IL324503A - Oxopiperazine derivatives for cancer treatment - Google Patents

Description

AMS-202407USWO OXOPIPERAZINE DERIVATIVES FOR THE TREATMENT OF A DISEASE OR DISORDER RELATED 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.

AMS-202407USWO 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:R1 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, 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-cycloalkyl;R2 is 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-OR 8, C1-3 alkanediyl-O-Ci-alkanediyl-O-C1-3 alkanediyl, C1-5 alkyl-NHCOR, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; with the proviso that when R2 is C(O)NR15R15, both R15 can form a ring wherein the ring contains the N of NR15R15 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R3 and R7 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8R״; or R3 and R7 are each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl;R4 is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-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-cycloalkyl; AMS-202407USWO R5 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, OR8, C1-3 alkyl-OR 8, and SR8; and wherein R5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;R6 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and Ccycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8R״; or R6 is C1-3 alkyl substituted by C(O)NR8R״; or R6 is 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 R6 can form a ring with any part of X; or R6 is imidazolidinone;R8 and R11 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-cycloalkanediyl, C1-3 alkanediyl-O-C1-7 alkanediyl, C1-7 heteroalkanediyl, and -S-C1-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)n R8 wherein 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 R9 or 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)NR10R12 or NR10R12, R10 and R12 can form a ring wherein the ring contains the N of NR10R12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R9 is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR 8, C1-5 alkyl-SR 8, C1-5 alkyl-NR 8R״, C1-5 alkyl-C(O)OR 8, C1-5 alkyl- C(O)NR8R״, C1-5 alkyl-C(O)R 10, CN, C(O)R8, C(O)NR8R״, C(O)OR8, NR8C(O)NR8R״, OC(O)NR8R״, SO2NR8R״, NR8SO2R8, OR8, NR8R״, and S(O)n R8 wherein n is 0, 1 or 2;R10 and R12 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-C1-3 alkanediyl-O-C1-alkanediyl, C1-3 alkyl-aryl, and C1-3 alkyl-heteroaryl, wherein the alkyl, alkenyl, alkynyl, AMS-202407USWO cycloalkyl, cycloalkenyl, alkanediyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, 0rNR8R״;R13 is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;R14 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, and C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; andeach R15 is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- ר cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR 8. [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.

AMS-202407USWO

[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 IBdepict mass spectrometry using Cellular Thermal Shift Assay (CETSA®) wherein NELF-C/NELF-D is detected at 1 pM Compound I’ (FIG. 1A) and absence of NELF-C/NELF-D detection with staurosporine (FIG. IB). [0020] FIG. 2depicts the CETSA® experimental setup for detecting protein interactions of small molecules. [0021] FIGs. 3A-3Cdepict results of the CETSA® experiment for treatment of intact cells with Compound L. FIGs. 3 A and 3B depict the stability rate change of Compound L or control and various proteins (ARHGEF28, LRRC14, RC3H2, ZCRB1, and NELFCD) at varying concentrations (1, 3, 10, and 30 pm) of Compound L. FIG. 3C showsmelting curves for NELFCD across four different concentrations of Compound L (20 nM, 100 nM, 6nM, and 3,000 nM). N = 5 for all except for 3000 nM where n=4. [0022] FIG. 4Adepicts the accumulation of RNA species (stress granules) following treatment with Compound L. FIG. 4Bdepicts a schematic modeling NELF-mediated transcription termination and DNA replication initiation (adapted from Nakayama et al.

AMS-202407USWO NELF coordinates Pol II transcription termination and DNA replication initiation. bioRxiv. 2024 Feb 1:2024.01.31.578294). [0023] FIGs. 5A - 5Cdepict the modeled binding site for Compound 1’. In FIG. 5A the blue complex is NELFC/NELFD, pink residue is NELFA, and yellow structure is Compound L. In FIG. 5B the hydrogen bonds are depicted with thin lines and exemplary residues are labeled. In FIG. 5C, the location of the Compound L binding site, including a hinge domain (arrow), is illustrated with NELFC/NELFD in blue and NELFA in pink. [0024] FIG. 6depicts disease free survival time of human subjects with over expression of NELFA, 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-7Eillustrate 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 1’ (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;ll:8741-8750).

AMS-202407USWO 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:R1 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, 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-cycloalkyl;R2 is 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-OR 8, C1-3 alkanediyl-O-Ci-alkanediyl-O-C1-3 alkanediyl, C1-5 alkyl-NHCOR, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; with the proviso that when R2 is C(O)NR15R15, both R15 can form a ring wherein the ring contains the N of NR15R15 and optionally one further AMS-202407USWO heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R3 and R7 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8R״; or R3 and R7 are each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl;R4 is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-cycloalkyl;R5 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-cycloalkenyl, OR8, C1-3 alkyl-OR 8, and SR8; and wherein R5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;R6 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8R״; or R6 is C1-3 alkyl substituted by C(O)NR8R״; or R6 is C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; and wherein R6 can form a ring with any part of X; or R6 is imidazolidinone;R8 and R11 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-cycloalkanediyl, C1-3 alkanediyl-O-C1-7 alkanediyl, C1-7 heteroalkanediyl, and -S-C1-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)n R8 wherein 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 R9 or 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 AMS-202407USWO with any part of X or R5, wherein the ring optionally contains a carbonyl group; with the proviso that when ¥ is C(O)NR10R12 or NR10R12, R10 and R12 can form a ring wherein the ring contains the N of NR10R12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R9 is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, C3-5 cycloalkyl, C1-5 alkyl-OR 8, C1-5 alkyl-SR 8, C1-5 alkyl-NR 8R״, C1-5 alkyl-C(O)OR 8, C1-5 alkyl- C(O)NR8R״, C1-5 alkyl-C(O)R 10, CN, C(O)R8, C(O)NR8R״, C(O)OR8, NR8C(O)NR8R״, OC(O)NR8R״, SO2NR8R״, NR8SO2R8, OR8, NR8R״, and S(O)n R8 wherein n is 0, 1 or 2;R10 and R12 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-C1-3 alkanediyl-O-C1-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, 0rNR8R״;R13 is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;R14 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, and C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; andeach R15 is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- ר cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR 8. [0030]In some embodiments, R1 is 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, Cm alkyl, or C3-5 cycloalkyl. [0031]In some embodiments, R1 is 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, Cm alkyl, or C3-5 cycloalkyl. [0032]In some embodiments, R1 is 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, R1 is H. [0034]In some embodiments, R1 is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4- ר cycloalkenyl, or C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl.

