Pyridazinone-derived compounds for the regulation of MYC and medical use

Abstract

Compositions, systems, and methods for modulating the expression or activity of MYC, and particularly for reducing or inhibiting it, in a cellular, animal, or human subject are described herein. Such compositions, systems, and methods are useful for preventing, ameliorating, or treating diseases, including cell proliferation diseases and disorders such as cancer, particularly MYC-driven cancers. Compositions comprising a compound of formula (I), as well as pharmaceutical compositions or medicaments thereof, are described. Methods of using such compositions for treating, preventing, or ameliorating diseases, including cell proliferation diseases and disorders such as cancer, particularly MYC-driven cancers, are also described. Compositions comprising conjugates and complexes of a compound of formula (I) that are useful in the methods also described herein are also described. Methods are described that include the use of a compound of formula (I) or a pharmaceutical composition thereof for reducing or inhibiting MYC expression or activity and / or for achieving one or more desirable phenotypic outcomes, such as a decrease in cancer cell growth or proliferation, a decrease in cancer cell viability, a decrease in tumor volume (i.e., tumor regression), a decrease in cancer metastasis, an increase in animal or human survival, or other desirable outcomes related to a particular phenotype (e.g., body weight, metabolism, etc.). Related medicaments, kits, and methods of delivery of such compositions are described. Methods for the development, manufacture, and / or synthesis of a compound of formula (I) and pharmaceutical compositions thereof are also described. Further, methods for diagnosis and testing that include detecting MYC expression or activity levels, and compositions comprising kits for diagnosis and testing are described.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 352,514, filed on June 15, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. The ASCII copy created on June 9, 2023, has a name of 20230609 - MYC.xml and a size of 23,426 bytes.

[0003] The present invention relates to compositions, systems, and methods for modulating, particularly reducing or inhibiting, the expression and / or activity of MYC in a cell, animal, or human subject. Such compositions, systems, and methods are useful for treating, preventing, or ameliorating diseases, including cell proliferation diseases and disorders such as cancer, particularly MYC - promoting cancers.

Background Art

[0004] In the following discussion, certain articles and processes are described for background and introductory purposes only. Nothing contained herein is to be construed as an "admission" of prior art. Applicants expressly reserve the right, if necessary, to show that the articles and processes referenced herein do not constitute prior art under the applicable statutory provisions.

[0005] The MYC family of proto-oncogenes consists of C-MYC (also known as MYC, MYCC, V-Myc myelocytomatosis viral oncogene homolog, BHLHe39, or MRTL), N-MYC (also known as MYCN, BHLHe37, V-Myc myelocytomatosis viral oncogene neuroblastoma-derived homolog, MYCNOT, MODED, or ODED), and L-MYC (also known as MYCL, LMYC, BHLHe38, MYCL1, or V-Myc myelocytomatosis viral oncogene lung cancer-derived homolog). In some embodiments, MYC refers to the MYC family of proto-oncogenes. In certain embodiments, MYC refers to C-MYC. In another particular embodiment, MYC refers to N-MYC. In some embodiments, MYC refers to polymorphs, isoforms, homologs, pseudogenes, or mutant forms of MYC. As used herein, MYC can refer to a gene, an RNA transcript, or a protein product obtained from the expression of a nucleic acid encoding MYC, unless otherwise specified or indicated.

[0006] Genes of the MYC family encode transcription factors that play important roles in the regulation of cell proliferation, cell cycle, cell growth, differentiation, angiogenesis, apoptosis, immunity, stress response, and tumorigenesis. Some examples of the roles of MYC are described in Ahmadi et al. (Ahmadi et al, Journal of Hematology and Oncology, 14, 121 (2021)), Shrestha et al. (Shrestha et al., Front. Oncol., 11, Article 694320 (2021)), Eilers et al. (Eilers et al., Genes Dev., 22(20):2755-2766 (2008)), Holzel et al. (Holzel et al., EMBO Reports, 21:1125-1132 (2001)), Greasley et al. (Greasley et al., Nucleic Acids Res., 28:446-453 (2000)), Trumpp et al. (Trumpp et al., Nature, 414:768-773 (2001)), Bouchard et al (Bouchard et al., Genes Devel., 15:2042-2047 (2001)), Menssen et al (Menssen et al., Proc. Natl. Acad. Sci. USA, 59:6274-6279 (2002)), and Nesbit et al. (Nesbit et al., Blood, 92:1003-1010 (1998)), and these disclosures, together with their references, are incorporated herein by reference in their entirety.

[0007] The MYC family contributes to the development of almost all cancers. Gain-of-function of MYC is commonly observed in cancers and can result from, for example, mutations, chromosomal rearrangements, gene amplifications, or increased expression. Some examples of the various mechanisms and pathways by which MYC can contribute to cancer development are described in Dhanasekaran et al. (Dhanasekaran et al., Nature Reviews Clinical Oncology, 19:23-36 (2022)), Gabay et al (Gabay et al., Cold Spring Harb. Perspect. Med., 4(6):a014241 (2014)), Dang et al. (Dang et al., Cell, 149(1):22-35 (2012)), He et al. (He et al., Science, 281:1509-1512 (1998)), and Rochlitz et al. (Rochlitz et al., Oncology, 53:448-454 (1996)), and these disclosures, together with their references, are hereby incorporated by reference in their entirety.

[0008] The MYC family is known to be a promoter of multiple different cancer types. C-MYC, for example, is known to promote cancers such as breast cancer, Burkitt lymphoma, cervical cancer, colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma), esophageal cancer, gastric cancer (e.g., gastric adenocarcinoma), glioblastoma (e.g., glioblastoma multiforme), head and neck squamous cell carcinoma, leukemia (e.g., myeloid leukemia), liver cancer, lung cancer (e.g., (e.g., non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma), non-Burkitt lymphoma, medulloblastoma, melanoma (e.g., skin cutaneous melanoma, uveal melanoma), mesothelioma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer (e.g., clear cell renal cell carcinoma), and rhabdomyosarcoma. N-MYC is known to promote cancers such as astrocytoma, low-grade glioma of the brain, breast cancer, glioblastoma, lung cancer (e.g., small cell lung cancer), medullary thyroid cancer, medulloblastoma, neuroblastoma, ovarian cancer, pancreatic cancer, pheochromocytoma and paraganglioma, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g., alveolar rhabdomyosarcoma), and testicular cancer. L-MYC is known to promote cancers such as small cell lung cancer.Different types of cancer promoted by C-MYC, N-MYC, and L-MYC are described in Schaub et al. (Schaub et al., Cell Systems, 6(3):282-300(2018)), Nesbit et al. (Nesbit et al., Oncogene, 18:3004-3016(1999)), Faskhoudi et al. (Faskhoudi et al., Pathol. Res. Pract., 233:153851(2022)), Liao et al. (Liao et al., Endocrine-Related Cancer, 7(3):143-164(2000)), Schneider et al. (Schneider et al., EJNMMI Res., 11(1):104(2021)), Shrestha et al. (Shrestha et al., Front. Oncol., 11:694320(2021)), Zimmerman et al. (Zimmerman et al., Cancer Discov., 8(3):320-335(2018)), Feng et al. (Feng et al., Ther. Adv. Med. Oncol., 12:1-16(2020)), Tang et al. (Tang et al., Cancer Lett., 273(1):35-43(2009)), Shroff et al. (Shroff et al., PNAS, 112(21):6539-6544(2015)), Durbin et al. (Durbin et al., Cancer Res., 80(14_Supplement):B10(2020)), and Chanvorachote et al. (Chanvorachote et al., Anticancer Research, 40:609-618(2020)), and these disclosures, together with their references, are incorporated herein by reference in their entirety.

