected from H, C1-7 alkyl, or C3-7 cycloalkyl.

26. The compound according to any one of the previous claims, wherein each R15is independently selected from H, C1-7 alkyl.

27. The compound according to any one of the previous claims, wherein X is selected from a bond, C1-7 alkanediyl, -0-, C 1-3 alkanediyl-O, -O-C1-7 alkanediyl, C1-3 alkanediyl-O- C1-7 alkanediyl, C 1-7 heteroalkanediyl, or -S-C 1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y, wherein the ring optionally contains a carbonyl group.

28. The compound according to any one of the previous claims, wherein X is selected from a bond and C1-7 alkanediyl, and wherein C1-7 alkanediyl of X can form a ring with any part of Y.

29. The compound according to any one of the previous claims, wherein X is selected from a bond, -O-C1-7 alkanediyl, -S-C1-7 alkanediyl and C1-7 alkanediyl, and wherein -O-C1-7 alkanediyl, -S-C1-7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5, wherein the ring optionally contains a carbonyl group.

30. The compound according to any one of the previous claims, wherein Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O- heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein when Y is C(O)NR10R12or NR10R12, Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

31. The compound according to any one of the previous claims, wherein Y is selected from H, C(O)NR10R12, C(0)OR10, NR10R12, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S-aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S- heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or aryl, heteroaryl wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

32. The compound according to any one of the previous claims, wherein Y is selected from C(O)NR10R12, NR10R12, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; S- aryl, O-aryl, S-heteroaryl, O-heteroaryl wherein the S-aryl, O-aryl, S-heteroaryl, O-heteroaryl are optionally substituted by one or more R9or R14; or heteroaryl wherein the heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ring with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

33. The compound according to any one of the previous claims, wherein the compound is of any one of Formulae (Va), (Vb), (Vc), or (Vd):or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

34. The compound according to any one of the previous claims, wherein the compound is of any one of Formulae (Via), (VIb), (Vic), or (VId):or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10and R12are as described herein.

35. The compound according to any one of the previous claims, wherein Y is selected from NR10R12and C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8; and wherein Y can form a ring with any part of X or R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

36. The compound according to any one of the previous claims, wherein R5is selected from H and C 1-7 alkyl; wherein C1-7 alkyl of R5can form a ring with any part of Y;wherein X is selected from a bond and C 1-7 alkanediyl, and wherein C 1-7 alkanediyl of X can form a ring with any part of Y;wherein Y is selected from NR10R12and C3-7-cycloalkyl optionally containing a heteroatom in the ring wherein the heteroatom is N and is optionally substituted by R8wherein R8is C1-7 alkyl;wherein Y can form a ring with any part of C1-7 alkanediyl of X or with any part of C1-7 alkyl of R5; with the proviso that when Y is NR10R12, R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8; andwherein R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, C1-3 alkyl-aryl, all these groups optionally substituted by halogen.

37. The compound according to any one of the previous claims, wherein R5is selected from Ci-7 alkyl, OR8, or SR8; wherein C1-7 alkyl, OR8or SR8of R5can form a ring with any part of X;wherein X is selected from -O-C1-7 alkanediyl, -S-C1-7 alkanediyl, or C1-7 alkanediyl, and wherein -O-C1-7 alkanediyl, -S-C1-7 alkanediyl or C1-7 alkanediyl of X can form a ring with any part of R5; andwherein Y is NR10R12wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

38. The compound according to any one of the previous claims,wherein R5is OR8, wherein R8of OR8is C1-7 alkyl, and wherein OR8of R5can form a ring with any part of X;wherein X is -O-C1-7 alkanediyl and wherein -O-C1-7 alkanediyl of X can form a ring with any part of R5; andwherein Y is NR10R12wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and four or five carbon atoms.

39. The compound according to any one of the previous claims, wherein the compound is of any one of Formulae (Vila), (Vllb), (Vile), (Vlld), (Vile), or (Vllf):or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein n8 is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, and R8are as described herein.