AMS-202407USWO

[0035]In some embodiments, R1 is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4- ר cycloalkenyl, or C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl of R1 is substituted by halogen, Cm alkyl, or C3-cycloalkyl. [0036]In some embodiments, R2 is selected from H, C(O)R14, C(O)NR15R15, C(O)OR15, C!. ר alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR 8, C1-alkanediyl-O-C1-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR 13, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl. [0037]In some embodiments, R2 is selected from H, C(O)R14, C(O)NR15R15, C(O)OR15, C!. ר alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR 8, C1-alkanediyl-O-C1-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR 13, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0038]In some embodiments, R2 is selected from H, C(O)R14, C(O)NR15R15, C(O)OR15, C!. ר alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-5 alkyl-OR 8, C1-alkanediyl-O-C1-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-NHCOR 13, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0039]In some embodiments, when R2 is C(O)NR15R15, both R15 can form a ring. [0040]In some embodiments, when R2 is C(O)NR15R15, both R15 can form a ring, the ring contains the N of NR15R15. [0041]In some embodiments, when R2 is C(O)NR15R15, both R15 can form a ring and the ring contains one further heteroatom selected from O and N. [0042]In some embodiments, when R2 is C(O)NR15R15, both R15 can 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 R2 is C(O)NR15R15, both R15 can form a ring and the ring contains one further heteroatom selected N, then the ring is substituted by R8. [0044]In some embodiments, R2 is H. [0045]In some embodiments, R2 is C(O)R14, C(O)NR15R15, or C(O)OR15. [0046]In some embodiments, R2 is C1-7 alkyl, C2-7 alkenyl, C 2-7 alkynyl, C3-7 cycloalkyl, C4- ר cycloalkenyl, C1-5 alkyl-OR 8, C1-3 alkanediyl-O-C1-3 alkanediyl-O-C1-3 alkanediyl, C1-alkyl-NHCOR 13, or C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl. [0047]In some embodiments, R2 is C(O)NR15R15.

AMS-202407USWO

[0048]In some embodiments, R3 and R7 are 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, 0rNR8R״; or R3 and R7 are each independently C1-3 alkyl substituted by aryl or heteroaryl. [0049]In some embodiments, R3 and R7 are 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 NR8R״; or R3 and Rare each independently C1-3 alkyl substituted by aryl or heteroaryl. [0050]In some embodiments, R3 and R7 are 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, 0rNR8R״; or R3 and R7 are each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0051]In some embodiments, R3 and R7 are 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, 0rNR8R״; or R3 and R7 are each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0052]In some embodiments, R3 and R7 are 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 NR8R״; or R3 and Rare each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0053]In some embodiments, R3 and R7 are 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 NR8R״; or R3 and Rare each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0054]In some embodiments, R3 is H. [0055]In some embodiments, R3 is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl. [0056]In some embodiments, R7 is H. [0057]In some embodiments, R7 is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

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[0058]In some embodiments, R3 is C1-3 alkyl substituted by aryl or heteroaryl. [0059]In some embodiments, R7 is C1-3 alkyl substituted by aryl or heteroaryl. [0060]In some embodiments, R4 is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-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, Cm alkyl, or C3-5 cycloalkyl. [0061]In some embodiments, R4 is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-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, Cm alkyl, or C3-cycloalkyl. [0062]In some embodiments, R5 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, C1-3 alkyl-OR 8, and SR8. [0063]In some embodiments, R5 is H. [0064]In some embodiments, R5 is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4- cycloalkenyl, OR8, C1-3 alkyl-OR 8, or SR8. [0065]In some embodiments, R5 can form a ring with any part of X or Y. [0066]In some embodiments, the ring of R5 contains a carbonyl group. [0067]In some embodiments, R6 is 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 NR8R״; or R6 is C1-3 alkyl substituted by C(O)NR8R״; or R6 is C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0068]In some embodiments, R6 is 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 NR8R״; or R6 is C1-3 alkyl substituted by C(O)NR8R״; or R6 is C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is substituted by halogen, Cm alkyl, or C3-5 cycloalkyl. [0069]In some embodiments, R6 can form a ring with any part of X. [0070]In some embodiments, R6 is imidazolidinone. [0071]In some embodiments, R8 andR 11 are 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, R8 is H. [0073]In some embodiments, R8 is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl.

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[0074]In some embodiments, R11 is H. [0075]In some embodiments, R11 is 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, -0-,C1-3 alkanediyl-O-, -O-C1-alkanediyl, -O-C3-9 cycloalkanediyl, C1-3 alkanediyl-O-Ci-7 alkanediyl, C1-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, Xis C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-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-cycloalkanediyl, or C1-3 alkanediyl-O-C1-7 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 and N.

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[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)n R8, 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 R9 or R [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 R9 or 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 R5 and the ring optionally contains a carbonyl group. [0105]In some embodiments, Y can form a ring with any part of X or R5 and the ring contains a carbonyl group. [0106]In some embodiments, when Y is C(O)NR10R12 or NR10R12, R10 and R12 can form a ring. [0107]In some embodiments, when Y is C(O)NR10R12 or NR10R12, R10 and R12 can form a ring, wherein the ring contains the N of NR10R12 and optionally one further heteroatom selected from O and N. [0108]In some embodiments, when Y is C(O)NR10R12 or NR10R12, R10 and R12 can form a ring, wherein the ring contains the N of NR10R12 and 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.