[0009] MYC is an important target for cell proliferation diseases and disorders such as cancer, as well as other diseases characterized by MYC gain-of-function, due to its broad pathogenic significance. Studies have shown that reducing the expression and / or activity of MYC can lead to a significant deceleration of tumor growth, a decrease in tumor size (i.e., tumor regression), and / or a decrease in metastasis in multiple models (such as animal models like cancer cell lines, cell-line derived xenograft (CDX) models, and patient-derived xenograft (PDX) models) for many cancer types, such as MYC-driven cancers. Therefore, it is necessary to discover modulators that can reduce or inhibit the expression and / or activity of MYC and are useful as therapeutic agents and research tools.

[0010] Compared to other types of modulators (such as nucleic acids, siRNA, antisense oligonucleotides, CRISPR, gene therapy, antibodies, etc.), small molecule compounds offer distinct advantages such as ease of administration (mostly can be administered orally), the ability to cross cell membranes and reach intracellular targets, tunability that allows for systemic distribution with or without distribution in the central nervous system (CNS), the ability to engage biological targets through various modes of action, and / or generally lower costs for development and manufacturing in most cases. However, MYC is a difficult target and is currently considered "undruggable" by small molecule compounds because the MYC protein lacks pockets or grooves that can function as good binding sites for small molecules. Small molecule compounds known in the art to target MYC often target indirectly (e.g., inhibitors of MYC-MAX protein-protein interactions) and lack efficacy and appropriate pharmacokinetic properties for in vivo applications.

[0011] Accordingly, in the art, there is a need for better means of reducing the expression and / or activity of MYC, as well as more effective therapies for treating, preventing, or ameliorating cell proliferation diseases and disorders such as cancer. This disclosure addresses this and other unmet needs in the art. A series of small molecule compounds and pharmaceutical compositions thereof, as well as methods of using the same, for reducing the expression and / or activity of MYC in a cell, animal, or human subject are disclosed. Such compositions, systems, and methods are useful for treating, preventing, or ameliorating diseases, particularly cell proliferation diseases and disorders such as cancer, and other diseases characterized by gain-of-function of MYC. SUMMARY OF THE INVENTION

[0012] The present invention relates to compounds of formula (I),

Chemical formula

[0013] Compositions comprising a compound of formula (I) disclosed herein, as well as pharmaceutical compositions or medicaments thereof, useful for treating, preventing, or ameliorating diseases, particularly cell proliferation diseases and disorders such as cancer, including MYC-promoted cancers, are described. Methods of using such compositions for treating, preventing, or ameliorating diseases, particularly cell proliferation diseases and disorders such as cancer, including MYC-promoted cancers, are also described. Compositions comprising conjugates and complexes of compounds of formula (I) useful in the methods also described herein are also described.

[0014] Methods are described that include the use of a compound of formula (I) or a pharmaceutical composition thereof, as disclosed herein, for reducing or inhibiting MYC expression or activity. For example, methods are described that include the use of a compound of formula (I) or a pharmaceutical composition thereof, as disclosed herein, to achieve one or more phenotypic outcomes such as a decrease in cancer cell growth or proliferation, a decrease in cancer cell viability, a decrease in apoptosis, a decrease in tumor volume (i.e., tumor regression), a decrease in cancer metastasis, an increase in survival time of an animal or human subject, or other desired outcomes related to a particular phenotype (e.g., body weight, metabolism, etc.). Related pharmaceuticals, kits, and methods of delivery of such compositions are described.

[0015] Methods for the development, manufacture, and / or synthesis of a compound of formula (I) as disclosed herein, and pharmaceutical compositions thereof, are also described. Further, methods for diagnosis and testing, including detecting MYC expression or activity levels, and compositions including kits for diagnosis and testing are described herein.

[0016] Other features and advantages of the invention will become apparent from the following detailed description and examples.

Best Mode for Carrying Out the Invention

[0017] The following description is presented to enable any person skilled in the art to make and use the invention, and is provided in the context of a patent application and its requirements. Various modifications to the exemplary embodiments and the genetic principles and features described herein will be readily apparent. The exemplary embodiments are mainly described with respect to specific processes and systems provided in a particular implementation. However, the processes and systems will also operate effectively in other implementations. Phrases such as "exemplary embodiment", "one embodiment", and "another embodiment" can refer to the same or different embodiments.

[0018] Exemplary embodiments are described with respect to methods and configurations having specific components. However, the methods and configurations can include more or fewer components than those shown, and the arrangement and type of components can be changed without departing from the scope of the present invention.

[0019] Exemplary embodiments are also described in the context of methods having specific steps. However, the methods and configurations operate effectively with additional steps and steps in a different order that do not conflict with the exemplary embodiments. Accordingly, the present invention is not intended to be limited to the embodiments shown, but should be accorded the widest scope consistent with the principles and features described herein and limited only by the appended claims.

[0020] Unless explicitly stated otherwise, the terms used herein are intended to have the plain and ordinary meaning understood by those of ordinary skill in the art. The following definitions are intended to assist the reader in understanding the present invention, but are not intended to change or otherwise limit the meaning of such terms unless specifically indicated. All publications referred to herein are incorporated by reference for the purpose of describing and disclosing formulations and processes that may be used in connection with the presently described invention.

[0021] Those of ordinary skill in the art can recognize, or confirm, many equivalents to the specific embodiments of the invention described herein in the detailed description and drawings using only routine experimentation. Such equivalents are intended to be encompassed by the claims.

