Oxopiperazine derivatives for the treatment of cancer

Abstract

The disclosure provides methods of treating a subject with a disease or disorder characterized by a modulated negative elongation factor complex (NELF) with a compound of Formula (Ia) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

Description

OXOPIPERAZINE DERIVATIVES FOR THE TREATMENT OF CANCERRELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 504,576, filed on May 26, 2023, and U.S. Provisional Application No. 63 / 513,220, filed on July 12, 2023, the contents of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] 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 one year to six years since the 1970s. However, for many cancers, 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 and diagnostic methods to determine the susceptibility of cancers to these drugs. Furthermore, small molecules that target negative elongation factor (NELF) have been identified for the treatment of cancer. NELF is a four-subunit protein complex (NELF-A, NELF-B, NELF-C / NELF-D, and NELF-E) that negatively impacts transcription by RNA polymerase II (Pol II) by pausing transcription about 20-60 nucleotides downstream from the transcription start site (TSS). Furthermore, acute loss of NELF-C protein globally perturbs Pol II transcription termination and also increases transcription elongation rate. This results in Pol II transcription into DNA replication initiation zones, and may link to failure of the cell cycle transition into S phase. Compounds targeting NELF and NELF subunits may be able to address an unmet need in the treatment of cancer.SUMMARY

[0003] In one aspect, the present disclosure provides, inter alia, a method of modulating negative elongation factor complex (NELF) comprising administering to a subject a compound of Formula (la) or a composition comprising a compound of Formula (la):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, and 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;R2is selected from H, C(O)R14, C(O)NR15R15, C(O)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, and 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(O)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, the ring is optionally substituted by R8;R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently 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, and 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, and 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, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R6is C1-3 alkyl substituted by C(O)NR8Rn; or R6is 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 R6is imidazolidinone;R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, and -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(O)OR10, R10NC(O)NR10R12, OC(O)R10, OC(O)NR10R12, S(O)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, and O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl is optionally substituted by one or more R9or R14; or Y is 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, the ring 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(O)OR8, C1-5 alkyl- C(O)NR8Rn, C1-5 alkyl-C(O)R10, CN, C(O)R8, C(O)NR8Rn, C(O)OR8, NR8C(O)NR8Rn, OC(O)NR8Rn, SO2NR8RU, NR8SO2R8, OR8, NR8RU, and S(O)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, and C1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl is 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, and 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 each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR8.

[0004] In some embodiments, the modulation is inhibition. In one aspect, the present disclosure provides a method wherein the modulation treats a disease or a disorder.

[0005] In some embodiments the negative elongation factor complex is negative elongation factor complex member B (NELFB).

[0006] In some embodiments, the negative elongation factor complex is negative elongation factor complex member C / D (NELFCD).

[0007] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0008] In some embodiments, the disease or disorder is cancer.

[0009] In some embodiments, the cancer comprises a liquid tumor or a solid tumor.

[0010] In some embodiments, the cancer is prostate cancer, renal cancer, pancreatic cancer, liver cancer, breast cancer, gastric cancer, testicular cancer, colorectal cancer, cervical cancer, ovarian cancer, head-and-neck cancer, esophageal cancer, leukemia, lymphoma, lung cancer, brain cancer, stomach cancer, cancer of the central nervous system, or skin cancer.

[0011] In some embodiments, the prostate cancer is castration resistant prostate cancer.

[0012] In some embodiments, the lung cancer is small-cell lung cancer.

[0013] In some embodiments, the leukemia is chronic myeloid leukemia, acute T lymphocytic leukemia, or chronic lymphocytic leukemia.

[0014] In some embodiments, the myeloma is multiple myeloma.

[0015] In some embodiments, the negative elongation factor complex (NELF) is overexpressed prior to treatment. In some embodiments, the overexpression of the NELF is an increase in expression of one NELF member (e.g., B or C / D) as compared to a control level of expression observed in individuals not having the disease or disorder.

[0016] 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 those 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 the peptides disclosed herein, the chemical structures will control.

[0017] Other features and advantages of the disclosure will be apparent from the following detailed description and claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

[0019] FIGs. 1A and IB depict mass spectrometry using Cellular Thermal Shift Assay (CETSA®) wherein NELF-C / NELF-D is detected at 1 pM Compound 1’ (FIG. 1A) and absence of NELF-C / NELF-D detection with staurosporine (FIG. IB).

[0020] FIG. 2 depicts the CETSA® experimental setup for detecting protein interactions of small molecules.

[0021] FIGs. 3A-3C depict results of the CETSA® experiment for treatment of intact cells with Compound 1’. FIGs. 3 A and 3B depict the stability rate change of Compound 1’ or control and various proteins (ARHGEF28, LRRC14, RC3H2, ZCRB1, and NELFCD) at varying concentrations (1, 3, 10, and 30 pm) of Compound 1’. FIG. 3C shows melting curves for NELFCD across four different concentrations of Compound 1’ (20 nM, 100 nM, 600 nM, and 3,000 nM). N = 5 for all except for 3000 nM where n=4.

[0022] FIG. 4A depicts the accumulation of RNA species (stress granules) following treatment with Compound 1’. FIG. 4B depicts a schematic modeling NELF -mediated transcription termination and DNA replication initiation (adapted from Nakayama et al.NELF coordinates Pol II transcription termination and DNA replication initiation. bioRxiv. 2024 Feb 1 :2024.01.31.578294).

[0023] FIGs. 5A - 5C depict the modeled binding site for Compound 1’ . In FIG. 5 A the blue complex is NELFC / NELFD, pink residue is NELF A, and yellow structure is Compound 1’. In FIG. 5B the hydrogen bonds are depicted with thin lines and exemplary residues are labeled. In FIG. 5C, the location of the Compound 1’ binding site, including a hinge domain (arrow), is illustrated with NELFC / NELFD in blue and NELF A in pink.

[0024] FIG. 6 depicts disease free survival time of human subjects with over expression of NELF A, NELFB, NELFCD, or NELFE analyzed with a Cox proportional hazards model. Solid lines represent survival time and dotted lines represent the 95% confidence interval. Red lines indicate high expression (defined as higher than the median expression value) and blue lines represent low expression (defined as lower than the median expression value) of the respective gene. FIG. 6 was generated using the Gene Expression Profiling Interactive Analysis tool (Tang, Z. et al. (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 10.1093 / nar / gkx247).

[0025] FIGs. 7A-7E illustrate the role of NELF in Colorectal cancer (CRC). FIG. 7A is a schematic illustrating the chromosomal location of NELFCD on the long arm of chromosome 20 identified as 20ql2.32 (upper). Additionally, amplification and mRNA up regulation are the main mutations found in patients with colorectal cancer (lower). FIG. 7B depicts relative NELFCD mRNA expression in colon adenocarcinoma tissue (red left) compared to adjected normal tissue (grey left) and rectum adenocarcinoma tissue (red right) compared to adjacent normal tissue (grey right). FIG. 7C depicts the correlation between copy number alteration and NELFCD mRNA expression in patients with colorectal cancer (based on data from The Cancer Genome Atlas Program (TCGA)). FIG. 7D illustrates the reduction in tumor size of mice injected with cells containing short hairpin RNA targeted at the mRNA of NELFCD genes (SW480-shNELFCD) compared to mice injected with a negative control (sh-NC, 5'-TTCTCCGAACGTGTCACGT-3'). FIG. 7E depicts mouse CDX tumor model data using HCT116 human colorectal cancer cells upon treatment with Compound L (3 mg / kg and 6 mg / kg daily via oral administration) and the recorded mean tumor volumes compared to vehicle control and Avastin® (administered at 10 mg / kg twice weekly) for the length of the study (38 days). FIGs. 7A and 7C are adapted from Li et al.: Oncotarget. 2017 Aug 10;8(45):78642-78659; FIGs. 7B and 7D are adapted from Song et al.: Onco Targets Ther. 2018 Dec 5; 11 :8741-8750).DETAILED DESCRIPTON

[0026] Provided herein are, inter alia, methods of modulating negative elongation factor complex (NELF) in a subject comprising administering to a subject a compound of Formula (la). Also provided herein are methods for treating a disease or disorder in a subject comprising administering a compound according to Formula la. In some embodiments, the disease or disorder is cancer and / or symptoms of cancer.

[0027] The present disclosure also relates to pharmaceutical compositions comprising a compound of Formula (la) and to their use in the treatment of disorders in which NELF is implicated, such as cancer.

[0028] The methods described herein provide certain advantages over other methods, including for example, the ability to target NELF. The methods described herein provide novel treatment options for subjects with cancer, or other diseases which result in aberrant NLEF expression and / or activity.Compounds of the present disclosure

[0029] In some embodiments, the compound is of Formula (la):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, and 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;R2is selected from H, C(O)R14, C(O)NR15R15, C(O)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, and 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(O)NR15R15, both R15can form a ring wherein the ring contains the N of NR15R15and optionally one furtherheteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently 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, and 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, and 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, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R6is C1-3 alkyl substituted by C(O)NR8Rn; or R6is 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 R6is imidazolidinone;R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, and -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(O)OR10, R10NC(O)NR10R12, OC(O)R10, OC(O)NR10R12, S(O)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, and O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl is optionally substituted by one or more R9or R14; or Y is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by one or more of R8; and wherein Y can form a ringwith 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, the ring 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(O)OR8, C1-5 alkyl- C(O)NR8Rn, C1-5 alkyl-C(O)R10, CN, C(O)R8, C(O)NR8Rn, C(O)OR8, NR8C(O)NR8Rn, OC(O)NR8Rn, SO2NR8RU, NR8SO2R8, OR8, NR8RU, and S(O)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, and C1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8Rn;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, and 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 each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR8.