40. The compound according to any one of the previous claims,wherein Y is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14.

41. The compound according to any one of the previous claims,wherein R5is selected from H and C1-7 alkyl;wherein X is selected from a bond and C1-7 alkanediyl;wherein Y is heteroaryl, wherein the heteroaryl is optionally substituted by one or more of R8; or S-heteroaryl, wherein the S-heteroaryl is optionally substituted by one or more R14.

42. The compound according to any one of the previous claims,wherein Y is C(O)NR10R12; and wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8.

43. The compound according to any one of the previous claims, wherein R5is selected from H and C 1-7 alkyl;wherein X is selected from a bond and C1-7 alkanediyl;wherein Y is C(O)NR10R12; and wherein R10and R12can form a ring wherein the ring contains the N of NR10R12and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, it is optionally substituted by R8; and wherein R10and R12are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C1-3 alkyl-aryl.

44. The compound according to any one of the previous claims, wherein Y is selected from S-aryl, O-aryl, S-heteroaryl, O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, O- heteroaryl are optionally substituted by one or more R9or R14.

45. The compound according to any one of the previous claims,wherein R5is selected from H and C1-7 alkyl;wherein X is selected from a bond and C1-7 alkanediyl,wherein Y is selected from O-aryl and O-heteroaryl, wherein the O-aryl or O-heteroaryl is optionally substituted by one or more R9;wherein R9is selected from H, C1-5 alkyl, halogen, C1-5 alkyl-NR8Rn, C 1-5 alkyl-C(0)0R8, Ci- 5 alkyl-C(0)NR8Rn, CN, C(0)R8, C(0)NR8Rn, C(0)0R8, and OR8.

46. The compound according to any one of the previous claims, wherein Y is C(0)OR10.

47. The compound according to any one of the previous claims, whereinwherein R5is selected from H and C1-7 alkyl;wherein X is selected from a bond and C 1-7 alkanediyl;wherein Y is C(0)0R10; andwherein R10is selected from H, C1-7 alkyl, C2-7 alkenyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, Ci- 3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-3 alkyl-aryl, or C 1-3 alkyl-heteroaryl, all these groups optionally substituted by ORx.

48. The compound according to any one of the previous claims, wherein Y is H.

49. The compound according to any one of the previous claims, whereinwherein R5is C1-7 alkyl;wherein X is a bond; andwherein Y is H.

50. The compound according to any one of the previous claims, wherein Y is CN.

51. The compound according to any one of the previous claims, whereinR5is H;X is Ci-7 alkanediyl; andY is CN.

52. The compound according to any one of the previous claims, wherein the compound is of any one of Formulae (Villa), (VUIb), (VIIIc), (Vllld), (VUIe), (Vlllf), (VHIg), (VHIh), (Villi), (VUIj), (VUIk), (VIII1):or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Qi and Q2 are each independently O, S, NR8, or CR8, and R1, R2, R3, R4, R6, R7, R8, and Y are as described herein.

53. The compound according to any one of the previous claims, wherein the compound is of any one of Formulae (IXa), (IXb), (IXc), or (IXd):or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nlO is 0, 1, 2, 3, 4, 5, 6, or 7, preferably 1, 2, or 3, and R1, R2, R3, R4, R6, R7, R10, R12and Y are as described herein.

54. A compound selected from the group consisting of:

55. A compound selected from the group consisting of:

56. The compound according to any one of the previous claims, wherein the compound is selected from a compound of any one of Table 2 or Table 3.

57. A pharmaceutical composition comprising a compound according to any one of the previous claims and a pharmaceutically acceptable diluent, excipient or carrier.

58. The pharmaceutical composition according to claim 57, further comprising an additional pharmaceutically active agent.

59. The pharmaceutical composition according to claim 58, wherein the additional pharmaceutically active agent comprises an additional cancer therapy.

60. The compound according to any one of claims 1-56 or the pharmaceutical composition according to claim 57 or 58 for use as a medicament.