[0022] For simplicity, specific embodiments are described herein with respect to the use of specific methods. It will be apparent to those of ordinary skill in the art reading this disclosure that the present invention is not intended to be limited to a particular application, but can be used in a wide variety of implementations.

[0023] For clarity of disclosure, and not by way of limitation, the detailed description of the invention is divided into subsections that describe or illustrate particular features, embodiments, or uses of the invention.

[0024] General Definitions 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 the embodiments pertain.

[0025] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0026] The terms "optional" or "optionally" are used to indicate that the subsequent described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0027] As used in this specification and the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" can refer to one or more compounds, and reference to "a method" includes reference to equivalent steps and processes known to those of ordinary skill in the art, and the like.

[0028] When ranges of values are provided, it is to be understood that each intervening value, between the upper and lower limits of that range - and any other stated value or intervening value in that stated range - is included within the invention. When the stated range includes upper and lower limits, ranges excluding either of those limits are also included in the invention.

[0029] "Nucleobase" or "base" is used interchangeably and refers to a nitrogen-containing compound that forms a nucleoside, which in turn is a component of a nucleotide. The five major or natural nucleobases are adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U). Other nucleobases, such as synthetic or modified nucleobases, are included herein and are detailed below.

[0030] "Nucleotide" refers to a compound that includes a nucleoside and a linking group, usually a phosphate linking group. Nucleotides include both natural and modified nucleotides.

[0031] "Motif" refers to a region or subsequence within the sequence of an oligonucleotide or polypeptide that has a particular functional or biological significance. Examples of motifs include nucleobase sequences within oligonucleotides such as DNA or RNA, which are recognized by DNA- or RNA-binding proteins or by functional RNAs (e.g., miRNA). Other examples of motifs include nucleobase sequences within RNA that are responsible for a particular function of the RNA, or amino acid sequences within a polypeptide that are responsible for a particular function of the polypeptide. A motif may also refer to the target site of a modulator on a DNA, RNA, or polypeptide target.

[0032] "Nucleic acid sequence", "nucleobase sequence", "nucleotide sequence", or simply "sequence" is used interchangeably and refers to the sequence of nucleobases on a nucleic acid molecule or oligonucleotide. A nucleic acid molecule can refer to a deoxyribonucleic acid (DNA) molecule or a ribonucleic acid (RNA) molecule.

[0033] As used herein, the term "gene" refers to a DNA sequence that is transcribed into mRNA and subsequently translated into a polypeptide, and / or a DNA sequence that is transcribed into a functional RNA that is not translated into a polypeptide.

[0034] As used herein, the term "RNA" refers to ribonucleic acid molecules. The process of transcription first results in the formation of precursor mRNA (pre-mRNA). In the case of protein-coding genes, the pre-mRNA is then processed into mature mRNA by removing introns by splicing and adding a 5' cap and a poly-A tail. The mature mRNA is used as a template by ribosomes for translation into polypeptides. As used herein, the term "RNA" includes pre-mRNA (sometimes also called heterogeneous nuclear RNA), mature mRNA, and RNA at any stage of processing. As used herein, the term "RNA" includes coding RNA that is translated into polypeptides and non-coding RNA (e.g., miRNA, tRNA, rRNA, etc.).

[0035] The terms "polypeptide", "oligopeptide", "peptide" and "protein" are used interchangeably and refer to polymers of two or more amino acids.

[0036] "Oligonucleotide" refers to a polymer containing two or more nucleotides.

[0037] "Allele", also called "variant" or "polymorphism", refers to one of at least two different nucleotide sequence variations at a given position (locus) in the genome. Thus, a particular allele of a polymorphic site refers to a particular version of the sequence with respect to the polymorphic site. "Variant" or "polymorphism" can also refer to a particular allele of a polymorphic site that is different from the reference genome.

[0038] A "polymorphic marker", also called a "polymorphic site" or simply a "marker", refers to a genomic site having at least two sequence variants or at least two alleles. Thus, the genetic association with a polymorphic marker refers to the association with at least one specific allele of that polymorphic marker. A "marker" can also refer to a specific allele of a polymorphic marker. Polymorphic markers can refer to any type of sequence variation found in the genome, including, but not limited to, single nucleotide polymorphisms (SNPs), curated SNPs (cSNPs), insertions, deletions, copy number variations (CNVs), codon expansions, methylation states, translocations, duplications, repeat expansions, rearrangements, multinucleotide polymorphisms, splice variants, microsatellite polymorphisms, etc. A "marker" can also refer to a "biomarker".

[0039] A "single nucleotide polymorphism" or "SNP" is a type of DNA variation in which a single nucleotide at a specific position in the genome differs between two or more individuals or two or more populations. Most SNPs have two alleles, and in such cases, an individual is either homozygous for one allele at the polymorphic site or heterozygous for both alleles.

[0040] An "insertion" or "deletion" is a variant having additional nucleotides or fewer nucleotides, respectively, compared to a reference DNA sequence.

[0041] A "microsatellite" is a type of polymorphic marker in which there are multiple small repeats of bases that are 2 - 8 nucleotides in length.

[0042] The term "associated with" refers to "within", or "correlates with", or "is in linkage disequilibrium with", or "is functionally related to", or any combination of these terms, and can be used interchangeably therewith. "Linkage disequilibrium" refers to the non-random association of alleles at different loci in a given population.

[0043] "Susceptibility" refers to the tendency, quality or risk that an individual has to develop a particular phenotype (e.g., trait or disease), or that an individual can resist, more or less, the development of a particular phenotype. This term encompasses a decrease in susceptibility to a disease, or a decrease in the risk of a disease, or protection against a disease. This term also encompasses an increase in susceptibility to a disease, or an increase in the risk of developing a disease.

[0044] The term "and / or" indicates "one or the other or both". In other words, it means that both or either of the items are involved.

[0045] The term "biomarker" refers to a biomolecule such as a protein, polypeptide, small molecule, metabolite, or nucleic acid sequence that is related to a phenotype such as a disease and whose measurement can be used to determine susceptibility to a disease, or prognosis of a disease, or diagnosis of a disease, or response to treatment of a disease.

[0046] The term "lookup table" is a table that associates one form of data with another form, or one or more forms of data with a predicted outcome (e.g., trait, disease, or other phenotype). A lookup table can contain information about the expression or activity level of one or more targets, or one or more polymorphic markers, and about the correlation between the expression or activity level of one or more targets, or alleles of a polymorphic marker, and a particular phenotype (e.g., trait or disease).