[0030] In some embodiments, R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and 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.

[0031] In some embodiments, R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0032] In some embodiments, R1is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl.

[0033] In some embodiments, R1is H.

[0034] In some embodiments, R1is 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.

[0035] In some embodiments, R1is 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 of R1is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0036] In some embodiments, R2is selected from H, C(O)R14, C(O)NR15R15, C(O)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, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl.

[0037] In some embodiments, R2is selected from H, C(O)R14, C(O)NR15R15, C(O)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, and 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.

[0038] In some embodiments, R2is selected from H, C(O)R14, C(O)NR15R15, C(O)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, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0039] In some embodiments, when R2is C(O)NR15R15, both R15can form a ring.

[0040] In some embodiments, when R2is C(O)NR15R15, both R15can form a ring, the ring contains the N of NR15R15.

[0041] In some embodiments, when R2is C(O)NR15R15, both R15can form a ring and the ring contains one further heteroatom selected from O and N.

[0042] In some embodiments, when R2is C(O)NR15R15, both R15can form a ring and the ring contains one further heteroatom selected N, then the ring is optionally substituted by R8.

[0043] In some embodiments, when R2is C(O)NR15R15, both R15can form a ring and the ring contains one further heteroatom selected N, then the ring is substituted by R8.

[0044] In some embodiments, R2is H.

[0045] In some embodiments, R2is C(O)R14, C(O)NR15R15, or C(O)OR15.

[0046] In some embodiments, R2is 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.

[0047] In some embodiments, R2is C(O)NR15R15.

[0048] In some embodiments, R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently C1-3 alkyl substituted by aryl or heteroaryl.

[0049] In some embodiments, R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently C1-3 alkyl substituted by aryl or heteroaryl.

[0050] In some embodiments, R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently 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.

[0051] In some embodiments, R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0052] In some embodiments, R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently 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.

[0053] In some embodiments, R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0054] In some embodiments, R3is H.

[0055] In some embodiments, R3is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0056] In some embodiments, R7is H.

[0057] In some embodiments, R7is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0058] In some embodiments, R3is C1-3 alkyl substituted by aryl or heteroaryl.

[0059] In some embodiments, R7is C1-3 alkyl substituted by aryl or heteroaryl.

[0060] In some embodiments, R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and 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.

[0061] In some embodiments, R4is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0062] In some embodiments, R5is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, and SR8.

[0063] In some embodiments, R5is H.

[0064] In some embodiments, R5is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR8, or SR8.

[0065] In some embodiments, R5can form a ring with any part of X or Y.

[0066] In some embodiments, the ring of R5contains a carbonyl group.

[0067] In some embodiments, R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R6is C1-3 alkyl substituted by C(O)NR8Rn; or R6is 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.

[0068] In some embodiments, R6is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R6is C1-3 alkyl substituted by C(O)NR8Rn; or R6is C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0069] In some embodiments, R6can form a ring with any part of X.

[0070] In some embodiments, R6is imidazolidinone.

[0071] In some embodiments, R8andR11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl.

[0072] In some embodiments, R8is H.

[0073] In some embodiments, R8is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0074] In some embodiments, R11is H.

[0075] In some embodiments, R11is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl.

[0076] In some embodiments, X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, and -S-C1-7 alkanediyl.

[0077] In some embodiments, X can form a ring or a polycyclic system with any part of R5, R6, or Y.

[0078] In some embodiments, X can form a ring with any part of R5, R6, or Y.

[0079] In some embodiments, X can form a polycyclic system with any part of R5, R6, or Y.

[0080] In some embodiments, the ring formed with X and any part of R5, R6, or Y optionally contains a carbonyl group.

[0081] In some embodiments, the ring formed with X and any part of R5, R6, or Y contains a carbonyl group.

[0082] In some embodiments, X is a bond.

[0083] In some embodiments, X is C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, or C4-6 cycloalkenediyl.

[0084] In some embodiments, X is -O-.

[0085] In some embodiments, X is C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, or C1-3 alkanediyl-O-Ci-7 alkanediyl.

[0086] In some embodiments, X is C1-7 heteroalkanediyl.

[0087] In some embodiments, X is -S-C1-7 alkanediyl.

[0088] In some embodiments, Y is selected from H, C(O)NR10R12, C(O)OR10, R10NC(O)NR10R12, OC(O)R10, OC(O)NR10R12, and S(O)nR8wherein n is 0, 1 or 2.

[0089] In some embodiments, Y is selected from SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, and C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N.

[0090] In some embodiments, Y is selected from SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, and C3-7-cycloalkyl containing a heteroatom in the ring selected from O and N.

[0091] In some embodiments, Y is selected from SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, and C3-7-cycloalkyl containing a heteroatom in the ring selected from O andN.

[0092] In some embodiments, Y is H.

[0093] In some embodiments, Y is C(O)NR10R12, C(O)OR10, R10NC(O)NR10R12, OC(O)R10, or OC(O)NR10R12.

[0094] In some embodiments, Y is S(O)nR8, wherein n is 0, 1 or 2.

[0095] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0096] In some embodiments, Y is SO2NR10R12, NR10SO2R10, NR10R12, or HNCOR8.

[0097] In some embodiments, Y is CN.

[0098] In some embodiments, Y is C3-7-cycloalkyl optionally containing a heteroatom in the ring selected from O and N.

[0099] In some embodiments, Y is C3-7-cycloalkyl containing a heteroatom in the ring selected from O and N.

[0100] In some embodiments, Y is C3-7-cycloalkyl containing a N heteroatom, wherein Y is optionally substituted by R8, S-aryl, O-aryl, S-heteroaryl, and O-heteroaryl, wherein the S- aryl, O-aryl, S-heteroaryl, or O-heteroaryl is optionally substituted by one or more R9or R14.

[0101] In some embodiments, Y is C3-7-cycloalkyl containing a N heteroatom, wherein Y is optionally substituted by R8, S-aryl, O-aryl, S-heteroaryl, and O-heteroaryl, wherein the S- aryl, O-aryl, S-heteroaryl, or O-heteroaryl is substituted by one or more R9or R14.

[0102] In some embodiments, Y is aryl or heteroaryl.

[0103] In some embodiments, Y can form a ring with any part of X or R5.

[0104] In some embodiments, Y can form a ring with any part of X or R5and the ring optionally contains a carbonyl group.

[0105] In some embodiments, Y can form a ring with any part of X or R5and the ring contains a carbonyl group.

[0106] In some embodiments, when Y is C(O)NR10R12or NR10R12, R10and R12can form a ring.

[0107] In some embodiments, 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.

[0108] In some embodiments, 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, further wherein if the one further heteroatom is N, the ring is optionally substituted by R8.

[0109] In some embodiments, 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, further wherein if the one further heteroatom is N, the ring is substituted by R8.

[0110] In some embodiments, 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(O)OR8, C1-5 alkyl-C(O)NR8Rn, C1-5 alkyl-C(O)R10, CN, C(O)R8, C(O)NR8Rn, C(O)OR8, NR8C(O)NR8Rn, OC(O)NR8RU, SO2NR8RU, NR8SO2R8, OR8, NR8RU, and S(O)nR8wherein n is 0, 1 or 2.

[0111] In some embodiments, R9is H.

[0112] In some embodiments, R9is a halogen.

[0113] In some embodiments, R9is C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, or C3-5 cycloalkyl.

[0114] In some embodiments, R9is C1-5 alkyl-OR8, C1-5 alkyl-SR8, C1-5 alkyl-NR8Rn, C1-5 alkyl-C(O)OR8, C1-5 alkyl-C(O)NR8Rn, or C1-5 alkyl -C(O)R10.

[0115] In some embodiments, R9is CN.

[0116] In some embodiments, R9is C(O)R8, C(O)NR8Rn, C(O)OR8, NR8C(O)NR8Rn, or OC(O)NR8Rn.

[0117] In some embodiment, R9is SO2NR8Rnor NR8SO2R8.

[0118] In some embodiments, R9is OR8.

[0119] In some embodiments, R9is NR8Rn.

[0120] In some embodiments, R9is S(O)nR8wherein n is 0, 1 or 2.

[0121] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0122] 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, and C1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8Rn.

[0123] 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, and C1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl is substituted by halogen, OR8, or NR8Rn.

[0124] 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, and C1-3 alkyl-heteroaryl.

[0125] In some embodiments, R10is H.

[0126] In some embodiments, R10is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn.

[0127] In some embodiments, R10is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is substituted by halogen, OR8, or NR8Rn.

[0128] In some embodiments, R10is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0129] In some embodiments, R10is C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3.

[0130] In some embodiments, R10is alkanediyl.

[0131] In some embodiments, R10is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8Rn.

[0132] In some embodiments, R10is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is substituted by halogen, OR8, or NR8Rn.

[0133] In some embodiments, R10is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl.

[0134] In some embodiments, R12is H.

[0135] In some embodiments, R12is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn.

[0136] In some embodiments, R12is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is substituted by halogen, OR8, or NR8Rn.

[0137] In some embodiments, R12is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0138] In some embodiments, R12is C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3.

[0139] In some embodiments, R12is alkanediyl.

[0140] In some embodiments, R12is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8Rn.

[0141] In some embodiments, R12is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is substituted by halogen, OR8, or NR8Rn.

[0142] In some embodiments, R12is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl.

[0143] In some embodiments, R13is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group.

[0144] In some embodiments, R13is C1-5 alkyl substituted by a bicyclic ring containing at least one heteroatom and a carbonyl group.