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[0109]In some embodiments, when Y is C(O)NR10R12 or NR10R12, R10 and R12 can form a ring, wherein the ring contains the N of NR10R12 and 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, R9 is selected from H, halogen, C1-5 alkyl, C2-5 alkenyl, C2-alkynyl, C35 cycloalkyl, C1-5 alkyl-OR 8, C1-5 alkyl-SR 8, C1-5 alkyl-NR 8R״, C1-5 alkyl- C(O)OR8, C1-5 alkyl-C(O)NR 8R״, C1-5 alkyl-C(O)R 10, CN, C(O)R8, C(O)NR8R״, C(O)OR8, NR8C(O)NR8R״, OC(O)NR8R״, SO2NR8R״, NR8SO2R8, OR8, NR8R״, and S(O)n R8 wherein n is 0, 1 or 2. [0111]In some embodiments, R9 is H. [0112]In some embodiments, R9 is a halogen. [0113]In some embodiments, R9 is C1-5 alkyl, C2-5 alkenyl, C2-5 alkynyl, or C3-5 cycloalkyl. [0114]In some embodiments, R9 is C1-5 alkyl-OR 8, C1-5 alkyl-SR 8, C1-5 alkyl-NR 8R״, C1-alkyl-C(O)OR 8, C1-5 alkyl-C(O)NR 8R״, or C1-5 alkyl-C(O)R 10. [0115]In some embodiments, R9 is CN. [0116]In some embodiments, R9 is C(O)R8, C(O)NR8R״, C(O)OR8, NR8C(O)NR8R״, or OC(O)NR8R״ [0117]In some embodiment, R9 is SO2NR8R״ or NR8SO2R8. [0118]In some embodiments, R9is OR8. [0119]In some embodiments, R9 is NR8R״. [0120]In some embodiments, R9 is S(O)n R8 wherein 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, R10 and R12 are each independently selected from H, C1-alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-C1-alkanediyl-O-C1-3 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, 0rNR8R״. [0123]In some embodiments, R10 and R12 are each independently selected from H, C1-alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-C1-alkanediyl-O-C1-3 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, 0rNR8R״.

AMS-202407USWO

[0124]In some embodiments, R10 and R12 are each independently selected from H, C1-alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-Ci-alkanediyl-O-C1-3 alkanediyl, C1-3 alkyl-aryl, and C1-3 alkyl-heteroaryl. [0125]In some embodiments, R10 is H. [0126]In some embodiments, R10 is 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 NR8R״. [0127]In some embodiments, R10 is 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, 0rNR8R״. [0128]In some embodiments, R10 is 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-C1-3 alkanediyl-O-C1-3. [0130]In some embodiments, R10 is alkanediyl. [0131]In some embodiments, R10 is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8R״. [0132]In some embodiments, R10 is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is substituted by halogen, OR8, or NR8R״. [0133]In some embodiments, R10 is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl. [0134]In some embodiments, R12 is H. [0135]In some embodiments, R12 is 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 NR8R״. [0136]In some embodiments, R12 is 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, 0rNR8R״. [0137]In some embodiments, R12 is 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-C1-3 alkanediyl-O-C1-3. [0139]In some embodiments, R12 is alkanediyl. [0140]In some embodiments, R12 is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is optionally substituted by halogen, OR8, or NR8R״. [0141]In some embodiments, R12 is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl, wherein the alkyl, aryl, or heteroaryl is substituted by halogen, OR8, or NR8R״.

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[0142]In some embodiments, R12 is C1-3 alkyl-aryl or C1-3 alkyl-heteroaryl. [0143]In some embodiments, R13 is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group. [0144]In some embodiments, R13 is C1-5 alkyl substituted by a bicyclic ring containing at least one heteroatom and a carbonyl group. [0145]In some embodiments, R14 is 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, R14 is 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, Cm alkyl, or C3-5 cycloalkyl. [0147]In some embodiments, R14 is 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, Cm alkyl, or C3-5 cycloalkyl. [0148]In some embodiments, R14 is 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, Cm 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, Cm alkyl, or C3-5 cycloalkyl. [0152]In some embodiments, R15 is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, OR8, and C1-3 alkyl-OR 8. [0153]In some embodiments, R15 is H. [0154]In some embodiments, R15 is C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, or C4-7 cycloalkenyl. [0155]In some embodiments, R15 is OR8 or C1-3 alkyl-OR 8. [0156]In some embodiments, the compound is of Formula (la), or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:R1 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-cycloalkenyl, and C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; AMS-202407USWO R2 is selected from H, C(O)R14, C(O)OR15, C1-7 alkyl, C3-7 cycloalkyl, C1-5 alkyl- OR8, C1-3 alkanediyl-O-C1-3 alkanediyl-O-C1-3 alkanediyl, C1-5 alkyl-NHCOR 13, and C1-alkyl substituted by aryl optionally substituted by halogen, C1-4 alkyl or C3-5 cycloalkyl;R3 and R7 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;R4 is 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;R5 is selected from H, C1-7 alkyl, OR8, and SR8; and wherein R5 can form a ring with any part of X or Y, wherein the ring optionally comprises a carbonyl group;R6 is selected from H and C1-7 alkyl;R8 and R11 are 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 R5 or 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)NR10R12 or NR10R12, Rand R12 can form a ring wherein the ring contains the N of NR10R12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the N is optionally substituted by R8;R10 and R12 are 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;R13 is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group;R14 is selected from H and C1-7 alkyl; andeach R15 is independently selected from H and C1-7 alkyl. [0157]In some embodiments, the compound of Formula (la) is of Formula (I) AMS-202407USWO (1)or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:R1 is C1-7 alkyl;R2 is 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;R3 and R7 are each H;R4 is C1-7 alkyl;R5 is selected from H, C1-7 alkyl, OR8, and SR8; and wherein R5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;R6 is selected from H and C1-7 alkyl;R8 and R11 are 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 R5 or 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, R10 and Rcan form a ring wherein the ring contains the N of NR10R12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R10 and R12 are 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;R13 is C1-5 alkyl substituted by a bicyclic ring optionally comprising at least one heteroatom and a carbonyl group;R14 is selected from H and C1-7 alkyl; andeach R15 is 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: AMS-202407USWO R1 is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, and C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl;R2 is selected from H, C(O)R14, C(O)OR15, C1-7 alkyl, C3.7 cycloalkyl, C1-alkanediyl-O-C1-3 alkanediyl-O-Ci-3 alkanediyl, C1-5 alkyl-OR 8, C1-5 alkyl-NHCOR 13, and C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl;R3 and R7 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl; andR4 is 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, Cm 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:R1 is selected from C3-7 alkyl, C3-7 cycloalkyl, and C1-3 alkyl substituted by aryl or heteroaryl;R2 is selected from H and C(O)R14, wherein R14 is C1-7 alkyl; or R2 is C1-7 alkyl, C3.cycloalkyl, C1-5 alkyl-OR 8, or C1-5 alkyl-NHCOR 13, wherein R13 is pentylamino-5- oxopentyl-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one; 0rR2is C1-3 alkyl substituted by aryl, wherein the aryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl;R3 and R7 are H; andR4 is 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), (11c), (Illa), (Illb), (Die), (Hid), (IVa), (IVb), (IVc), or (IVd): AMS-202407USWO or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof. [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): AMS-202407USWO R1 R1 AMS-202407USWO or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein nis 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 nis 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:R5 is C1-7 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), (VIIIb), (VIIIc), (Vllld), (Ville), (Vlllf), (Vlllg), (Vlllh), (Villi), (Vlllj), (Vlllk), (VIII1), (IXa), (IXb), (IXc), or (IXd):R1 R1nA ؛ r 7?Y° ° r R3 V N /ך R3r 4r7 °2 Y (vma); R1 R1r 'n 0 6 R'rAr 3^^N^/^N/XR R3^^r R4□7 Q2v Y R (VIIIc); R1 R1hn ^Y° O r 6 HN^ 1 ؟ R4Q2־> (vnie); r°°nV^nYSR° y R4 K R7 or “1 (viiib); r°0 r 4(; y (v1nd ^؛ r 7 q 2 0 r 6N ן Y Q2־Q1 (Vlllf); AMS-202407USWO or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Qand Q2 are each independently O, S, NR8, or CR8 and nlO is 0, 1, 2, 3, 4, 5, 6, or 7. [0165]In some embodiments, the compound of Formula (la) is of Formula (Villi), (VlUk), (VIIII), (IXc), or (IXd): AMS-202407USWO (VIIIl); or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein Qand Q2 are each independently O, S, NR8, or CR8 and 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: HN A' (Compound 1). [0168] In some embodiments, Compound lisa methanesulfonic acid salt (mesylate).