[0047] "Computer-readable medium" refers to a medium for storing information that can be accessed by a custom or commercially available computer interface. Some examples of computer-readable media include, but are not limited to, optical storage media, magnetic storage media, memory, punch cards, or other commercially available media.

[0048] "Nucleic acid sample" refers to a DNA or RNA sample obtained from an individual. Nucleic acid samples can be obtained from any source containing DNA or RNA, such as, for example, blood, saliva, tissue samples, cerebrospinal fluid, amniotic fluid, etc.

[0049] "Sample" generally refers to any sample, such as a biological sample obtained from an individual.

[0050] "Subject" may be interchangeable with "patient" or "individual" and refers to a living multicellular vertebrate, including both human and non-human mammals, unless otherwise indicated.

[0051] "Subject in need of treatment" may include a subject having a disease, disorder, or condition that responds to treatment with a compound disclosed herein. For example, "subject in need of treatment" may include a subject having a cell proliferative disease, disorder, or condition such as cancer described herein. "Subject in need of treatment" may include a subject having a cell proliferative disease, disorder, or condition such as cancer associated with MYC expression or activity.

[0052] The term "therapeutic agent" refers to an agent that can be used to prevent, treat, or ameliorate symptoms associated with a disease.

[0053] The terms "response to a treatment method", "response to a treatment", or "response to the administration of a modulator" refer to the result of any type of treatment on an individual and include beneficial effects, neutral effects, and harmful effects.

[0054] The term "therapeutically effective amount" refers to the amount of a therapeutic agent that elicits a desired response, such as a reduction in the signs and symptoms associated with a disease, when administered alone or in combination with one or more additional therapeutic agents. In many cases, a therapeutically effective amount provides the desired response without causing significant side effects in the subject to whom it is administered. The effective amount of a drug administered to a particular subject in a particular case is not always effective for treating the conditions / diseases described herein, even if such an amount is considered by one of ordinary skill in the art to be a therapeutically effective amount.

[0055] The term "modulator" refers to a compound that affects (also referred to as "modulates") the signaling, activity, or expression of a polypeptide or nucleic acid sequence, and includes both activators and inhibitors. A modulator that increases or upregulates the signaling, activity, or expression of a polypeptide or nucleic acid sequence is referred to as an "activator". A modulator that inhibits, reduces, decreases, or downregulates the signaling, activity, or expression of a polypeptide or nucleic acid sequence is referred to as an "inhibitor". "Modulate" refers to the act of modulating as defined above, and can be carried out using a modulator. Unless otherwise specified, "modulate" or "modulating" refers to the act of modulating as defined above, and includes both increasing or upregulating the signaling, activity, or expression of a polypeptide or nucleic acid sequence, and inhibiting, reducing, decreasing, or downregulating the signaling, activity, or expression of a polypeptide or nucleic acid sequence.

[0056] The term "antisense modulator" refers to a modulator that affects the signaling, activity, or expression of at least one nucleic acid sequence through some form of complementary binding or hybridization to a nucleic acid molecule. Common forms of antisense modulators include antisense oligonucleotides (ASOs), as well as nucleic acids used in the RNAi mechanism for gene regulation, which include, but are not limited to, miRNAs, siRNAs, and short hairpin RNAs (shRNAs).

[0057] The term "amplify" or "amplifying" refers to increasing the copy number of a nucleotide sequence. An example of amplification is the "polymerase chain reaction", where a sample containing a nucleotide sequence is contacted with a pair of oligonucleotide primers. The primers hybridize to the nucleotide sequence, extend under appropriate conditions, and then dissociate from the nucleotide sequence. This process is repeated to increase the copy number of the nucleotide sequence. Other methods can be used for amplification and are known to those skilled in the art.

[0058] The term "isolated" refers to a purified, enriched, or concentrated population of molecules. "Isolated" also refers to the act of enriching or concentrating a particular molecule, compound, or complex so that its purity is increased.

[0059] The term "tissue" refers to an aggregate of cells that form a specific physiological function in an organism.

[0060] The term "delivery", when used in the context of a drug, agent, or pharmaceutical composition, refers to the administration of the drug, agent, or pharmaceutical composition to an assay mixture, cultured cells, an animal, or a human subject or patient.

[0061] A "carrier", also referred to as a "vehicle" or "excipient", is one or more molecules used to assist in the delivery of one or more other molecules when used in the context of a drug, agent, or pharmaceutical composition. Examples of carriers include, but are not limited to, gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, and polyethylene glycol.

[0062] "Cancer" refers to the abnormal growth of cells that proliferate in an uncontrolled manner and, in some cases, tend to metastasize. The term "cancer" includes, but is not limited to, astrocytoma, breast cancer, low-grade glioma, Burkitt lymphoma, cervical cancer, colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma), esophageal cancer, gastric cancer (e.g., gastric adenocarcinoma), glioblastoma (e.g., glioblastoma multiforme), head and neck squamous cell carcinoma, leukemia (e.g., myeloid leukemia), liver cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma), non-Burkitt lymphoma, medullary thyroid cancer, medulloblastoma, melanoma (e.g., cutaneous melanoma, uveal melanoma), mesothelioma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, kidney cancer (e.g., clear cell renal cell carcinoma), retinoblastoma, rhabdomyosarcoma, and testicular cancer.

[0063] "Improvement" is a reduction in the severity of a disease as measured by at least one indicator of that disease. The indicator can be a symptom of the disease or a marker associated with the disease and can be evaluated objectively or subjectively. In certain embodiments, "improving" can mean slowing, stopping, or reversing the progression of the disease.

[0064] A "dose" is a specific unit of a pharmaceutical composition provided for administration. In some embodiments, a dose can refer to a specific amount of a pharmaceutical composition administered over a period of time. A dose can refer to the total amount of a pharmaceutical composition administered or the amount of a pharmaceutical composition administered per unit of time.

[0065] Chemical Definition This specification discloses novel chemical substances and uses of chemical substances. The chemical substances may be described using terms known in the art and are further described below.

[0066] The nomenclature used herein is based on the IUPAC systematic nomenclature or other nomenclatures commonly used and understood by those skilled in the art.

[0067] Any open valency appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of hydrogen, unless otherwise indicated.

[0068] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on a parent molecule.

[0069] The term "substituted" indicates that the designated group has one or more substituents. Any group can have multiple substituents, and when various possible substituents are provided, the substituents are independently selected and may be the same, but do not have to be the same. The term "unsubstituted" means that the designated group has no substituents. The term "optionally substituted" means that the designated group is either unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents.