[0145] In some embodiments, R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and C1-3 alkyl substituted by aryl or heteroaryl.

[0146] In some embodiments, R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and 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.

[0147] In some embodiments, R14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0148] In some embodiments, R14is H.

[0149] In some embodiments, R14is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, or C1-3 alkyl substituted by aryl or heteroaryl.

[0150] In some embodiments, R14is 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.

[0151] In some embodiments, R14is 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 substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl.

[0152] In some embodiments, R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR8.

[0153] In some embodiments, R15is H.

[0154] In some embodiments, R15is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

[0155] In some embodiments, R15is OR8or C1-3 alkyl-OR8.

[0156] In some embodiments, the compound is of Formula (la), 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, and 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(O)R14, C(O)OR15, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl- OR8, C1-3 alkanediyl-O-Ci-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, and C1-3 alkyl substituted by aryl optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;R4is selected from C1-7 alkyl, C3-7 cycloalkyl, and 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, OR8, and SR8; and wherein R5can form a ring with any part of X or Y, wherein the ring optionally comprises a carbonyl group;R6is selected from H and C1-7 alkyl;R8and R11are each independently selected from H, C1-7 alkyl, and C3-7 cycloalkyl;X is selected from a bond, C1-7 alkanediyl, -O-C1-7 alkanediyl and -S-C1-7 alkanediyl; and wherein X can form a ring or a polycyclic system with any part of R5or Y, wherein the ring optionally contains a carbonyl group;Y is selected from H, C(O)NR10R12, NR10R12, CN, C3-7-cycloalkyl optionally comprising a heteroatom in the ring selected from O and N wherein if the heteroatom is N it is optionally substituted by R8, and heteroaryl 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 comprises 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, the N is optionally substituted by R8;R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, and C1-3 alkyl-aryl wherein the alkyl, cycloalkyl, or alkyl-aryl is optionally substituted by halogen;R13is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;R14is selected from H and C1-7 alkyl; and each R15is independently selected from H and C1-7 alkyl.

[0157] In some embodiments, the compound of Formula (la) is of Formula (I)or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:R1is C 1-7 alkyl;R2is selected from H, C(O)R14, C(O)OR15, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl- NHCOR13, and C1-3 alkyl substituted by aryl, wherein the aryl or is optionally substituted by halogen;R3and R7are each H;R4is C 1-7 alkyl;R5is selected from H, C1-7 alkyl, OR8, and 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 and C1-7 alkyl;R8and R11are each independently selected from H, C1-7 alkyl, and C3-7 cycloalkyl;X is selected from a bond, C1-7 alkanediyl, -O-C1-7 alkanediyl, and -S-C1-7 alkanediyl; and wherein X can form a ring with any part of R5or Y;Y is selected from H, NR10R12, and 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; or Y is 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, the ring is optionally substituted by R8;R10and R12are each independently selected from H, C1-7 alkyl, C3-7 cycloalkyl, and C1-3 alkyl-aryl, wherein the alkyl, cycloalkyl, and aryl are optionally substituted by halogen;R13is C1-5 alkyl substituted by a bicyclic ring optionally comprising at least one heteroatom and a carbonyl group;R14is selected from H and C1-7 alkyl; and each R15is independently selected from H and C1-7 alkyl.

[0158] In some embodiments, the compound is of Formula (la), or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:R1is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and 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(O)R14, C(O)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, and C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl;R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl; andR4is selected from C1-7 alkyl, C3-7 cycloalkyl, and 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.

[0159] In some embodiments, the compound is of Formula (la), or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:R1is selected from C3-7 alkyl, C3-7 cycloalkyl, and C1-3 alkyl substituted by aryl or heteroaryl;R2is selected from H and C(O)R14, wherein R14is C1-7 alkyl; or R2is C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl-OR8, or C1-5 alkyl-NHCOR13, wherein R13is pentylamino-5- oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; or R2is C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, C1-4 alkyl, or C3-5 cycloalkyl;R3and R7are H; andR4is selected from C3-7 alkyl, C3-7 cycloalkyl, and C1-3 alkyl substituted by aryl or heteroaryl.

[0160] In some embodiments, the compound of Formula (la) is of Formula (Ila), (lib), (lie), (Illa), (Illb), (IIIc), (Hid), (IVa), (IVb), (IVc), or (IVd):

[0161] In some embodiments, the compound of Formula (la) is of Formula (Va), (Vb), (Vc), (Vd), (Via), (VIb), (Vic), (Vid), (Vila), (Vllb), (Vile), (Vlld), (Vile), or (Vllf):or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein n5 is 0, 1, 2, 3, 4, 5, 6, or 7 and n8 is 0, 1, 2, 3, 4, 5, 6, or 7.

[0162] In some embodiments, the compound of Formula (la) 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.

[0163] In some embodiments, the compound is of Formula (la), or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:R5is C 1-7 alkyl or H;X is a bond or C1-7 alkanediyl; andY is H or CN.

[0164] In some embodiments, the compound of Formula (la) is of Formula (Villa), (Vlllb), (Vine), (Vllld), (Ville), (Vlllf), (Vlllg), (Vlllh), (Villi), (Vlllj), (Vlllk), (VIII1), (IXa), (IXb), (IXc), or (IXd):or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Qi and Q2 are each independently O, S, NR8, or CR8and nlO is 0, 1, 2, 3, 4, 5, 6, or 7.

[0165] In some embodiments, the compound of Formula (la) is of Formula (Villi), (Vlllk), (VIII1), (IXc), or (IXd):or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Qi and Q2 are each independently O, S, NR8, or CR8and nlO is 0, 1, 2, 3, 4, 5, 6, or 7.

[0166] In some embodiments, the compound of Formula (la) is of Formula (IXd):or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

[0167] In some aspects, the compound of Formula (la) is a Compound 1 which may be identified with the IUPAC name of (S)-3-isobutyl-l-((S)-4-methyl-l-((S)-8-methyl-3-(pyrrolidin- 1 -ylmethyl)- 1 , 5-dioxa-9-azaspiro[5.5]undecan-9-yl)- 1 -oxopentan-2 - yl)piperazin-2-one and / or the following chemical structure:(Compound 1).

[0168] In some embodiments, Compound l is a methanesulfonic acid salt (mesylate).

[0169] In some aspects, the compound of Formula (la) is a Compound 1’ which may be identified with the name (S)-3-isobutyl-l-((S)-4-methyl-l-((3R,6s,8S)-8-methyl-3- (pyrrolidin- 1 -ylmethyl)- 1 , 5-dioxa-9-azaspiro[5.5]undecan-9-yl)- 1 -oxopentan-2 - yl)piperazin-2-one, (S)-l-[(S)-l-({(S)-8-Methyl-3-[(l-pyrrolidinyl)methyl]-l,5-dioxa-9- aza-9-spiro[5.5]undecyl } carbonyl)-3 -methylbutyl]-3 -isobutyl-2-piperazinone, (3 S)- 1 -[(2S)-4-methyl-l-oxo-l-[(3s,6s,8S)-8-methyl-3-(pyrrolidin-l-ylmethyl)-l,5-dioxa-9- azaspiro[5.5]undecan-9-yl]pentan-2-yl]-3-(2-methylpropyl)piperazin-2-one, and / or the following chemical structure:(Compound 1’).

[0170] In some embodiments, Compound 1’ is a methanesulfonic acid salt (mesylate).

[0171] In some embodiments, Compound 1 is Compound 1’.

[0172] In some embodiments, Compound 1 ’ binds NELF-C / NELF-D (also referred to herein as “NELFCD”). In some embodiments, the Compound 1’ binding site is near the NELFA- NELFCD interaction. In some embodiments, the NELFA-NELFCD interaction is a hinge site.

[0173] In some embodiments, Compound 2 is the inactive stereoisomer of Compound 1’. In some embodiments, Compound 2 is:

[0174] In some embodiments, Compound 2 does not bind in the NELFCD active site.

[0175] In some aspects, the compound of Formula (la) is a Compound 3 and a Compound 4 with chemical structures as follows:(Compound 3) and(Compound 4).

[0176] In some embodiments, Compound 3 and Compound 4 do not bind in the NELFCD active site.

[0177] In some embodiments, a compound of Formula (la) is selected from Table 1.Table 1: Compounds according to Formula (la)

[0178] The preparation of the compounds of the disclosure can be found in PCT Publication No. WO2019 / 118973A1 which is incorporated by reference in its entirety for all purposes.

[0179] 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. In some embodiments, the preparation of a compound of the disclosure is described below in General Scheme I, General Scheme II, and General Scheme III.General Scheme 1 (Method A)

[0180] 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 R2is C(O)R14, C(O)NR15R15or C(O)OR15are obtained by acylation of the secondary amine. The compounds where is R2 not the above are obtained by reductive amination of the secondary amine with the appropriate aldehyde or ketone.General Scheme 2 (Method Bl and B2)

[0181] Method Bl : Using the appropriate precursor Illa 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.

[0182] Method B2: Z can be elaborated into the desired functional group using reaction sequences described in Table X. In cases where the 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. The compounds where R2is C(O)R14, C(O)NR15R15or C(O)OR15are obtained by acylation of the secondary amine at this point. The compounds where R2is not the above are obtained by reductive amination of the secondary amine with the appropriate aldehyde or ketone.General Scheme 3 (Method C)

[0183] 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 I. When P2 is a protected alcohol such as OTHP or OTB DMS, 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.Compositions of the present disclosure

[0184] The disclosure also provides pharmaceutical compositions comprising a compound of Formula (la) of the present disclosure and a pharmaceutically acceptable diluent, adjuvant, excipient, or carrier.