61. The compound according to any one of claims 1-56 or the or the pharmaceutical composition according to claim 57 or 58 for use in a method for preventing or treating cancer in a subject in need thereof.

62. The compound according to any one of claims 1-56 or the pharmaceutical composition according to claim 57 or 58 for the use in the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

63. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising the compound of any one of claims 1-56 or the pharmaceutical composition of claim 57 or 58.

64. The method or composition for use according to any one of claims 61-63, wherein the cancer comprises a solid tumor or a liquid tumor.

65. The method or composition for use according to claim 64, wherein the solid tumor is a primary tumor or a metastatic tumor.

66. The method or composition for use according to claim 64, wherein the solid tumor is a carcinoma, a sarcoma, a myeloma, a germ cell tumor, a carcinoid tumor, a neuroendocrine tumor or a tumor of mixed type.

67. The method or composition for use according to claim 64, wherein the cancer comprises a lymphoma, a leukemia, a brain cancer, a nervous system cancer, a breast cancer, a cervical cancer, an ovarian cancer, a colorectal cancer, a stomach cancer, a gastric cancer, a kidney cancer, a liver cancer, a lung cancer, an oesophageal cancer, a pancreatic cancer, a prostate cancer, a colon cancer, a skin cancer or a head-and-neck cancer.

68. The method or composition for use according to claim 64, wherein the liquid tumor is a leukemia or a lymphoma.

69. The method of composition for use according to any one of claims 61-66, wherein the cancer is Stage 1, Stage XXA, Stage PB, Stage XXXA, Stage iilB, Stage !IIC, or Stage IV cancer.

70. The method or composition for use according to any one of claims 61-69, wherein the subject is a mouse, a rat, a rabbit, a non-human primate or a human.

71. The method or composition for use according to claim 70, wherein the human is a child, an adolescent or an adult.

72. The method of composition for use according to any one of claims 61-71, wherein the compound or pharmaceutical composition is suitable for oral administration.

73. The method of composition for use according to any one of claims 61-71, wherein the compound or pharmaceutical composition is suitable for parenteral administration.

74. The method or composition for use according to claim 73, wherein the parenteral administration comprises subcutaneous administration, intravenous injection, intravenous infusion, intraperitoneal injection, intramuscular injection or intratumoral injection.

75. The method or composition for use according to any one of claims 61-74, wherein the method or use of the composition further comprises at least one additional cancer therapy.

76. The method or composition for use according to claim 75, wherein the at least one additional cancer therapy comprises a standard of care for the cancer.

77. The method or composition for use according to claim 75 or 76, wherein the at least one additional cancer therapy comprises surgical resection of the cancer, radiation therapy, or a combination thereof.

78. The method or composition for use according to claim 75, wherein the at least one additional cancer therapy comprises administration of at least one additional cancer therapeutic agent.

79. The method or composition for use according to claim 78, wherein the administration comprises simultaneous administration of the compound or pharmaceutical composition and the at least one additional cancer therapeutic agent.

80. The method or composition for use according to claim 79, wherein the compound or pharmaceutical composition and the at least one additional cancer therapeutic agent are in the same composition.

81. The method or composition for use according to claim 78, wherein the administration comprises administration in temporal proximity of the compound or pharmaceutical composition and the at least one additional cancer therapeutic agent.

82. The method or composition for use according to claim 78, wherein the administration comprises sequential administration of the compound or pharmaceutical composition and the at least one additional cancer therapeutic agent.

83. The method or composition for use according to any one of claims 78-82, wherein the at least one additional cancer therapeutic agent comprises a chemotherapeutic agent.

84. The method or composition for use according to claim 83, wherein thechemotherapeutic agent comprises a platinum compound, an alkylating agent, an antitumor antibiotic, a taxane, an antimetabolite, a nucleoside analog, a topoisomerase inhibitor, a hypomethylating agent, a proteasome inhibitor, an epipodophyllotoxin, a DNA synthesis inhibitor, a vinca alkaloid, a tyrosine kinase inhibitor, a nitrosourea, hexamethylmelamine, mitotane, an angiogenesis inhibitor, a steroid, a hormonal agent, an aromatase inhibitor, arsenic trioxide, tretinoin, a nonselective cyclooxygenase inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitors, or a combination thereof.