[0070] When indicating the number of substituents, the term "one or more" refers to the range from one substituent to the maximum possible number of substitutions, i.e., the range from the substitution of one hydrogen by a substituent to the substitution of all hydrogens.

[0071] The term "moiety" refers to an atom or group of covalently bonded atoms that is attached to another atom or molecule by one or more chemical bonds and thereby forms part of a molecule. For example, the variable A in formula (I) 1 , A 2 , R 1 , R 2 R B , and Z refer to moieties attached to the core structure of formula (I) by one or more covalent bonds.

[0072] As used herein, an asterisk " * ", a plus sign "+", or a dotted line may be used to specify the point of attachment of any radical group, moiety, and / or substituent.

[0073] The term "alkyl" refers to straight-chain or branched saturated hydrocarbon groups in all isomeric forms. In certain embodiments, alkyl refers to a straight-chain or branched group of 1 to 12, 1 to 10, 1 to 8, 1 to 7, 1 to 6, 1 to 4, or 1 to 2 carbon atoms, and is herein referred to as C 1-12 -alkyl, C 1-10 -alkyl, C 1-8 -alkyl, C 1-7 -alkyl, C 1-6 -alkyl, C 1-4 -alkyl, or C 1-2 -alkyl, respectively. Some specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl.

[0074] The term "alkylene" refers to the diradical of an alkyl group (e.g., -(CH2) n -, wherein n is an integer, e.g., an integer from 1 to 20). An exemplary alkylene group is -CH2CH2-. Other examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, hexylene, and the like.

[0075] The terms "halo", "halogen", and "halide" are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. One specific example of a halogen is fluoro.

[0076] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is substituted with the same or different halogen atoms. Examples of haloalkyl include monofluoromethyl (-CH2F), difluoromethyl (-CHF2), trifluoromethyl (-CF3), 2,2,2-trifluoroethyl (-CH2CF3), and the like. "Perhaloalkyl" indicates an alkyl group in which all hydrogen atoms of the alkyl group are replaced by the same or different halogen atoms.

[0077] As used herein, the term "heteroalkyl" refers to an "alkyl" group in which at least one carbon atom is replaced by a heteroatom (e.g., an O, N, or S atom). An example of a heteroalkyl group is an "alkoxy" group.

[0078] As used herein, the term "alkenyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon double bond, e.g., a straight-chain or branched group having 2 to 12, 2 to 10, 2 to 8, 2 to 7, 2 to 6, or 2 to 4 carbon atoms, which are herein referred to as C 2-12 -alkenyl, C 2-10 -alkenyl, C 2-7 -alkenyl, C 2-6 -alkenyl, or C 2-4 -alkenyl, respectively.

[0079] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond, e.g., a straight-chain or branched group having 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms, which are herein referred to as C 2-12 -alkynyl, C 2-10 -alkynyl, C 2-8 -alkynyl, C 2-6 -alkynyl, or C 2-4 -alkynyl, respectively.

[0080] The terms "amine" and "amino" refer to the formula -NR a R crefers to the group, where R a and R c are, independently, hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl, or another group. Alternatively, R a and R c can, together with the nitrogen to which they are attached, form a heterocycloalkyl. The term "primary amino" refers to a group where both R a and R c are hydrogen. The term "secondary amino" refers to a group where R a is hydrogen and R c is a group other than hydrogen. The term "tertiary amino" refers to a group where both R a and R c are groups other than hydrogen. Examples of secondary and tertiary amino groups include methylamino, ethylamino, propylamino, isopropylamino, phenylamino, benzylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, and the like.

[0081] The term "alkoxy", "alkoxyl", or "-O-alkyl" refers to an alkyl group as defined above that is attached to the remainder of the molecule by an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, and the like. For example, when other moieties such as alkenyl, alkynyl, heteroalkyl, etc. are attached to the remainder of the molecule by an oxygen atom, it can be represented by -O-alkenyl, -O-alkynyl, -O-heteroalkyl, etc., respectively.

[0082] The term "ether" refers to two hydrocarbons covalently bonded by an oxygen atom.

[0083] As used herein, the term "carbonyl" refers to the radical -C(O)-.

[0084] The term "oxo" refers to an oxygen atom double-bonded to carbon or another element.

[0085] As used herein, the term "carboxamide" refers to the radical -C(O)NRR f , where R and R f may be the same or different substituents. R and R f are, for example, independently, alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl, etc.

[0086] As used herein, the term "carboxy" or "carboxyl" refers to the radical -COOH or its corresponding salt, such as -COONa, etc.

[0087] As used herein, the term "amide" or "amido" or "amidyl" refers to a radical in the form of -R g C(O)N(R d ), -R g C(O)N(R d )R e -, -C(O)NR d R e e, or -C(O)NH2, where R g , R d and R e are, for example, each independently, alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro, etc.

[0088] The term "bicyclic ring system" can refer to two rings fused to each other via a common single or double bond (fused bicyclic ring system), or two rings fused together via an array of three or more common atoms (bridged bicyclic ring system), or two rings fused together via a common single atom (spiro bicyclic ring system). The bicyclic ring system can be saturated, partially unsaturated, unsaturated or aromatic. The bicyclic ring system can include rings in which one or more carbon atoms are replaced by the same or different heteroatoms selected from N, O and S.

[0089] The term "cycloalkyl" refers to a saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3 to 12, 3 to 10, 3 to 8, 3 to 6, 4 to 8, or 4 to 6 carbons per ring, and is herein referred to as C 3-12 -cycloalkyl, C 3-10 -cycloalkyl, C 3-8 -cycloalkyl, C 3-6 -cycloalkyl, C 4-8 -cycloalkyl, or C 4-6 -cycloalkyl for short. Unless otherwise specified, the cycloalkyl group is optionally substituted at one or more ring positions, for example, by alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halo, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl or thiocarbonyl, etc. In certain embodiments, the cycloalkyl group is unsubstituted, i.e., non-substituted.