[0185] In some embodiments, the compound of Formula (la) is present in a therapeutically effective amount.

[0186] In some embodiments, the pharmaceutical composition further comprises another pharmaceutically active agent.

[0187] 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.

[0188] In some embodiments, the invention provides a pharmaceutical composition comprising Compound 1 and at least one pharmaceutically acceptable diluent, adjuvant, excipient, or carrier.

[0189] In some embodiments, the invention provides a pharmaceutical composition comprising Compound 1’ and at least one pharmaceutically acceptable diluent, adjuvant, excipient, or carrier.

[0190] In some embodiments, the pharmaceutical compositions comprise a compound of the present disclosure in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier, adjuvant, diluent, or excipient.

[0191] In some embodiments, the pharmaceutical compositions of this application can be administered to humans and other animals orally, rectally, parenterally, intraci sternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, or as an oral or nasal spray.

[0192] The preparation of the compounds of the disclosure may be found in PCT Publication No. WO2019 / 118973A1 which is incorporated by reference in its entirety for all purposes.Methods of the present disclosure

[0193] In some aspects, the disclosure provides methods of modulating NELF, wherein the method comprises administering to a subject a compound of Formula (la) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

[0194] In some aspects, the disclosure provides methods of modulating NELF, wherein the method comprises administering Compound 1, or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, to a subject.

[0195] In some aspects, the disclosure provides methods of modulating NELF, wherein the method comprises administering Compound L, or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, to a subject.

[0196] In some aspects, the disclosure also provides methods of modulating NELF, wherein the method comprises administering to a subject a composition comprising a compound of Formula (la) or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

[0197] In some aspects, the disclosure also provides methods of modulating NELF, wherein the method comprises administering to a subject a composition comprising Compound 1 or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

[0198] In some aspects, the disclosure also provides methods of modulating NELF, wherein the method comprises administering to a subject a composition comprisingCompound 1’ or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof.

[0199] In some embodiments, the compound or composition is administered in a therapeutically effective amount.

[0200] In some embodiments, the disclosure provides a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in modulating NELF in a subject. In some embodiments, the disclosure provides a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in modulating NELF in a subject.

[0201] In some embodiments, the disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in modulating NELF in a subject. In some embodiments, the disclosure provides a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in modulating NELF in a subject.

[0202] In some embodiments, the disclosure provides Compound L, or a pharmaceutically acceptable salt thereof, for use in modulating NELF in a subject. In some embodiments, the disclosure provides a composition comprising Compound L, or a pharmaceutically acceptable salt thereof, for use in modulating NELF in a subject.

[0203] In some embodiments, the disclosure provides use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the modulation of NELF in a subject. In some embodiments, the disclosure provides use of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the modulation of NELF in a subject.

[0204] In some embodiments, the disclosure provides use of a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for the modulation of NELF in a subject. In some embodiments, the disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof, for the modulation of NELF in a subject.

[0205] In some embodiments, the disclosure provides use of a composition comprising Compound L, or a pharmaceutically acceptable salt thereof, for the modulation of NELF in a subject. In some embodiments, the disclosure provides use of Compound L, or a pharmaceutically acceptable salt thereof, for the modulation of NELF in a subject.

[0206] In some embodiments, the disclosure provides use of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of NELF in a subject. In some embodiments, the disclosure also provides use of a composition comprising a compound of Formula (la), or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for the modulation of NELF in a subject.

[0207] In some embodiments, the disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of NELF in a subject. In some embodiments, the disclosure also provides use of a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of NELF in a subject.

[0208] In some embodiments, the disclosure provides use of Compound L, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of NELF in a subject. In some embodiments, the disclosure also provides use of a composition comprising Compound L, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of NELF in a subject.

[0209] In some embodiments, modulating NELF treats a disease or disorder.

[0210] In some embodiments, modulation is inhibition.

[0211] The present disclosure also provides methods of treating a disease or disorder in a subject wherein NELF is implicated comprising administering to a subject, a compound of Formula (la), or a pharmaceutically acceptable salt thereof.

[0212] The present disclosure also provides methods of treating a disease or disorder in a subject wherein NELF is implicated comprising administering Compound 1 or a pharmaceutically acceptable salt thereof, to a subject.

[0213] The present disclosure also provides methods of treating a disease or disorder in a subject wherein NELF is implicated comprising administering Compound L, or a pharmaceutically acceptable salt thereof, to a subject.

[0214] In some embodiments, the disclosure provides a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein NELF is implicated. In some embodiments, the disclosure provides a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein NELF is implicated.

[0215] In some embodiments, the disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein NELF is implicated. In some embodiments, the disclosure provides a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein NELF is implicated.

[0216] In some embodiments, the disclosure provides Compound 1’, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein NELF is implicated. In some embodiments, the disclosure provides a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein NELF is implicated.

[0217] In some embodiments, the disclosure provides use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the treatment of a disease or a disorder in a subject wherein NELF is implicated. In some embodiments, the disclosure provides use of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the treatment of a disease or a disorder in a subject wherein NELF is implicated.

[0218] In some embodiments, the disclosure provides use of a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or a disorder in a subject wherein NELF is implicated. In some embodiments, the disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or a disorder in a subject wherein NELF is implicated

[0219] In some embodiments, the disclosure provides use of a composition comprising Compound L, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or a disorder in a subject wherein NELF is implicated. In some embodiments, the disclosure provides use of Compound L, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or a disorder in a subject wherein NELF is implicated.

[0220] In some embodiments, the disclosure provides use of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein NELF is implicated. In some embodiments, the disclosure also provides use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein NELF is implicated.

[0221] In some embodiments, the disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein NELF is implicated. In some embodiments, the disclosure also provides use of a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein NELF is implicated.

[0222] In some embodiments, the disclosure provides use of Compound 1’, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein NELF is implicated. In some embodiments, the disclosure also provides use of a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein NELF is implicated.

[0223] In some embodiments, the disease or disorder where NELF is implicated is Human immunodeficiency virus (HIV), Wolf-Hirschhorn syndrome (WHS), an inflammatory disease, disorder, or condition, or a neurological disease.

[0224] The present disclosure also provides methods of treating a disease or disorder in a subject wherein NELF is implicated comprising administering to a subject, a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof.

[0225] The present disclosure also provides methods of treating a disease or disorder in a subject wherein NELF is implicated comprising administering to a subject, a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof.

[0226] The present disclosure also provides methods of treating a disease or disorder in a subject wherein NELF is implicated comprising administering to a subject, a composition comprising Compound L, or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the compound or composition is administered in a therapeutically effective amount.

[0228] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a pediatric subject. In some embodiments, the subject is an adult subject.

[0229] In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer is a solid tumor.

[0230] In some embodiments, the cancer is prostate cancer, renal cancer, pancreatic cancer, liver cancer, breast cancer, gastric cancer, testicular cancer, colorectal cancer, cervical cancer, ovarian cancer, head-and-neck cancer, esophageal cancer, leukemia, lymphoma, lung cancer, brain cancer, stomach cancer, cancer of the central nervous system, or skin cancer.

[0231] In some embodiments, the cancer is pancreatic cancer, osteosarcoma, gastric cancer, prostate cancer, breast cancer, small cell lung cancer, adenocarcinoma, neuroendocrine cancer, melanoma, lymphoma, or leukemia.

[0232] In some embodiments, the cancer the cancer is lung cancer, prostate cancer, or stomach cancer.

[0233] In some embodiments, the cancer is prostate cancer. In some embodiments, the prostate cancer is castration resistant prostate cancer.

[0234] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is small-cell lung cancer.

[0235] In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is renal cell carcinoma.

[0236] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is associated with a BRCA1 mutation. In some embodiments, the subject has a BRCA germline mutation. In some embodiments, BRCA mutation results in BRCA-1 deficient cells.

[0237] In some embodiments, the cancer is leukemia. In some embodiments, the leukemia is chronic myeloid leukemia, acute T lymphocytic leukemia, or chronic lymphocytic leukemia.

[0238] In some embodiments, the cancer is the cancer is a myeloma. In some embodiments, the myeloma is multiple myeloma. In some embodiments, the administration of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, to a subject, results in RNA accumulation outside of the nucleus.

[0239] In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is a colon adenocarcinoma. In some embodiments, the cancer is a rectum adenocarcinoma. In some embodiments, the colorectal cancer is associated with in an overexpression of NELFCD compared to healthy or noncancerous tissue. In some embodiments, the colorectal cancer is associated in increase in copy number alteration of NELFCD. In some embodiments, NELF expression is correlated with copy number alteration.

[0240] In some embodiments, the administration of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, to a subject, results in stress granule accumulation outside of the nucleus.

[0241] In some embodiments, the administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject, results in stress granule accumulation outside of the nucleus.

[0242] In some embodiments, the administration of Compound 1’, or a pharmaceutically acceptable salt thereof, to a subject, results in stress granule accumulation outside of the nucleus.

[0243] In some embodiments, the cancer causes or results in aberrant NELF expression or activity.

[0244] In some embodiments, the compound of Formula (la) is Compound 1. In some embodiments, the compound of Formula (la) is Compound 1’. In some embodiments, the compound of Formula (la) is a compound selected from the compounds described in Table Lin some embodiments, the disease or disorder is associated with aberrant NELF activity or expression.

[0245] In some embodiments, the aberrant NELF activity or expression is caused by a mutation in gene encoding NELF or a NELF member. In some embodiments, the aberrant NELF activity or expression is related to a mutation in the gene encoding NELF or a NELF member.