85. The method or composition for use according to any one of claims 78-82, wherein the at least one additional cancer therapeutic agent comprises a biological agent.

86. The method or composition for use according to claim 85, wherein the biological agent comprises an antibody therapy, an adoptive cell therapy, an enzyme, a cytokine, a growth factor, an inhibitor of a growth factor, a gene therapy a cancer vaccine or a combination thereof.

87. The method or composition for use according to claim 86, wherein the antibody therapy comprises ituximab, cetuximab, obinutuzumab, ofatumumab, ibritumomab, brentuximab, bevacizumab, panitumumab, pembrolizumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozogamicin, bevacizumab, catumaxomab, denosumab, obinutuzumab, ofatumumab, ramucirumab, pertuzumab, ipilimumab, nivolumab, nimotuzumab, lambrobzumab, pidibzumab, siltuximab, tremelimumab.

88. The method or composition for use according to claim 86, wherein the adoptive cell therapy comprises a chimeric antigen receptor T cell (CAR-T) therapy.

89. The method or composition for use according to claim 88, wherein the adoptive cell therapy is autologous or allogeneic.

90. The method or composition for use according to any one of claims 78-82, wherein the at least one additional cancer therapeutic agent comprises an immune checkpoint inhibitor.

91. The method or composition for use according to claim 90, wherein the immune checkpoint inhibitor comprises nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab or ipilimumab.

92. The method or composition for use according to claim 86, wherein the antibody therapy comprises a VEGFA antibody.

93. The method or composition for use according to claim 92, wherein the VEGFA antibody comprises bevacizumab (Avastin®).

94. The method or composition for use according to any one of claims 61-93, wherein the method or use of the composition alleviates a sign or a symptom of the cancer.

95. The method or composition for use according to claim 94, wherein alleviating a sign or a symptom of the cancer comprises a reduction in tumor volume, a reduction in tumor size, a reduction in tumor number, a decrease in the rate of growth of a tumor or a combination thereof.

96. A kit, comprising the compound according to any one of claims 1-56 or the pharmaceutical composition according to claim 57 or 58 and instructions for use in treating cancer in a subject in need thereof.

97. The kit according to claim 96, further comprising at least one additional cancer therapeutic agent.

98. The kit according to claim 97, wherein the at least one additional cancer therapeutic agent comprises a chemotherapeutic agent.

99. The kit according to claim 98, wherein the chemotherapeutic agent comprises a platinum compound, an alkylating agent, an antitumor antibiotic, a taxane, an antimetabolite, a nucleoside analog, a topoisomerase inhibitor, a hypomethylating agent, a proteasomeinhibitor, an epipodophyllotoxin, a DNA synthesis inhibitor, a vinca alkaloid, a tyrosine kinase inhibitor, a nitrosourea, hexamethylmelamine, mitotane, an angiogenesis inhibitor, a steroid, a hormonal agent, an aromatase inhibitor, arsenic trioxide, tretinoin, a nonselective cyclooxygenase inhibitor, a selective cyclooxygenase-2 (COX-2) inhibitors, or a combination thereof.

100. The kit of claim according to claim 97, wherein the at least one additional cancer therapeutic agent comprises a biological agent.

101. The kit according to claim 100, wherein biological agent comprises an antibody therapy, an adoptive cell therapy, an enzyme, a cytokine, a growth factor, an inhibitor of a growth factor, a gene therapy a cancer vaccine or a combination thereof.

102. The kit according to claim 97, wherein the at least one additional cancer therapeutic agent comprises an immune checkpoint inhibitor.

103. The kit according to claim 102, wherein the immune checkpoint inhibitor comprises nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab or ipilimumab.

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