[0090] The term "partially unsaturated carbocyclic" refers to a cyclic hydrocarbon containing at least one double bond between ring atoms and in which at least one ring of the carbocycle is not aromatic. Partially unsaturated carbocycles can be characterized according to the number of ring carbon atoms. For example, a partially unsaturated carbocycle may contain 5 to 14, 5 to 12, 5 to 10, 5 to 8, or 5 to 6 ring carbon atoms, and is thus referred to as a 5- to 14-membered, 5- to 12-membered, 5- to 10-membered, 5- to 8-membered, or 5- to 6-membered partially unsaturated carbocycle, respectively. Partially unsaturated carbocycles may be in the form of monocyclic carbocycles, bicyclic carbocycles, tricyclic carbocycles, bridged carbocycles, spirocyclic carbocycles, or other carbocyclic ring systems. Examples of partially unsaturated carbocyclic groups include cycloalkenyl groups and bicyclic carbocyclic groups that are partially unsaturated. Unless otherwise specified, a partially unsaturated carbocyclic group is optionally substituted at one or more ring positions, for example, by alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amide, amidino, amino, aryl, arylalkyl, azide, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamide, sulfonyl, or thiocarbonyl. In certain embodiments, the partially unsaturated carbocycle is unsubstituted, i.e., non-substituted.

[0091] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a saturated or partially unsaturated, non-aromatic, monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings), or bridged cyclic ring system containing 3 to 12, 3 to 10, 3 to 8, 3 to 6, 4 to 8, or 4 to 6 carbons per ring, with one or more of the ring-forming atoms being heteroatoms such as, for example, N, O, or S. A cycloheteroalkyl or heterocycloalkyl group can include spiro rings. Examples of monocyclic saturated cycloheteroalkyl or heterocycloalkyl groups include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, and the like. Examples of bicyclic saturated cycloheteroalkyl or heterocycloalkyl groups include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, and the like. Examples of partially unsaturated cycloheteroalkyl or heterocycloalkyl groups include dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, dihydropyranyl, and the like. Also included in the definition of cycloheteroalkyl or heterocycloalkyl are moieties having one or more aromatic rings fused to the non-aromatic heterocycle (i.e., having a common bond), such as phthalimidyl, naphthalimidyl, and benzo derivatives of the heterocycle, such as 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, and the like. A cycloheteroalkyl or heterocycloalkyl group having one or more fused aromatic rings can be attached via either the aromatic or non-aromatic moiety.The definition of cycloheteroalkyl or heterocycloalkyl also includes moieties in which one or more ring-forming atoms are substituted with one or two oxo or sulfide groups. In some embodiments, a cycloheteroalkyl group or a heterocycloalkyl group has 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 heteroatoms (e.g., N, O, or S). In some embodiments, a cycloheteroalkyl or heterocycloalkyl group contains 0, 1, 2, 3, 4, or 5 double bonds. In some embodiments, a cycloheteroalkyl group or a heterocycloalkyl group contains 0, 1, or 2 triple bonds.

[0092] The term "N-heterocycloalkyl" refers to a heterocycloalkyl group containing at least one nitrogen ring atom, and the point of attachment of the heterocycloalkyl radical to the remainder of the molecule is via a nitrogen ring atom. Examples of N-heterocycloalkyl include 1,4-diazepanyl, hexahydropyrrolo[1,2-a]pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl, etc., and the point of attachment of the heterocycloalkyl radical to the remainder of the molecule is via a nitrogen ring atom.

[0093] The term "cycloalkylene" refers to a cycloalkyl group that is unsaturated at one or more ring linkages.

[0094] The term "aryl" refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. The term "aryl" also includes polycyclic ring systems having two or more carbocyclic rings (the rings being "fused rings") where two or more carbons are common to two adjacent rings, with at least one of the rings being aromatic and the other rings being, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl, and / or aryl. Unless otherwise specified, the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, carboxylic acid, -C(O)alkyl, -CO2alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, -CF3, -CN, and the like. In certain embodiments, the aromatic ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, the aromatic ring is unsubstituted, i.e., non-substituted. In certain embodiments, the aryl group has a 6- to 10-membered ring structure.

[0095] The terms "heterocyclyl" and "heterocyclic group" refer to saturated, partially unsaturated, or aromatic ring systems, or combinations thereof, containing 3 to 12, 3 to 10, 3 to 8, 3 to 6, 4 to 8, or 4 to 6 carbons per ring, where one or more of the ring-forming atoms are heteroatoms such as, for example, N, O, or S. As used herein, "heterocyclyl" includes "aryl" groups in which at least one of the ring-forming atoms is a heteroatom such as, for example, N, O, or S. In some embodiments, the heterocyclyl group has 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 heteroatoms (e.g., N, O, or S). The number of ring atoms in a heterocyclyl group can be specified using the Cx-y nomenclature, where x and y are integers designating the number of ring atoms. For example, C 3-6 heterocyclyl group refers to a saturated or partially unsaturated 3- to 6-membered ring structure in which one or more of the ring atoms are heteroatoms such as, for example, N, O, or S. "C 3-6 " indicates that the heterocycle contains a total of 3 to 6 ring atoms, including any heteroatoms that are ring atoms.

[0096] It is contemplated that the terms described herein can be appended to form chemically related combinations such as, for example, "carboxyheterocycloalkyl", "arylalkylheteroaryl", or "aminoalkylheterocyclyl". The definitions described herein apply regardless of whether the terms in question appear alone or in combination. The last member of the combination is the radical attached to the remainder of the molecule. The other members of the combination are attached to the linking radical in reverse order with respect to the literal sequence. For example, the combination "aminoalkylheterocyclyl" refers to a heterocyclyl radical substituted by an alkyl substituted by an amino group.

[0097] The terms "compounds of the invention", "compounds of the disclosure", "disclosed compounds", and "compounds of the present invention" refer to the compounds disclosed herein and their stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts).

[0098] When the compounds of the present invention are solids, it is understood by those skilled in the art that these compounds, as well as their solvates and salts, may exist in different solid forms, particularly different crystalline forms, and all of them are intended to be within the scope of the present invention and the specific formula.

[0099] The term "chiral center" means a carbon atom bonded to four non-identical substituents. The term "chiral" refers to embodiments that cannot be superimposed on their mirror images, while the term "achiral" refers to embodiments that can be superimposed on their mirror images. Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light.

[0100] The definitions and conventions of stereochemistry used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. When describing optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule around the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit., 5:385; errata 511 (1966)). The prefixes D and L or (+) and (-) are used to indicate the sign of the rotation of plane-polarized light by the compound, and (-) or L indicates that the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory.

[0101] The compounds of the present invention can have one or more chiral centers and / or double bonds, and can thus exist as stereoisomers such as geometric isomers, enantiomers or diastereomers. Whenever a chiral center and / or double bond is present in the chemical structure, all stereoisomers associated with that chiral center and / or double bond are intended to be encompassed by the present invention. The term "stereoisomer" as used herein encompasses all geometric isomers, enantiomers or diastereomers, and mixtures thereof.