AMS-202407USWO

[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, (3S)-1- [(2S)-4-methyl-l-oxo-1-[(3 s,6s,8S)-8-methyl-3-(pyrrolidin-l-ylmethyl)-!, 5-dioxa-9- azaspiro[5.5]undecan-9-yl]pentan-2-yl]-3-(2-methylpropyl)piperazin-2-one, and/or the following chemical stmcture: 0Av NVA (Compound !’). [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 !’.In some embodiments, Compound 2 is: (Compound 2). [0174]In some embodiments, Compound 2 does not bind in the NELFCD active site. [0175]In some aspects, the compound of Formula (1a) is a Compound 3 and a Compound with chemical structures as follows: (Compound 3) and AMS-202407USWO (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 (1a) is selected from Table 1.

Table 1: Compounds according to Formula (la) Structure Compound Name 0 ^N/y5•0 0 YCR (S)-1 -[(S)-3-Methyl- 1 -({4-[(l -methyl- 1H-imidazol-2-yl)methyl]- 1 -piperidyl}carbonyl)butyl]-4-acetyl-3-isobutyl-2- piperazinone Pon (S)-1 -[(S)-3-Methyl- 1 -({4-[(l -methyl- 1H- imidazol-2-yl)methyl]- 1 - piperidyl}carbonyl)butyl]-4-(cyclopropylmethyl)-3-isobutyl-2-piperazinone .C 0 MS o Ethyl l-{(5)-2-[(5)-3-isobutyl-2-oxo-l-piperazinyl]-4-methylvaleryl}-4-methyl-4- piperidinecarboxylate HN^^0 0 0 ו Methyl (1 - { (5)-2- [(5)-3 -i sobutyl-2-oxo-1 -piperazinyl]-4-methylvaleryl}-4- piperidyl)acetate HN^^0 0 0 (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 4-methylvaleryl}-4-piperidyl)acetamide AMS-202407USWO Structure Compound Name ס (5)-l-[(5)-3-Methyl-l-({4-[2-(methylamino)-2- oxoethyl ] -1 -piperi dy 1} carb ony !)butyl ] -3 - isobutyl-2-piperazinone0 1 H X .0(5)-l-[(5)-l-({4-[2-(Dimethylamino)ethyl]-l-HN Opiperidyl }carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone1 1 n (5)-l-[(5)-2-(4-{2-[7V-Ethyl(isopropyl)amino]-2-HN 0 0 ! oxoethyl } -1 -piperidyl)- 1 -(cyclopropylmethyl)-2- oxoethyl]-3-(cyclopropylmethyl)-2-piperazinone O JL /O/ o ^n^OJQ (5)-l -[(5)-3-Methyl- 1 -({4-[(l -methyl- 1H- imidazol-2-yl)methyl]- 1 -piperidyl}carbonyl)butyl]-3-isobutyl-4-(2- methoxy ethyl)-2-piperazinone HN^^0 0 (5)-1 - { (5)-3 -Methyl- 1 - [(4-phenethyl -1 - piperidyl)carbonyl]butyl}-3-isobutyl-2- piperazinone Y (5)-1 - [ (5)-3 -Methyl- 1 -({ 4- [(3 -py ri dyl)m ethyl 11 ־ -HN^^ O Oj O ^؟piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone JL ^0 Ethyl (1 - { (5)-2- [(5)-3 -i sobutyl-2-oxo-1 -HN^0 ־piperazinyl]-4-methylvaleryl}-4-—، /k,*p1pendyl)acetatekj । ך ויו 1^'־־׳־^ AMS-202407USWO Structure Compound Name HN/^^° 0 0 ^N'"' (5)-l-[(5)-l-({4-[2-(Dimethylamino)-2- oxoethyl]-l-piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl-2-piperazinone HN/^^° 0 (5)-1 -{ (5)-1 -[(4-Benzyl- 1 -piperi dyl)carbonyl]-3 - methylbutyl } -3 -i sobutyl-2-piperazinone HN^^° 0 (5)-1 -{ (5)-1 -[(4-Isopentyl- 1 -piperi dyl)carbonyl]- -methylbutyl } -3 -i sobutyl-2-piperazinone HN^^° 0 AA 0' (5)-l-[(5)-l-{(8-Azaspiro[4.5]decan-8- oyl)carbonyl}-3-methylbutyl]-3-isobutyl-2- piperazinone /O hn^ oL JL < ך n (5)-1 -[(5)-3 -Methyl- 1 -({ 4-[(l -methyl-4-m ethyl- l/Z-imidazol-2-yl)methyl]- 1 -piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone HN/^^° 0 y״OJ) (5)-1 -[(5)-1 -({4-[( 1 -Cyclopropyl- 1H-imidazol-2- yl)methyl]-l-piperidyl}carbonyl)-3- methylbutyl]-3-isobutyl-2-piperazinone HN/^^° 0 ؛ OJ ^؟ '3- ^N (5)-l -[(5)-3-Methyl- 1 -({4-[(l -methyl-5-methyl- l//-imidazol-2-yl)methyl]- 1 -piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone AMS-202407USWO Structure Compound Name C 0 k JSL A J; O Fa I (Al-[(A3־Methyl-l-({4-[(l-methyl-4,5- dimethyl- l/Z-imidazol-2-yl)m ethyl]- 1 - piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone HN/^A° 0 k A J: f 1 Ji V- X^/ X/X/A (5)-l-[(Al-({4-[(l-Ethyl-4,5-dimethyl-l/Z- imidazol-2-yl)methyl]- 1 -piperidyl } carbonyl)-3 - methylbutyl]-3-isobutyl-2-piperazinone 0 C . k JX A / JnA ך: I 1 JI A -Xp/ X^X^'N (5)-1 -[(A1 -({4-[( 1 -Isopropyl-4,5-dimethyl- H- imidazol-2-yl)methyl]- 1 -piperidyl } carbonyl)-3 - methylbutyl]-3-isobutyl-2-piperazinone HN^A° 0 A kLx/°x؛ Methyl l-{(5)-2-[(A3-isobutyl-2-oxo-l-piperazinyl]-4-methylvaleryl}-4- piperidinecarboxylate HN^A° o k/N^k^ xA A/x/°'^ 0 Ethyl l-{(5)-2-[(A3-isobutyl-2-oxo-l-piperazinyl]-4-methylvaleryl}-4- piperidinecarboxylate HN^^0 O k ,N^ A A^N^I oh (5)-1 - [(5)-1 - {[4-(2-Hydroxy-2-m ethylpropyl)- 1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl- 2-piperazinone HN^A° 0 xA k/^O^^x^,Li (5)-1 - [(5)-3 -Methyl- 1 - {[4-methyl-4-(phenoxy methyl)- 1 -pip eri dyl ] carb ony 1} butyl ] -3 - isobutyl-2-piperazinone AMS-202407USWO Structure Compound Name HN^^0 0 1 T TJ) (5)-1 - [(5)-3 -Methyl- 1 - {[4-( 1 -phenoxy ethyl)- 1 - piperi dyl ] carb ony 1} butyl ] -3 -i sobuty 1 -2 - piperazinone 0 . X 0 HN y ״ T -# 1 N (5)-1 - [(5)-1 - {[4-( l/f-Imidazol-2-yl)-1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl-2-piperazinone Q (5)-l -[(5)-3-Methyl- 1 -({4-[(l -methyl- H- O 1 _N. A n-a : I % I imidazol-2-yl)methyl]- 1 -piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone .C 0 C 1 _N. A J YU NW) "Va/a/A 1 (5)-l-[(5)-3-Methyl-l-({4-[(l-methyl-4,5- dipropyl- 1/Z-imidazol -2-yl)methyl]- 1 - piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone HN/^^'° 0 YQ (5)-l-[(5)-3-Methyl-l-({4-[(l-methyl-5-propyl- l//-imidazol-2-yl)methyl]- 1 -piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone A ^0 HN y 0 (5)-1 - [(5)-1 - {[4-( l/f-Imidazol-4-yl)-1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl-2-piperazinone — 1 1 T V'lMH n=/ -0AF3 > H2N A^o 0 0 _ O^CFs (5)-1 -{ (5)-2-[4-(2-Aminoethyl)- 1 -piperidyl]- 1 -(cyclopropylmethyl)-2-oxoethyl}-3-(cyclopropylmethyl)-2-piperazinone (2TFA) AMS-202407USWO Structure Compound Name A O° 1 (5)-l-[(5)-2-(4-{2-[A-Methyl(isopentyl)amino]- 2-oxoethyl } -1 -piperidyl)- 1 -(cyclopropylmethyl)- 2-oxoethyl]-3-(cyclopropylmethyl)-2- piperazinone HzN^A o MY _ O^CFa A 0XS _ O^CFa (5)-1 -{ (5)-2-[4-(2-Aminoethyl)- 1 -piperidyl]- 1 - (cyclopropylmethyl)-2-oxoethyl}-3-neopentyl-2- piperazinone (2TFA) HN'^Y® k^-y^^׳^NHs (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 4-methylvaleryl}-4-ethyl-4-piperidyl)acetamide .C 0 k/N^A^ri- K (5)-l-[(5)-l4})־-[(l-Cyclopropyl-4,5-dimethyl- l//-imidazol-2-yl)methyl]- 1 -piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl- 2-piperazinone HN^A° 0 rk(5)-1 - [(5)-1 - [(4- {[ 1 -(Cy clopropylmethyl)-4, 5 - dimethyl- l/Z-imidazol-2-yl]methyl } -1 - piperidyl)carbonyl]-3-methylbutyl]-3-isobutyl-2- piperazinone HN^Y° 0 0 A (5)-l-[(5)-l7]-2}-4)]־V-Methyl(isopentyl)amino]- 2-oxoethyl}-4-methyl-l-piperidyl)carbonyl]-3- methylbutyl]-3-isobutyl-2-piperazinone HN^0 o An^n^ °'^'־^ N ־^^ (5)-l-[(5)-l7]-2}-4)]־V-Ethyl(isopropyl)amino]- 2-oxoethyl}-4-methyl-l-piperidyl)carbonyl]-3- methylbutyl]-3-isobutyl-2-piperazinone HN^0 0 ° kN " “ ־׳ (5)-l-[(5)-l7]-2}-4)]־V-Methyl(isopentyl)amino]- -methyl-2-oxoethyl} -1 -piperi dyl)carbonyl]-3 - methylbutyl]-3-isobutyl-2-piperazinone AMS-202407USWO Structure Compound Name HN/^^° O (5)-l-[(5)-l-[(4-{2-[7V-Ethyl(isopropyl)amino]- -methyl-2-oxoethyl} -1 -piperi dyl)carbonyl]-3 - methylbutyl]-3-isobutyl-2-piperazinone 0 ׳،^° HN n: C 1 W N (S)-1-[(S)-3-Methyl- 1-({ 4-[(2-methyl-2Z/- pyrazol-3 -yl)methyl]- 1 -piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone HN^^0 0 (5)-1 - [(5)-1 - {[4-(2-Hydroxy ethyl)- 1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl- 2-piperazinone O ־،^° HN (5)-1 - [(5)-1 - {[4-(Hy droxymethyl)- 1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl- 2-piperazinone HN^^0 0 OUL ^؟ (5)-1 -{ (5)-1 -[(4-Isobutyl- 1 -piperi dyl)carbonyl]- -methylbutyl } -3 -i sobutyl-2-piperazinone I .-N ، OM * /x - ..׳■■,״-■״״ -.,״״■י .. (5)-1 - { (5)-3 -Methyl- 1 - [(4-propyl- 1 - piperidyl)carbonyl]butyl}-3-isobutyl-2- piperazinone ° 1 Ph/ (5)-l-[(5)-2-(4-{2-[7V-Ethyl(isopropyl)amino]-2- oxoethyl } -1 -piperidyl)- 1 -benzyl-2-oxoethyl]-3 - isobutyl-2-piperazinone AMS-202407USWO Structure Compound Name HN׳^^° O o - X (S)-1-[(S)-1-[(4-{2-[N-Methyl(isopentyl)amino]-2-oxoethyl }-I-piperi dyl)carbonyl]-2-methylpropyl]-3-isobutyl-2-piperazinone .C o 0 1 (5)-l-[(5)-l-[(4-{2-[7V-Ethyl(isopropyl)amino]- 2-oxoethyl }-I-piped dyl)carbonyl]-2- methylpropyl]-3-isobutyl-2-piperazinone •T? ■ - . r, - (2-( 1 -((5)-2-((5)-3 -i sobutyl-2-oxopiperazin-1 - yl)-3-phenylpropanoyl)piperidin-4-yV-7V- isopentyl-TV-methylacetamide L X Vs H A-^- An0^ T (6S)-6-(5-{5-[(S)-4-[(S)-l-({4^(Dimethylamino)ethyl]-l-piperidyl}carbonyl)-3- methylbutyl]-2-isobutyl-3-oxo-l-piperazinyl]pentylamino}-5-oxopentyl)-7-thia-2.4-diazabicyclo[3.3.0]octan-3-one HN^v^° 0 (S)-1 - [(S)-3 -Methyl- 1 -({ 4- [2-( 1 - pyrrolidinyl)ethyl]- 1 -piperidyl } carbonyl)butyl]-3-isobutyl-2-piperazinone HN'^^° ^vX^A 1 1XX ^F (S)-1 - [(S)-1 - {[4-(2- {7V-Methyl [(p- fluorophenyl)methyl]amino} ethyl)- 1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl- 2-piperazinone HN0^^׳ O /N^ (5)-1 - [(5)-3 -Methyl- 1 - { (9-methyl-3,9-diaza-3 - spiro[5 .5 ]undecyl )carbonyl }butyl]-3 -isobutyl-2- piperazinone AMS-202407USWO Structure Compound Name .C 0 ،؛ 1 (5)-1 - [(5)-3 -Methyl- 1 - {[4-(phenoxymethyl)- 1 - piperi dyl ] carb ony 1} butyl ] -3 -i sobuty 1 -2 - piperazinone .C 0 1.n. A N n-^x = I 1 i، 7 1 H (5)-1 -[(5)-1 -({4-[( l/Mmidazol-2-yl)methyl]- 1 - piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl- 2-piperazinone „C 0 L A J ؛׳<- O z/ Y/Y/^r/ 1 H (5)-l-[(5)-l-({4-[(4,5-Dimethyl-l/Z-imidazol-2- yl)methyl]-l-piperidyl}carbonyl)-3- methylbutyl]-3-isobutyl-2-piperazinone .C o L .N^ A. V=״ ןAA^n Z 1 H (5)-1 -[(5)-1 -({4-[( 1,3 -Benzimidazol-2- yl)methyl]-l-piperidyl}carbonyl)-3- methylbutyl]-3-isobutyl-2-piperazinone HN^Y°o L .N^ Ji / ; O ?V 1 (5)-1 -[(5)-3 -Methyl- 1 -({ 4-[(l -methyl- 1,3 -diaza- 4,5,6,7-tetrahydro-l/Z-inden-2-yl)methyl]-l- piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone HN/^^ 0 LyA'OY״׳־^' (5)-l-[(5)-l-[(4-{2-[7V-Methyl(isopentyl)amino]- 2-oxoethyl }-I-piperi dyl)carbonyl]-3- methylbutyl]-3-(cyclopropylmethyl)-2- piperazinone HN׳^^ O ° — ، ''ך/ (5)-l-[(5)-l-[(4-{2-[7V-Ethyl(isopropyl)amino]- 2-oxoethyl }-I-piperi dyl)carbonyl]-3- methylbutyl]-3-(cyclopropylmethyl)-2- piperazinone AMS-202407USWO Structure Compound Name .C 0 ׳ (5)-1 -[(5)-1 -({4-[3 -(Dimethylamino)propyl]- 1 - piperidyl}carbonyl)-3-methylbutyl]-3-isobutyl- 2-piperazinone /L ,0 HN y 0 'ך/'־ (S)-l-[(5)-l-[(4-{2-[A-Ethyl(isobutyl)amino]ethyl } -1 -piperidyl)carbonyl]-3-methylbutyl]-3-isobutyl-2- piperazinone HN/^^° 0 (5)-l-{(5)-3-Methyl-l-[(l'-methyl-4,4'- bipiperidyl- 1 -yl)carbonyl]butyl } -3 -isobutyl-2- piperazinone HN/^^° 0 (5)-l-[(5)-3-Methyl-l-{(2-methyl-2,9-diaza-9- spiro[5 .5 ]undecyl )carbonyl }butyl]-3 -isobutyl-2- piperazinone HN^^0 0 ^v-Nx (5)-l-[(5)-3-Methyl-l-{(2-methyl-2,7-diaza-7- spiro[3.5]nonyl)carbonyl}butyl]-3-isobutyl-2- piperazinone HN^^0 0 ^NYn » ، Y^Nx ^׳׳ o (5)-1 - [(5)-1 - {[4-( Acetylaminomethyl)- 1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl- 2-piperazinone HN^^0 0 ן [/ ״ ,- ־ ^NHs [(2S,4A)-1 - { (S)-2- [(S)-3 -Isobutyl-2-oxo-1 - piperazinyl]-4-methylvaleryl}-2-methyl-4- piperidyl]acetamide AMS-202407USWO Structure Compound Name HN/^^° 0 .