[0246] In some embodiments, the disease or disorder is caused by aberrant NELF activity or expression. In some embodiments, the aberrant NELF expression is an overexpression of NELF or NELF members as compared to a control level of expression observed in individuals not having the disease or disorder. In some embodiments, the aberrant expression is an amplification of the NELF or NELF members as compared to a control level of expression observed in individuals not having the disease or disorder. In some embodiments, the aberrant expression is an amplification of the gene encoding NELF or NELF members as compared to a control level of expression observed in individuals not having the disease or disorder. In some embodiments, the overexpression of NELF or NELF members is an overexpression of NELFCD.

[0247] In some embodiments, the administration of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, to a subject, results in the modulation of NELF expression or activity.

[0248] In some embodiments, the administration of a compound of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject, results in the modulation of NELF expression or activity.

[0249] In some embodiments, the administration of Compound L, or a pharmaceutically acceptable salt thereof, to a subject, results in the modulation of NELF expression or activity.

[0250] In some embodiments, the modulation of NELF expression or activity treats the disease or disorder.

[0251] In some embodiments, the administration of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, to a subject, results in the downregulation of NELF expression or activity.

[0252] In some embodiments, the administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject, results in the downregulation of NELF expression or activity.

[0253] In some embodiments, the administration of Compound L, or a pharmaceutically acceptable salt thereof, to a subject, results in the downregulation of NELF expression or activity.

[0254] In some embodiments, the downregulation of NELF is a downregulation of NELFCD.

[0255] In some embodiments, the downregulation of NELF expression or activity results in the treatment of the disease or disorder. In some embodiments, the disease or disorder treated by NELF downregulation is colorectal cancer.

[0256] The present disclosure provides a method of identifying a subject for treatment with a compound of Formula (la), or a pharmaceutically acceptable salt thereof, the method comprising: i) determining if a subject has a 20q amplification; and ii) identifying the subject for treatment with a compound of Formula (la), or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0257] The present disclosure provides a method of identifying a subject for treatment with Compound 1, or a pharmaceutically acceptable salt thereof, the method comprising: i) determining if a subject has a 20q amplification; and ii) identifying the subject for treatment with Compound 1, or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0258] The present disclosure provides a method of identifying a subject for treatment with Compound L, or a pharmaceutically acceptable salt thereof, the method comprising: i) determining if a subject has a 20q amplification; and ii) identifying the subject for treatment with Compound L, or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0259] The present disclosure provides a method of identifying a subject for treatment with a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, the method comprising: i) determining if a subject has a 20q amplification; andii) identifying the subject for treatment with a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0260] The present disclosure provides a method of identifying a subject for treatment with a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, the method comprising: i) determining if a subject has a 20q amplification; and ii) identifying the subject for treatment with a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0261] The present disclosure provides a method of identifying a subject for treatment with a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, the method comprising: i) determining if a subject has a 20q amplification; and ii) identifying the subject for treatment with a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0262] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: i) determining if a subject has a 20q amplification; and ii) administering to the subject a compound of Formula (la), or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0263] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: i) determining if a subject has a 20q amplification; and ii) administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject when the subject is identified as having a 20q amplification.

[0264] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: i) determining if a subject has a 20q amplification; and ii) administering Compound 1’, or a pharmaceutically acceptable salt thereof, to the subject when the subject is identified as having a 20q amplification.

[0265] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: i) determining if a subject has a 20q amplification; and ii) administering to the subject a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0266] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: i) determining if a subject has a 20q amplification; and ii) administering to the subject a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0267] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising: i) determining if a subject has a 20q amplification; and ii) administering to the subject a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, when the subject is identified as having a 20q amplification.

[0268] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein the subject has a 20q amplification.

[0269] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering Compound 1, or a pharmaceutically acceptable salt thereof, to the subject, wherein the subject has a 20q amplification.

[0270] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering Compound 1’, or a pharmaceutically acceptable salt thereof, to the subject, wherein the subject has a 20q amplification.

[0271] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, wherein the subject has a 20q amplification.

[0272] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject, a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the subject has a 20q amplification.

[0273] The present disclosure provides a method of treating a disease or disorder in a subject, the method comprising administering to the subject, a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, wherein the subject has a 20q amplification.

[0274] In some embodiments, the disclosure provides a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein the subject has a 20q amplification.

[0275] In some embodiments, the disclosure provides Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein the subject has a 20q amplification.

[0276] In some embodiments, the disclosure provides Compound 1’, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein the subject has a 20q amplification.

[0277] In some embodiments, the disclosure provides a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein the subject has a 20q amplification.

[0278] In some embodiments, the disclosure provides a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein the subject has a 20q amplification.

[0279] In some embodiments, the disclosure provides a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject wherein the subject has a 20q amplification.

[0280] In some embodiments, the disclosure provides use of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein 20q is amplified. In some embodiments, the disclosure also provides use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein 20q is amplified.

[0281] In some embodiments, the disclosure provides use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein 20q is amplified. In some embodiments, the disclosure also provides use of a composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein 20q is amplified.

[0282] In some embodiments, the disclosure provides use of Compound 1’, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein 20q is amplified. In some embodiments, the disclosure also provides use of a composition comprising Compound 1’, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder wherein 20q is amplified.

[0283] In some embodiments, determining if a subject has a 20q amplification comprises performing a cytological analysis of a biological sample from the subject using any suitable method known in the art for determining the presence of a 20q amplification.

[0284] In some embodiments, determining if a subject has a 20q amplification comprises performing sequencing analysis of a biological sample from the subject.

[0285] In some embodiments, determining if a subject has a 20q amplification comprises microarray analysis.

[0286] In some embodiments, determining if a subject has a 20q amplification comprises karyotype analysis.

[0287] In some embodiments, 20q amplification is related to a disease or disorder. In some embodiments, 20q amplification causes a disease or disorder. In some embodiments, 20q amplification is characterized by an amplification of one or more of PLAGL2, POFUT1, PIGU, AAR2, ZSWIM3, STAU1, NELFCD, and / or YTHDF1. In some embodiments, 20q amplification is characterized by an amplification of NELFCD.

[0288] In some embodiments, the disease or disorder is indicated by a mutation of the chromosome 20q region. In some embodiments, the mutation of the chromosome 20q region is amplification. In some embodiments, the disease or disorder is indicated by amplification of the chromosome 20q region.

[0289] In some embodiments of the proceeding methods, the disease or disorder is cancer. In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is prostate cancer, renal cancer, pancreatic cancer, liver cancer, breast cancer, gastric cancer, testicular cancer, colorectal cancer, cervical cancer, ovarian cancer, head-and-neck cancer, esophageal cancer, leukemia, lymphoma, lung cancer, brain cancer, stomach cancer, cancer of the central nervous system, or skin cancer.

[0290] Negative elongation factor (NELF) is a four-subunit (also referred to herein as a four-member) complex comprising NELF-A, NELF-B (also referred to as COBRA1), NELF-C / NELF-D, and NELF-E. NELF is found in the nucleus and is known to negatively impact transcription. NELF forms a complex with DISF (5,6-Dichloro-l-P-D- ribofuranosylbenzimidazole (DRB)-sensitivity inducing factor) and RNA Polymerase II (Pol II). It is thought that NELF impacts transcription and gene expression through RNA polymerase II by slowing the Pol II speed and pausing about 20-60 nucleotides downstream from the transcription start site (TSS).

[0291] In some embodiments, the NELF complex is negative elongation factor complex member B (NELFB).In some embodiments, the NELF complex is negative elongation factor complex member C / D (NELFCD). NELFCD is located on the long arm of chromosome 20 (20q) at location 20ql3.32.

[0292] In some embodiments, NELFB and NELFC or NELFD are used to bring together the NELF A and NELFE subunits.

[0293] In some embodiments, the administration of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, to a subject, results in RNA accumulation outside of the nucleus. In some embodiments, the administration of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, to a subject, results in stress granule accumulation outside of the nucleus.

[0294] In some embodiments, the administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject, results in RNA accumulation outside of the nucleus. In some embodiments, the administration of Compound 1, or a pharmaceutically acceptable salt thereof, to a subject, results in stress granule accumulation outside of the nucleus.

[0295] In some embodiments, the administration of Compound 1’, or a pharmaceutically acceptable salt thereof, to a subject, results in RNA accumulation outside of the nucleus. In some embodiments, the administration of Compound 1’, or a pharmaceutically acceptable salt thereof, to a subject, results in stress granule accumulation outside of the nucleus.

[0296] In some embodiments, a compound of the present disclosure binds to the NELF complex or a member of the NELF complex which results in the modulation of NELF expression and / or activity. In some embodiments, a compound of the present disclosure binds NELFCD which results in the modulation of NELF expression and / or activity. In some embodiments, a compound of the present disclosure binds near the NELFA- NELFCD interaction which results in the modulation of NELF expression and / or activity. In some embodiments, the NLEFA-NELFCD interaction is a hinge site.Biological Assays

[0297] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0298] Furthermore, high-throughput screening can be used to accelerate analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0299] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0300] In some embodiments, the biological assay is described in the Examples herein.

[0301] In some embodiments, binding is measured using Cellular Thermal Shift Assay (CETSA®). CETSA® is a technique for measuring and identifying a compound binding to target proteins. CETSA® detects a change in protein thermal stability induced by ligand binding. In some embodiments, the binding is measured using CETSA® utilizing mass spectroscopy as a detection method. In some embodiments, CETSA® is combined with thermal proteome profiling (TPP) which allows for unbiased proteome wide analysis of ligand-interacting proteins.