[0102] The compounds of the present invention can exist in the form of optically pure enantiomers, or mixtures of enantiomers, such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. Compositions comprising, consisting essentially of, or consisting of enantiopure compounds are also contemplated herein, and such compositions can comprise, consist essentially of, or consist of at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of the compounds of formula (I) disclosed herein.

[0103] It is understood that schematic depictions of chemical structures, such as general chemical structures, encompass all stereoisomeric forms of the designated compounds unless otherwise indicated. One of ordinary skill in the art will recognize that a structure can implicitly depict a chiral center. Thus, throughout this specification, the disclosed compounds include all enantiomers, stereoisomers, racemic mixtures, and optically pure isomeric forms.

[0104] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0105] The term "pharmaceutically acceptable acid addition salts" refers to salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid), and organic acids of the classes of aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acids, and sulfonic acids (e.g., formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid), which are pharmaceutically acceptable salts.

[0106] The term "pharmaceutically acceptable base addition salts" means salts formed with organic bases or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (e.g., isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperizine, piperidine, N-ethylpiperidine, and polyamine resins).

[0107] Compound The present invention relates to a compound of formula (I),

Chemical formula

[0108] Particular embodiments of the invention are compounds of formula (I), and their pharmaceutically acceptable salts, tautomers, N-oxides, and solvates.

[0109] All embodiments regarding the specific A 1 , A 2 , R 1 , R 2 , R B , Z, d, h, i, j, k, and m disclosed herein are another A 1 , A 2 , R 1 , R 2, R B It is understood that it can be combined with any other embodiments regarding Z, d, h, i, j, k, and m.

[0110] A specific embodiment of the present invention is a compound of formula (I), wherein A 1 is hydrogen, C 1-7 -alkyl, C 2-7 -alkenyl, C 3-8 -cycloalkyl, aryl, or heterocyclyl, A 2 is hydrogen, C 1-7 -alkyl, C 2-7 -alkenyl, C 3-8 -cycloalkyl, aryl, or heterocyclyl, R 1 is hydrogen, halo, C 1-7 -alkyl, C 2-7 -alkenyl, C 3-8 -cycloalkyl, aryl, or heterocyclyl, R 2 is hydrogen, halo, C 1-7 -alkyl, C 2-7 -alkenyl, C 3-8 -cycloalkyl, aryl, or heterocyclyl, or alternatively A 2 and R 2 together form C 1-7 -alkylene, or C 2-7 -alkenylene, Z is C 1-7 -alkylene, C 2-7 -alkenylene, -CH2-, -(CH2)2-, -CH2(CH)2-, -C(=O)-, -C(=O)CH2-, -C(=O)(CH2)2-, -C(=O)CH2O-, -C(=O)(CH2)2O-, -C(=O)CH(CH3)O-, -C(=O)O-, -C(=O)OCH2-, -C(=O)O(CH2)2-, -C(=O)NH-, -C(=O)NHCH2-, -C(=O)NH(CH2)2-, -S(=O)2-, -S(=O)2CH2-, or -S(=O)2(CH)2-, h is 1, 2, or 3, i is 0, 1, or 2, j is 0, 1, 2, or 3, k is 0, 1, 2, or 3, m is 0 or 1, R B represents a non-hydrogen substituent, and each R B is independently deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino, R B When the substituent is present, it is covalently bonded to any ring atom in place of hydrogen, provided that it does not exceed the maximum valence of the ring atom to which R B is bonded, d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13, C 1-7 -alkyl, C 2-7 -alkenyl, C 1-7 -alkylene, C 2-7 -alkenylene, C 3-8 -cycloalkyl, aryl, and heterocyclyl are each independently substituted or unsubstituted, provided that j and k are not both 0 in the same compound, a compound, as well as its pharmaceutically acceptable salts, tautomers, N-oxides, and solvates.

[0111] In certain embodiments of the present invention, R 1 is hydrogen, halo, C 1-7 -alkyl, C 2-7 -alkenyl, C3-8 - cycloalkyl, aryl, or heterocyclyl, especially hydrogen or C 1-7 - alkyl, for the compound of formula (I).

[0112] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 2 is hydrogen, halo, C 1-7 - alkyl, C 2-7 - alkenyl, C 3-8 - cycloalkyl, aryl, or heterocyclyl, especially hydrogen or C 1-7 - alkyl, for the compound of formula (I).

[0113] Certain embodiments of the present invention relate to compounds of formula (I) wherein A 2 and R 2 together form C 1-7 - alkylene or C 2-7 - alkenylene, especially propylene or butylene, for the compound of formula (I).

[0114] Certain embodiments of the present invention relate to compounds of formula (I) wherein R B is bromo, chloro, fluoro, or iodo, especially fluoro, for the compound of formula (I).

[0115] Certain embodiments of the present invention relate to compounds of formula (I) wherein Z is C 1-7 - alkylene, C 2-7 - alkenylene, -CH2-, -(CH2)2-, -CH2(CH)2-, -C(=O)-, -C(=O)CH2-, -C(=O)(CH2)2-, -C(=O)CH2O-, -C(=O)(CH2)2O-, -C(=O)CH(CH3)O-, -C(=O)O-, -C(=O)OCH2-, -C(=O)O(CH2)2-, -C(=O)NH-, -C(=O)NHCH2-, -C(=O)NH(CH2)2-, -S(=O)2-, -S(=O)2CH2-, or -S(=O)2(CH)2-, especially -CH2-, -(CH2)2-, -C(=O)-, -C(=O)CH2-, or -C(=O)NH-, for the compound of formula (I).

[0116] Certain embodiments of the present invention relate to compounds of formula (I) wherein m is 0 or 1, particularly 0. To avoid misunderstanding, when m is 0, A in formula (I) 1 the Z moiety bridging A 1 and N is replaced by a direct single covalent bond between A

[0117] Certain embodiments of the present invention relate to compounds of formula (I) wherein m is 0 or 1, particularly 1.

[0118] Certain embodiments of the present invention relate to compounds of formula (I) wherein d is 0, 1, 2, 3, or 4, particularly 0, 1, or 2.

[0119] Certain embodiments of the present invention relate to compounds of formula (I) wherein h is 1, 2, or 3, particularly 1.

[0120] Certain embodiments of the present invention relate to compounds of formula (I) wherein i is 0, 1, or 2, particularly 0. To avoid misunderstanding, when i in -[CH2]- of formula (I) i is 0, that particular -CH2- linkage is replaced by a direct single covalent bond.