*^NH2 [(25,45)-1 - {(5)-2- [(5)-3 -Isobutyl-2-oxo-1 - piperazinyl]-4-methylvaleryl}-2-methyl-4- piperidyl]acetamide 1^0HN J 0^Ny،V/ INH (5)-1 - [(5)-3 -Methyl- 1 - { (3 -oxo-2,8-diaza-8- spiro[4.5]decyl)carbonyl}butyl]-3-isobutyl-2- piperazinone JI ^0 HN 0 NH HNA (5)-5 -(1 - { (5)-2-[(5)-3 -Isobutyl-2-oxo-1 - piperazinyl]-4-methylvaleryl}-4-piperidyl)-5-methyl-2,4-imidazolidinedione JI ^0 HN 0 NH HNA (5)-5 -(1 - {(5)-2- [(5)-3 -Isobutyl-2-oxo-1 - piperazinyl]-4-methylvaleryl}-4-piperidyl)-5-methyl-2,4-imidazolidinedione .Co 0 nh 2 (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 4-methylvaleryl}-4-methyl-4-piperidyl)acetamide HN^^° 0 1H H (5)-1 -[(5)-3 -Methyl- 1 -({4-[(4-methyl- 1H- imidazol-2-yl)methyl]- 1 -piperi dyl } carb ony !)butyl ] -3 -i sobuty 1 -2 - piperazinone ^^z^ y—Z G T y—ZT y—Z 1.