[0302] In some embodiments, binding is measured using a proteome integral solubility alteration (PISA) assay. In some embodiments, CETSA® in combination with TPP is referred to as PISA. PISA is a technique for measuring and identifying compound binding to target proteins. PISA provides analysis of the changes in the amount of the soluble fraction of proteins in response to heat exposure using quantitative proteomics by Mass Spectrometry. In some embodiments, the PISA method can be applied to living cells for studying target engagement in vivo or using protein lysates to identify in vitro ligandinteracting proteins.

[0303] In some embodiments, binding is interrogated using computational or in silico techniques. In some embodiments, binding is interrogated using computational ligand binding or molecular docking software. In some embodiments, protein structures are identified using Protein Data Bank (PDB). In some embodiments, hydrogens are added to the structure using Reduce (version 3.3.160602; Word et al., 1999). In some embodiments, structures are prepared for molecular docking studies using Ligprep (Schrodinger, LLC, New York, NY, 2023 -vl). In some embodiments, partial electronic charges are calculated for each atom of the compound using Maetro (Schrodinger, LLC, New York, NY, 2023 -vl).In some embodiments, the structures are visually inspected to identify potential binding sites using the Bodil Modeling Environment (v.0.9; Lehtonen et al., 2004). In some embodiments, molecular docking is performed using Plants (version 1.2; Korb et al., 2007) to model the binding of a compound of the present disclosure to a protein of interest (e.g. NELF). Other suitable software systems would be known to a person of ordinary skill in the art.Definitions

[0304] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. Notwithstanding the foregoing, and except where stated otherwise, the following definitions apply throughout the specification and claims.

[0305] As used herein, “alkyl”, “Ci, C2, C3, C4, C5or C6alkyl” or “Ci-C6alkyl” is intended to include Ci, C2, C3, C4, Cs or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C2, C3, C4, Cs or Ce branched saturated aliphatic hydrocarbon groups. For example, CrC6alkyl is intends to include CbC2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-Ce for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0306] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-Ce for straight chain, C3-Ce for branched chain). The term “C2-Ce” includes alkenyl groups containing two to six carbon atoms. The term “C3-Ce” includes alkenyl groups containing three to six carbon atoms.

[0307] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-Ce for straight chain, C3-Ce for branchedchain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “Cs-Ce” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6 alkenylene linker” or “C2-C6 alkynylene linker” is intended to include C2, C3, C4, C5 or Ce chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6alkenylene linker is intended to include C2, C3, C4, C5 and Ce alkenylene linker groups

[0308] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or Cs-Cs). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0309] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1, 2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6- diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, 1- oxaspiro[4.5]decanyl, l-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofuran]- yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4- c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1, 4,5,6- tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4, 5,6,7- tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2- methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl,2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be nonaromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0310] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.

[0311] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1- 4 or 1-5 or 1-6 heteroatoms, or e.g. , 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulphur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, as defined). The nitrogen and sulphur heteroatoms may optionally be oxidized (i.e., N^O and S(O)P, where p = 1 or 2). It is to be noted that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0312] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodi oxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine, and the like.

[0313] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulphhydryl, alkylthio, arylthio, thiocarboxylate, sulphates, alkylsulphinyl, sulphonato, sulphamoyl, sulphonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][l,3]dioxole-5-yl).

[0314] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), then 2 hydrogen atoms on the atom are replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0315] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0316] When any variable (e.g., R) 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 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0317] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or the corresponding anion, -O'.

[0318] As used herein, the term “halo” or “halogen” refers to fluorine, chlorine, bromine and iodine.

[0319] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in theliterature, 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; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); 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), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art. In some embodiments, the compounds of the present disclosure may be prepared as described in WO 2022 / 036080, which is incorporated by reference herewith in its entirety for all purposes.

[0320] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0321] Optionally substituted moieties (such as optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted aryl moieties include those which are halogen and / or Ci-Ce alkyl substituted; substituted heteroaryl moieties include 2,6-dimethylpyridinyl; and substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2, 2,6,6- tetramethyl-piperidinyl, and 2,2,6,6-tetramethyl-l,2,3,6-tetrahydropyridinyl.

[0322] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement.Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.

[0323] As used herein the term “geometric isomer” refers to cyclic compounds having at least two substituents, wherein the two substituents are both on the same side of the ring (cis) or wherein the substituents are each on opposite sides of the ring (trans). When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.

[0324] When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geometric isomers in the mixture.

[0325] Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer. When a compound with one chiral center is named or depicted without indicating the stereochemistry of the chiral center, it is understood that the name or structure encompasses both possible enantiomeric forms (e.g., both enantiomerically-pure, enantiomerically-enriched or racemic) of the compound. When a compound with two or more chiral centers is named or depicted without indicating the stereochemistry of the chiral centers, it is understood that the name or structure encompasses all possible diastereomeric forms (e.g., diastereomerically pure, diastereomerically enriched and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures) of the compound.

[0326] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0327] When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is theweight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0328] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0329] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0330] The term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0331] Compounds having basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, methanesulfonic acid (mesylate), succinic acid, and trifluoroacetic acid). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). In some embodiments, Formula (la) is a citric acid salt. In some embodiments, Formula (la) is a methanesulfonic acid salt (mesylate).

[0332] Unless explicitly indicated otherwise, the terms “approximately” and “about” are synonymous. In some embodiments, “approximately” and “about” refer to the recited amount, value, or duration ± 5%, ± 4.5%, ± 4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ± 0.5% ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01%. In another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ± 0.5%. In yet another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±1%. In yet another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±0.5%. In yet another embodiment, “approximately” and “about” refer to the listed amount, value, or duration ±0.1%.

[0333] As used herein, “pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

[0334] The pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5thEd., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitableformulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF 19) published in 1999. The carriers, diluents and / or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0335] In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0336] In some embodiments, the pharmaceutical composition is formulated for intravenous administration.

[0337] 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.

[0338] It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in 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, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0339] As used herein the term “modulation” includes the inhibition of one or more functions of NELF, the increase in one or more functions of NELF, or a qualitative change in one or more functions of NELF.

[0340] The precise amount of compound administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The term “effective amount” means an amount when administered to the subject which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control.

[0341] As used herein, the terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0342] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, the particular treatment).

[0343] The compounds or the corresponding pharmaceutical compositions taught herein can be administered to a patient in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. The compounds of the present teachings may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0344] One of skill in the art can select from a variety of administration regimens and will understand that an effective amount of a particular a compound or pharmaceutical composition of the disclosure may be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and / or the judgment of the prescribing physician.

[0345] Cancer is a disease caused by the uncontrolled division of cells in the body. 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.EXEMPLARY EMBODIMENTS

[0351] Exemplary Embodiment 1. A method of modulating negative elongation factor complex (NELF) comprising administering to a subject a compound of Formula (la):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, and 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;R2is selected from H, C(O)R14, C(O)NR15R15, C(O)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-3alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR13, and 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(O)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, the ring is optionally substituted by R8;R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently 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, and 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, and 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, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R6is C1-3 alkyl substituted by C(O)NR8Rn; or R6is 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 R6is imidazolidinone;R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, and -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(O)OR10, R10NC(O)NR10R12, OC(O)R10, OC(O)NR10R12, S(O)nR8wherein n is 0, 1 or 2, SO2NR10R12, NR10SO2R10, NR10R12, HNCOR8, CN, C3-7-cycloalkyl optionally containing a heteroatom in the ring selected fromO and N, wherein if the heteroatom is N it is optionally substituted by R8, S-aryl, O-aryl, S- heteroaryl, and O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl is optionally substituted by one or more R9or R14; or Y is 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, the ring 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(O)OR8, C1-5 alkyl- C(O)NR8Rn, C1-5 alkyl-C(O)R10, CN, C(O)R8, C(O)NR8Rn, C(O)OR8, NR8C(O)NR8Rn, OC(O)NR8Rn, SO2NR8RU, NR8SO2R8, OR8, NR8RU, and S(O)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, and C1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8Rn;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, and 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 each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR8.

[0352] Exemplary Embodiment 2. A composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in modulating negative elongation factor complex (NELF) in a subject.

[0353] Exemplary Embodiment 3. A compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in modulating negative elongation factor complex (NELF) in a subject.

[0354] Exemplary Embodiment 4. Use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the modulation of negative elongation factor complex (NELF) in a subject.

[0355] Exemplary Embodiment 5. Use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of negative elongation factor complex (NELF) in a subject.

[0356] Exemplary Embodiment 6. Use of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the modulation of negative elongation factor complex (NELF) in a subject.

[0357] Exemplary Embodiment 7. Use a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of negative elongation factor complex (NELF) in a subject.

[0358] Exemplary Embodiment 8. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the modulation treats a disease or disorder.

[0359] Exemplary Embodiment 9. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the compound of Formula (la) is Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

[0360] Exemplary Embodiment 10. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the compound of Formula (la) is Compound 1 ’ :(Compound 1’), or a pharmaceutically acceptable salt thereof.

[0361] Exemplary Embodiment 11. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the negative elongation factor complex is negative elongation factor complex member B (NELFB).

[0362] Exemplary Embodiment 12. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the negative elongation factor complex is negative elongation factor complex member C / D (NELFCD).

[0363] Exemplary Embodiment 13. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the subject is a mammal.

[0364] Exemplary Embodiment 14. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the subject is a human.

[0365] Exemplary Embodiment 15. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the disease or disorder is cancer.