T y^Z i x..§> u1 ס דכ דכ ־ דכ דכCD CD ' s 3. r = 27׳ 7 0S' S O CD B £■ ־ 7 £ ■؛״LJ r——1־ 1 • 7CO 1דכ סcr <<£. 2• Q-'> 0 ך ؛ ton> 9* 11—■ 9 y דכo pd '7 . 3 5 ד|.S3 9 0^ H—1׳ 5 8 ،־ cr rt ״" O 9 4^B 1 1■ < to o OJ 1|s <1r?2، Ch w 3^tzi o ? ׳؛! 12 . N rPs*— 1 D > כ 7 >§-< ? £״w '2221r2 0 ־CD O. 5o ،ב، ؛ 4 ؛y s■» r S O' UJ ? 11 ׳؛! N * 1 — 1 D > כ 7 >9 ، Lnס ► L " o דכ to* 5 ־ 5 .־ 2 " — 2 5 - ؛ : 2 S ■ 2 לל s2^0* KL■ — । סo ' S$ X o§־«-£;35* tS) PD * Er > דכ - 7 ► q דכ►S PPM 9• w r. § ' 9 oG oN o /-^ !-^ דכ דכ ל ؛؛؟ 5 ► 5 ►<כ o 4.. ' 0. 9 1N S- 2. gA8־S> S1H o g 2. Hi fc r |כ 7 >Q. =r cr£ " r X to G2CD Er- 12. %" 3 "§- ؛ p 2 2. 4^ _PD C4. 1 CjNS o7 S ־ל 2SO o3-9 S9. HCl- Q.P3o 2O. to’^7 qB M S^•4־ #35= »12. l=:؛ UJ AMS-202407USWO AMS-202407USWO Structure Compound Name HN^^° 0 (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 4-methylvaleryl}-4-piperidyl)acetonitrile C 0 1 0 (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] -4-methylvaleryl}-4-piperidyl)methanesulfonamide An^، q ؟ Nx ^/(1 - {(5)-2- [(5)3־ -Isobutyl-4-methyl-2-oxo- 1 - piperazinyl]-4-methylvaleryl}-4- piperidyl)acetamide 1 A(S)-1 -[(S)-3-Methyl- 1 -({4-[(l -methyl- 1H- L _N. A n-a : L 1 1 7 1 imidazol-2-yl)methyl]- 1 -piperidyl}carbonyl)butyl]-3-isobutyl-4-methyl- 2-piperazinone A Ao (S)-1 -[(S)-3-Methyl- 1 -({4-[(l -methyl- 1H-^N A° 0Yonimidazol-2-yl)methyl]- 1 -piperidyl}carbonyl)butyl]-4-cyclopropyl-3- isobutyl-2-piperazinone A ^0 HN^Y 0 (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 3-phenylpropionyl }-4-piperidyl)acetamide jO A /0 HN Y 0 (l-{(5)-2-[(5)-3-Benzyl-2-oxo-l-piperazinyl]-4-methylvaleryl }-4-piperidyl)acetamide AMS-202407USWO Structure Compound Name .C 0 o(1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - -methylbutyryl } -4-piperidyl)acetamide 0q(1 - { (5)-2- [(5)-3 -(Cy clopropylmethyl)-2-oxo- 1 - piperazinyl]-4-methylvaleryl}-4- piperidyl)acetamide HN^^ 0 0(1 - { (5)-2- [(5)-3 -(Cy clopropylmethyl)-2-oxo- 1 - piperazinyl]valeryl}-4-piperidyl)acetamide HN^^ 0 o(1 - { (5)-2- [(5)-3 -(Cy clopropylmethyl)-2-oxo- 1 - piperazinyl]hexanoyl}-4-piperidyl)acetamide HN^^ 0 (1 - { (5)-2- [(5)-3 -(Cy clopropylmethyl)-2-oxo- 1 - piperazinyl]-4,4-dimethylvaleryl}-4- piperidyl)acetamide C 0 ׳׳؛،׳׳׳ X^N ן/ H (5)-1 - { (5)-3 -Methyl- 1 - [(4-propionylamino- 1 - piperidyl)carbonyl]butyl}-3-isobutyl-2- piperazinone HN־^^° O 'x |1"NH (5)-1 - [(5)-3 -Methyl- 1 - {[4-(5 -oxo-3 - pyrrolidinyl)-l-piperidyl]carbonyl}butyl]-3-isobutyl-2-piperazinone AMS-202407USWO Compound Name (5)-1 -[(5)-1 - {(2,9-Diazaspiro[5 .5]undecan-9- oyl)carbonyl}-3-methylbutyl]-3-isobutyl-2- piperazinone (5)-1 - [(5)-1 - {[4-(2-Acetylaminoethyl)- 1 - piperidyl]carbonyl}-3-methylbutyl]-3-isobutyl-2-piperazinone 8-{(5)-2-[(5)-3-Isobutyl-2-oxo-l-piperazinyl]-4- methy 1 val ery 1} -1,3,8 -tri aza-2-spiro[4.5]decanone (S)-1 -[(S)-3-Methyl- 1 -({4-[(l -methyl- 1H-imidazol-2-yl)methyl]- 1 -piperidyl}carbonyl)butyl]-4-[(/2-fluorophenyl)methyl]-3-isobutyl-2-piperazinone 3 -(1 - {(5)-2- [(5)-3 -Isobutyl-2-oxo-1 - piperazinyl]-4-methylvaleryl}-4- piperidyl)propionamide (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 4-methylvaleryl} -3-piperi dyl)acetamide AMS-202407USWO Structure Compound Name 0 - { (5)-2-[(5)-3 -Isobutyl-2-oxo-1 -piperazinyl]-4- methylvaleryl}-4-piperidinecarboxamide 1 0 JI HN^0 ^־ (1 - {(5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl]hexanoyl}-4-piperidyl)acetamide JI /0 HN y 0 (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 3-cyclopropylpropionyl }-4-piperidyl)acetamide 0 0 (1 - { (5)-2- [(5)-3 -Butyl-2-oxo-1 -piperazinyl]-3 - cyclopropylpropionyl }-4-piperidyl)acetamide HN J^° O (1 - { (5)-2- [(5)-3 -Butyl-2-oxo-1 -piperazinyl]hexanoyl}-4-piperidyl)acetamide HnJ^0 0 (1 - { (5)-2- [(5)-3 -Butyl-2-oxo-1 - 1 _N. A ^rn 0ךpiperazinyl]valeryl}-4-piperidyl)acetamide AMS-202407USWO Structure Compound Name 0 L n 1L(1 - { (5)-2- [(5)-3 -(Cy clopropylmethyl)-2-oxo- 1 - piperazinyl}-3-cyclopropylpropionyl} -4-piperidyl)acetamide HN^^0 0 Y (1 - { (5)-2- [(5)-3 -Butyl-2-oxo-1 -piperazinyl]-4- methylvaleryl }-4-piperidyl)acetamide HN/^^° 0 NH2 ؟ Y ^O 0 1 (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 4-methylvaleryl)-4-piperidyloxy)acetamide C 0(1 - {(5)-2- [(5)-3 -Neopentyl-2-oxo-1 - piperazinyl]valeryl}-4-piperidyl)acetamide . 0 ^nx ^*xn/ o(1 - {(5)-2- [(5)-3 -Neopentyl-2-oxo-1 - piperazinyl]hexanoyl}-4-piperidyl)acetamide C 0(1 - {(5)-2- [(5)-3 -Neopentyl-2-oxo-1 - piperazinyl]-4-methylvaleryl}-4- ^NxX^N^Y 0 Y^piperidyl)acetamide C 0 I N A __ (1 - {(5)-2- [(5)-3 -Neopentyl-2-oxo-1 - piperazinyl]-3-cyclopropylpropionyl} -4-/ v^n^Y 0 x/x -^NHz piperidyl)acetamide AMS-202407USWO Structure Compound Name HIST /N־>°O ^'NHz (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] -4,4-dimethylvaleryl}-4-piperidyl)acetamide HN/ ^0o /^NHz (1 - { (5)-2- [(5)-2-Oxo-3 -propyl- 1 -piperazinyl] -4,4-dimethylvaleryl}-4-piperidyl)acetamide HIV /N־ >% V^N־^ /^NH2 (1 - {(5)-2- [(5)-3 -Neopentyl-2-oxo-1 - piperazinyl]-4,4-dimethylvaleryl}-4- piperidyl)acetamide Hw /N־>°O 0 ^NHz (1 - {(5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl]propionyl}-4-piperidyl)acetamide HIT /N־^0o ■^NHz (1 - { (5)-2- [(5)-3 -Isobutyl-2-oxo-1 -piperazinyl] - 3-cyclohexylpropionyl }-4-piperidyl)acetamide HIT /N.

Claims (27)

AMS-202407USWO CLAIMS

1. A method of modulating negative elongation factor complex (NELF) comprising administering to a subject a compound of Formula (la):R1 or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:R1 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, 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-cycloalkyl;R2 is 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-C1-alkanediyl-O-C1-3 alkanediyl, C1-5 alkyl-NHCOR, and C1-3 alkyl substituted by cycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, aryl, or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; with the proviso that when R2 is C(O)NR15R15, both R15 can form a ring wherein the ring contains the N of NR15R15 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R3 and R7 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally substituted by halogen, OR8, or NR8R״; or R3 and R7 are each independently C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl;R4 is selected from C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-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-cycloalkyl;R5 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, C4-cycloalkenyl, OR8, C1-3 alkyl-OR8, and SR8; and wherein R5 can form a ring with any part of X or Y, wherein the ring optionally contains a carbonyl group;R6 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, and C4-cycloalkenyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or cycloalkenyl is optionally 110 AMS-202407USWO substituted by halogen, OR8, or NR8R״; or R6 is C1-3 alkyl substituted by C(O)NR8R״; or R6 is 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 R6 can form a ring with any part of X; or R6 is imidazolidinone;R8 and R11 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, and C4-7 cycloalkenyl;X is selected from a bond, C1-7 alkanediyl, C2-7 alkenediyl, C2-7 alkynediyl, C3-cycloalkanediyl, C4-6 cycloalkenediyl, -0-, C1-3 alkanediyl-O-, -O-C1-7 alkanediyl, -O-C3-cycloalkanediyl, C1-3 alkanediyl-O-C1-7 alkanediyl, C1-7 heteroalkanediyl, and -S-C1-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)nR8 wherein 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 R9 or 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)NR10R12 or NR10R12, R10 and R12 can form a ring wherein the ring contains the N of NR10R12 and optionally one further heteroatom selected from O and N, wherein if the one further heteroatom is N, the ring is optionally substituted by R8;R9 is 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-NR8R״, C1-5 alkyl-C(O)OR8, C1-5 alkyl- C(O)NR8R״, C1-5 alkyl-C(O)R10, CN, C(O)R8, C(O)NR8R״, C(O)OR8, NR8C(O)NR8R״, OC(O)NR8R״, SO2NR8R״, NR8SO2R8, OR8, NR8R״, and S(O)nR8 wherein n is 0, 1 or 2;R10 and R12 are each independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C1-3 alkanediyl-O-C1-3 alkanediyl-O-C1-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, 0rNR8R״;R13 is C1-5 alkyl substituted by a bicyclic ring optionally containing at least one heteroatom and a carbonyl group; ill AMS-202407USWO R14 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, Ccycloalkenyl, and C1-3 alkyl substituted by aryl or heteroaryl, wherein the aryl or the heteroaryl is optionally substituted by halogen, Cm alkyl, or C3-5 cycloalkyl; andeach R15 is independently selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3- ר 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: 112 AMS-202407USWO (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 F: h (Compound F),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, 113 AMS-202407USWO 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. 114 AMS-202407USWO

27. The method, compound, composition, or use of any one of the preceding claims, wherein the subject has a 20q amplification. 115