[0366] Exemplary Embodiment 16. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer comprises a liquid tumor or a solid tumor.

[0367] Exemplary Embodiment 17. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is prostate cancer, renal cancer, pancreatic cancer, liver cancer, breast cancer, gastric cancer, testicular cancer, colorectal cancer, cervical cancer, ovarian cancer, head-and-neck cancer, esophageal cancer, leukemia, lymphoma, lung cancer, brain cancer, stomach cancer, cancer of the central nervous system, or skin cancer.

[0368] Exemplary Embodiment 18. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is pancreatic cancer, osteosarcoma, gastric cancer, prostate cancer, breast cancer, small cell lung cancer, adenocarcinoma, neuroendocrine cancer, melanoma, lymphoma or leukemia.

[0369] Exemplary Embodiment 19. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is lung cancer, prostate cancer, or stomach cancer.

[0370] Exemplary Embodiment 20. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is prostate cancer.

[0371] Exemplary Embodiment 21. The method, compound, composition, or use of Exemplary Embodiment 20, wherein the prostate cancer is castration resistant prostate cancer.

[0372] Exemplary Embodiment 22. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is lung cancer.

[0373] Exemplary Embodiment 23. The method, compound, composition, or use of Exemplary Embodiment 22, wherein the lung cancer is small-cell lung cancer.

[0374] Exemplary Embodiment 24. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is colon cancer.

[0375] Exemplary Embodiment 25. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is leukemia.

[0376] Exemplary Embodiment 26. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the leukemia is chronic myeloid leukemia, acute T lymphocytic leukemia, or chronic lymphocytic leukemia.

[0377] Exemplary Embodiment 27. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is myeloma.

[0378] Exemplary Embodiment 28. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the myeloma is multiple myeloma.

[0379] Exemplary Embodiment 29. The method, compound, composition, or use of Exemplary Embodiment 15, wherein the cancer is renal cell carcinoma.

[0380] Exemplary Embodiment 30. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the modulation is inhibition.

[0381] Exemplary Embodiment 31. The method of any one of the preceding Exemplary Embodiments, wherein negative elongation factor complex (NELF) is overexpressed.

[0382] Exemplary Embodiment 32. The method of Exemplary Embodiment 51, wherein the overexpression of a NELF member is an increase in expression of a NELF member as compared to a control level of expression observed in individuals not having the disease or disorder.

[0383] Exemplary Embodiment 33. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the compound of Formula (la) is selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0384] Exemplary Embodiment 34. The method, compound, composition, or use of any one of the preceding Exemplary Embodiments, wherein the compound is selected from a genus or compound disclosed in PCT / US2018 / 066027, which is herein incorporated by reference.EXAMPLESExample 1: Compound 1’- protein interactionsMethods

[0385] The proteome integral solubility alteration (PISA) assay, commonly named “PISA” was applied using either intact HCT116 colon cancer cells or HCT116 cell lysates (lysed by3x freeze thaw). A schematic of an exemplary experimental set up is shown in FIG. 2. The whole cell or cell lysates were prepared at 4 concentrations (30, 10, 3, and 1pm) and subsequently incubated for 60 min at 37°C (whole cell) or 15 minutes at room temperature (lysate). The assay was performed using water as a negative control and 10 pm staurosporine as the positive control.

[0386] Each drug-treated or vehicle-treated sample was exposed to a gradient of temperatures (44-66 °C), inducing protein aggregation and precipitation (method described in Savitski M. M., et al. (2014) Tracking of cancer drugs in living cells was performed by thermal profiling of the proteome. 346(6205): 1255784, the contents of which are incorporated herein in their entirety). Each soluble fraction was then isolated (as the supernatant after 20 minutes of centrifugation at 30.0xg) and recomposed into one sample to allow for Tandem Mass Tag (TMT) labeling of the individual samples. Subsequently, quantitative proteomics was applied across all multiplexed biological samples. Proteins interacting with the tested molecules (e.g., targets and off-targets), show reproducible changes in their soluble amount compared to vehicle-treated controls.

[0387] Additionally, a targeted MS detection method was developed including four peptides of NELFCD (AVETVHNLCCNENK, WVDWTVSEPR, GALNPADITVLFK and FPVVAMGVLK). Peptide quantification was achieved through the inclusion of heavy isotope-labelled peptide standards for each of the targeted peptides. Melt- and shift curves of NELFCD were generated in intact HCT116 cells incubated with 20, 100, 600 or 3000 nM of Compound 1, or without compound (control), for 60 minutes at 37 °C. Thereafter, the cells were subjected to a heat challenge of twelve temperatures between 37 and 52 °C determined light-to-heavy (LH) ratios were used to evaluate the relative peptide abundance in the heat-treated samples.Results

[0388] When Compound 1’ was applied to intact HCT116 cells and those cells were subjected to a range of elevated temperatures, a change in the stability of the NELFCD protein was detected (FIG. 1 A; FIG. 3B, red) at the lowest concentration used (z.e., 1 pM of Compound 1).

[0389] In contrast, when the kinase inhibitor staurosporine was applied to intact HCT116 cells and subjected to a range of temperatures, no change in the stability of NELFCD was detected (FIG. IB; FIG. 3B, blue).

[0390] Further, the target MS detection method indicates that Compound 1 induced a concentration dependent stabilization of the target, which was seen for each single peptideinvestigated forNELFCD (FIG. 3C). The maximum was seen at about 600 nm and detection achieved at 100 nm. The data is summarized in Table 2 below.Table 2

[0391] These results support the conclusion that Compound 1’ interacts with NELF.Example 2: Compound 1’ and RNA SynthesisMethodsU2OS cells (human bone osteosarcoma cells) were studied for changes in global RNA synthesis rate following pulse treatment with Compound 1’ by using fluorescent staining of newly transcribed RNA via metabolic labeling with 5-ethynyluridine (5-EU). 300,000 U2OS cells were seeded in 6-well plates 24 hours prior to the first treatment. Cells were fixed 24, 6, 2, or 1 hours after the start of a 2h 3 pM Compound 1’ pulse, or 1 hour after 100 pM 5,6-Dichloro-l-P-D-ribofuranosyl-benzimidazole (DRB) treatment as positive control and vehicle as negative control. Cells were incubated with 5-EU in the last 30 min prior to fixation. Cells were washed once in PBS before fixation with 4% PFA for 15 minutes. Cells were permeabilized using PBS containing 0.5% triton-X for 15 minutes. Staining of the cells was done using Click-iT® RNA Imaging Kit (Cl 0329) according to manufacture’s instructions. The samples were subsequently stained with 0.5 pg / mL DAPI for 15 minutes before mounting them on glass slides using ProLong™ Glass Antifade Mountant (Invitrogen, cat #P36980). The cells were imaged using a ScanR fluorescence microscope (Olympus) using a DAPI and FITC filter set.Results

[0392] A marked accumulation of RNA in dot-like structures (so-called stress-granules) was seen following treatment with Compound 1’ at 24 hours post application with strong RNA staining detected outside the nucleus (FIG. 4A). The NELF complex has been shown to directly bind to the Cap-binding complex (CBC) and to regulate 3' end processing for histonemRNAs (See e.g., Narita et al., 2007, Schulze and Cusack, 2017, the contents of which are incorporated herein in their entirety).

[0393] Consistent with this depletion or inhibition of NELFC / D or other members of the NELF-complex (for example, NELFA-E) compromises 5’RNA cap stability causing premature termination of some RNAs (See e.g., Aoi et. al. 2020) and may conceivably lead to accumulation of dysfunctional (non-translatable) RNAs. Without wishing to be bound by theory, the RNA-accumulation in dot-like structures seen in response to treatment with Compound 1’ may be the consequence of inhibition of NELF complex activity (See, e.g., Narita et al., 2007 (https: / / doi.Org / 10.1016 / j.molcel.2007.04.011); Schulze and Cusack, 2017 (https: / / doi.org / 10.1038 / s41467-017-01402-w); Aoi et al. 2020 (https: / / doi.Org / 10.1016 / j.molcel.2020.02.014)). Additionally, NELF expression results in the termination of Pol II transcription at the proximal polyadenylation signal (PAS) before Pol II reaches the DNA Replication Initiation (RI) zone. If NELF is absent or inactivated (e.g., through adminstrati on of Compound L), Pol II transcription is extended to the distal PAS, imparing replication in the RI zone and resulting in cell quiescence (FIG. 4B).Example 3: NELF-Compound 1’ binding modelsMethods

[0394] The structure of NELFCD (PDB ID: 5L3X, with NELFA complex removed) was obtained from the Protein Data Bank (PDB) (retrieved on June 26, 2023). Hydrogens were added to the NELFCD structure using Reduce (version 3.3.160602; Word et al., 1999). Protonation states of the amino acids His, Asp, Glu, and Cys and side chain orientation of Gin and Asn were confirmed by visually analyzing their surrounding hydrogen bonding networks.

[0395] The structure of Compound 1 ’ was obtained from Inthera in 2D SMILES file format. The compound was prepared for molecular docking studies by converting it to a 3D format using Ligprep (Schrodinger, LLC, New York, NY, 2023-vl). Protonation states of all atoms were assigned, and hydrogens were added (pH 7.4). Partial electronic charges were calculated for each atom of the compound in Maestro (Schrodinger, LLC, New York, NY, 2023-vl).

[0396] The NELFCD structure was visually inspected in the Bodil Modeling Environment (v.0.9; Lehtonen et al., 2004) to identify potential binding sites for Compound L. Multiple sites with a pocket-like or cavity-like structure were detected, and molecular docking with Plants (version 1.2; Korb et al., 2007) was performed to model the binding of Compound Linto these sites. Multiple docking solutions were generated for all studied sites, and the docking score was utilized to obtain top-scored poses of each site for visual evaluation.ResultsFIG. 5 illustrates a top scoring result of the docking of Compound 1’ to NELFCD with a binding cavity that supports a possible confirmation of Compound 1’, most polar atoms of Compound 1’ used in favorable interactions, and only minor overlaps of the structure of Compound 1 ’ and NELFCD. In FIG. 5 A the blue complex is NELF-C / NELF-D, pink residue is NELF-A, and yellow structure is Compound 1’. In FIG. 5B the hydrogen bonds are depicted with thin lines and exemplary residues are labeled. For example, Q263 interacts with NELFA with its side chain amide, and the same Q263 can accept a hydrogen bond from Compound 1’ with its main chain carbonyl oxygen atom. In FIG. 5C, the location of the NLFCD hinge site is identified with a red arrow (FIG. 5C, left and middle). Without wishing to be bound by theory, it is thought that the hinge domain may allow the structure of NELFCD to open slightly to allow for the induced fit of Compound 1 ’ . Additionally, NELFA has two alpha-helices (residues Prol38-Glyl54) interacting with the site that forms the suggested Compound L binding site, however, based on this model, no direct interactions of NELFA and Compound L are identified beyond a shared interaction with residue Q263.Example 4: NELF and NELF member amplificationMethods

[0397] 300.000 U2OS cells were seeded out in 6-well plates 24 hrs prior to the timepoint of the treatment. Cells were fixed 24, 6, 2 or 1 hrs after the start of a 2h 3 pM 454 pulse, or after 1 hour without treatment as negative control. During the last 30 minutes before fixation 1 mM 5-EU was included in each well. Cells were washed once in PBS before fixation with 4% PFA for 15 minutes. Cells were permeabilized using PBS containing 0.5% triton-X for 15 minutes. Staining of the cells was done using Click-iT® RNA Imaging Kit (Cl 0329) according to the manufacture’s instruction. The cells were subsequently stained with 0.5 pg / mL DAPI for 15 minutes before mounting them on glass slides using ProLong™Glass Antifade Mountant (Invitrogen, cat #P36980). The cells were imaged using a ScanR fluorescence microscope (Olympus) using a DAPI and FITC filter set. The average 5-EU intensity per nuclei was plotted for each condition.Results

[0398] Daily oral administration of Compound 1’ in a colorectal cancer mouse CDX model resulted in a reduction of mean tumor volume for administration of Compound 1’ at 3mg / kg and 6 mg / kg, when compared to twice per day IV administration of the commercially available agent Avastin® or vehicle control (FIG. 7E).

[0399] Without wishing to be bound by theory, the literature has indicated that the overexpression of NELF subunits / members is correlated with worsening disease prognosis compared to patients with lower expression.

[0400] For example, prostate cancer patients with higher than average NELF A, NELFB, NELFCD, or NELFE expression (FIG. 6, red) have a lower disease free survival rate compared to patients with lower NELF A, NELFB, NELFCD, or NELFE expression (FIG.6, blue) as analyzed over 150 months with a Cox proportional hazard model. Figure 6 depicts disease free survival time of human subjects with over expression of NELF A, NELFB, NELFCD, or NELFE analyzed with a Cox proportional hazards model. Solid lines represent survival time and dotted lines represent the 95% confidence interval. Red lines indicate high expression (defined as higher than the median expression value) and blue lines represent low expression (defined as lower than the median expression value) of the respective gene. Data was generated using the Gene Expression Profiling Interactive Analysis tool (Tang, Z. et al. (2017) GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res, 10.1093 / nar / gkx247).

[0401] Additionally, it has been shown that colorectal cancer tissue is associated with an increase in NELFCD mRNA expression compared to healthy, non-diseased tissue (FIG. 7A and 7B). This overexpression is also shown to be correlated with increased copy number alterations (FIG. 7C). Upon downregulation of NELFCD, a decrease in tumor size can be observed in a mouse tumor model (FIG. 7D). Methods for FIG. 7B and FIG. 7D are described in Song et al.: Onco Targets Ther. 2018 Dec 5; 11 :8741-8750. Methods for FIG. 7A and 7C are described in Li et al.: Oncotarget. 2017 Aug 10;8(45):78642-78659 and Carvalho et al.: Gut. 2009 Jan;58(l):79-89 (TH1L=NELFCD).

[0402] Figure 7E depicts colon cancer mouse CDX model of human HCT116 cells. Compound 1 ’ was tested at 3 mg / kg and 6 mg / kg daily via oral administration in comparison to Avastin applied i.v. twice weekly. Tumor growth graphs are presented covering the Compound 1 ’ treatment period.EQUIVALENTS

[0403] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, thepreferred methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, 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. All patents and publications cited in this specification are incorporated by reference.

[0404] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the disclosure to the precise form disclosed, but by the claims appended hereto.

Claims

CLAIMS1. A method of modulating negative elongation factor complex (NELF) comprising administering to a subject a compound of Formula (la):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, and 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;R2is selected from H, C(O)R14, C(O)NR15R15, C(O)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, and 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(O)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, the ring is optionally substituted by R8;R3and R7are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8Rn; or R3and R7are each independently 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, and 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, and 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, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionallysubstituted by halogen, OR8, or NR8Rn; or R6is C1-3 alkyl substituted by C(O)NR8Rn; or R6is 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 R6is imidazolidinone;R8and R11are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-9 cycloalkanediyl, C4-6 cycloalkenediyl, -O-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-7 heteroalkanediyl, and -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(O)OR10, R10NC(O)NR10R12, OC(O)R10, OC(O)NR10R12, S(O)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, and O-heteroaryl, wherein the S-aryl, O-aryl, S-heteroaryl, or O-heteroaryl is optionally substituted by one or more R9or R14; or Y is 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, the ring 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(O)OR8, C1-5 alkyl- C(O)NR8Rn, C1-5 alkyl-C(O)R10, CN, C(O)R8, C(O)NR8Rn, C(O)OR8, NR8C(O)NR8Rn, OC(O)NR8Rn, SO2NR8RU, NR8SO2R8, OR8, NR8RU, and S(O)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, and C1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8Rn;R13is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;I l lR14is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, and 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 each R15is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- 7 cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR8.

2. A composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in modulating negative elongation factor complex (NELF) in a subject.

3. A compound of Formula (la), or a pharmaceutically acceptable salt thereof, for use in modulating negative elongation factor complex (NELF) in a subject.

4. Use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the modulation of negative elongation factor complex (NELF) in a subject.

5. Use of a composition comprising a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of negative elongation factor complex (NELF) in a subject.

6. Use of a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the modulation of negative elongation factor complex (NELF) in a subject.

7. Use a compound of Formula (la), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the modulation of negative elongation factor complex (NELF) in a subject.

8. The method, compound, composition, or use of any one of the preceding claims, wherein the modulation treats a disease or disorder.

9. The method, compound, composition, or use of any one of the preceding claims, wherein the compound of Formula (la) is Compound 1 :(Compound 1), or a pharmaceutically acceptable salt thereof.

10. The method, compound, composition, or use of any one of the preceding claims, wherein the compound of Formula (la) is Compound 1’:(Compound 1’), or a pharmaceutically acceptable salt thereof.

11. The method, compound, composition, or use of any one of the preceding claims, wherein the negative elongation factor complex is negative elongation factor complex member B (NELFB).

12. The method, compound, composition, or use of any one of the preceding claims, wherein the negative elongation factor complex is negative elongation factor complex member C / D (NELFCD).

13. The method, compound, composition, or use of any one of the preceding claims, wherein the subject is a human.

14. The method, compound, composition, or use of any one of the preceding claims, wherein the disease or disorder is cancer.

15. The method, compound, composition, or use of claim 14, wherein the cancer comprises a liquid tumor or a solid tumor.

16. The method, compound, composition, or use of claim 14, wherein the cancer is prostate cancer, renal cancer, pancreatic cancer, liver cancer, breast cancer, gastric cancer,testicular cancer, colorectal cancer, cervical cancer, ovarian cancer, head-and-neck cancer, esophageal cancer, leukemia, lymphoma, lung cancer, brain cancer, stomach cancer, cancer of the central nervous system, or skin cancer.

17. The method, compound, composition, or use of claim 14, wherein the cancer is lung cancer, prostate cancer, or stomach cancer.

18. The method, compound, composition, or use of claim 17, wherein the prostate cancer is castration resistant prostate cancer.

19. The method, compound, composition, or use of claim 17, wherein the lung cancer is small-cell lung cancer.

20. The method, compound, composition, or use of claim 14, wherein the cancer is leukemia or myeloma.

21. The method, compound, composition, or use of claim 20, wherein the leukemia is chronic myeloid leukemia, acute T lymphocytic leukemia, or chronic lymphocytic leukemia.

22. The method, compound, composition, or use of claim 20, wherein the myeloma is multiple myeloma.

23. The method, compound, composition, or use of claim 14, wherein the cancer is renal cell carcinoma.

24. The method, compound, composition, or use of any one of the preceding claims, wherein the modulation is inhibition.

25. The method, compound, composition, or use of any one of the preceding claims, wherein negative elongation factor complex (NELF) is overexpressed.

26. The method, compound, composition, or use of claim 25, wherein the overexpression of the NELF is an increase in expression of NELF B or C / D as compared to a control level of expression observed in individuals not having the disease or disorder.

27. The method, compound, composition, or use of any one of the preceding claims, wherein the subject has a 20q amplification.

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