[0121] Certain embodiments of the present invention relate to compounds of formula (I) wherein i is 0, 1, or 2, particularly 1.

[0122] Certain embodiments of the present invention relate to compounds of formula (I) wherein j is 0, 1, 2, or 3, particularly 1.

[0123] Certain embodiments of the present invention relate to compounds of formula (I) wherein j is 0, 1, 2, or 3, particularly 2.

[0124] Certain embodiments of the present invention relate to compounds of formula (I) wherein k is 0, 1, 2, or 3, particularly 1.

[0125] Certain embodiments of the present invention relate to compounds of formula (I) wherein k is 0, 1, 2, or 3, particularly 2.

[0126] Certain embodiments of the present invention relate to compounds of formula (I) wherein h is 1, i is 1, j is 2, k is 2, and m is 0.

[0127] Certain embodiments of the present invention relate to compounds of formula (I) in which one or more hydrogens are replaced by deuterium, thereby imparting useful properties to the compound, such as, for example, extending the residence time of the active drug species in plasma to achieve better efficacy and / or avoiding adverse side effects.

[0128] Certain embodiments of the present invention are A 1 is as follows,

Chemical formula

[0129] In a particular embodiment of the present invention, R 3 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0130] In a particular embodiment of the present invention, R 4 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0131] In a particular embodiment of the present invention, R 5 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0132] In a particular embodiment of the present invention, R 6 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0133] In a particular embodiment of the present invention, R 7 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0134] In a particular embodiment of the present invention, R 3 , R 4 , R 5 , R 6 , or R 7 One of them is other than hydrogen, relates to a compound of formula (I).

[0135] In a particular embodiment of the present invention, R 3 , R 4 , R 5 , R 6 , or R 7 At least one of them is deuterium, C 1-7 -alkyl (such as methyl, ethyl, propyl, isopropyl, etc.), C 3-8-Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino, related to the compound of formula (I).

[0136] Certain embodiments of the present invention are such that A 1 is selected from the group consisting of

Chemical formula

[0137] Certain embodiments of the present invention are related to the compound of formula (I) wherein n is 0.

[0138] Certain embodiments of the present invention relate to compounds of formula (I) wherein n is 1 or 2.

[0139] Certain embodiments of the present invention relate to A 1 being selected from the group consisting of, compounds of formula (I).

Chemical formula

[0140] Certain embodiments of the present invention are A 1 being as follows,

Chemical formula

[0141] there is no 8 R is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0142] A particular embodiment of the present invention is that R 9 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0143] A particular embodiment of the present invention is that R 10 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0144] A particular embodiment of the present invention is that R 11 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0145] A particular embodiment of the present invention is that R 12 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0146] A particular embodiment of the present invention is that R 13 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0147] A particular embodiment of the present invention is that R 14 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, relates to a compound of formula (I).

[0148] A particular embodiment of the present invention is that R 8 , R 9 , R 10, R 11 , R 12 , R 13 , or R 14 relates to a compound of formula (I) wherein one of them is other than hydrogen.

[0149] In a particular embodiment of the present invention, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , or R 14 relates to a compound of formula (I) wherein at least one of them is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino.

[0150] In a particular embodiment of the present invention, A 1 is selected from the group consisting of

Chemical formula

[0151]

Chemical formula

[0152] A particular embodiment of the present invention relates to a compound of formula (I) wherein p is 0.

[0153] A particular embodiment of the present invention relates to a compound of formula (I) wherein p is 1 or 2.

[0154] A particular embodiment of the present invention relates to a compound of formula (I) wherein A 1 is selected from the group consisting of:

Chemical formula

[0155] A particular embodiment of the present invention is wherein A 1 is as follows,

Chemical formula

[0156] Particular embodiments of the present invention relate to compounds of formula (I) wherein R 15 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0157] Particular embodiments of the present invention relate to compounds of formula (I) wherein R 16 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0158] Particular embodiments of the present invention relate to compounds of formula (I) wherein R 17 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0159] Certain embodiments of the present invention relate to compounds of formula (I) in which R 18 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0160] Certain embodiments of the present invention relate to compounds of formula (I) in which R 19 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0161] Certain embodiments of the present invention relate to compounds of formula (I) in which R 20 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0162] Certain embodiments of the present invention relate to compounds of formula (I) in which R 21 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0163] Certain embodiments of the present invention relate to compounds of formula (I) in which R 22 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0164] Certain embodiments of the present invention relate to compounds of formula (I) in which one of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , or R 22 is other than hydrogen.

[0165] Certain embodiments of the present invention relate to compounds of formula (I) in which at least one of R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , or R 22 is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C3-8 -Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino, relating to the compound of formula (I).

[0166] Certain embodiments of the present invention are 1 A is selected from the group consisting of

Chemical formula

[0167] ​Certain embodiments of the present invention relate to compounds of formula (I) wherein q is 0.

[0168] Certain embodiments of the present invention relate to compounds of formula (I) wherein q is 1 or 2.

[0169] Certain embodiments of the present invention relate to compounds of formula (I) wherein A 1 is selected from the group consisting of:

Chemical formula

[0170] Certain embodiments of the present invention relate to compounds of formula (I) wherein A 1 is as follows:

Chemical formula

[0171] In a particular embodiment of the invention, R 23 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl, relates to a compound of formula (I).

[0172] In a particular embodiment of the invention, R 24 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl, relates to a compound of formula (I).

[0173] In a particular embodiment of the invention, R 25 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl, relates to a compound of formula (I).

[0174] In a particular embodiment of the invention, R 26 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl, relates to a compound of formula (I).

[0175] In a particular embodiment of the invention, R 27 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl, relates to a compound of formula (I).

[0176] In a particular embodiment of the invention, R 23 , R 24 , R 25 , R 26 , or R 27 relates to a compound of formula (I), provided that one of them is other than hydrogen.

[0177] In a particular embodiment of the invention, R 23 , R 24 , R 25 , R 26 , or R 27 relates to a compound of formula (I), provided that at least one of them is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C3-8 -Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino, related to the compound of formula (I).

[0178] A specific embodiment of the present invention is A 1 is selected from the group consisting of

Chemical formula

[0179] Certain embodiments of the present invention relate to compounds of formula (I) wherein r is 0.

[0180] Certain embodiments of the present invention relate to compounds of formula (I) wherein r is 1 or 2.

[0181] Certain embodiments of the present invention relate to compounds of formula (I) wherein A 1 is selected from the group consisting of:

Chemical formula

[0182] Certain embodiments of the present invention wherein A 1 is as follows:

Chemical formula

[0183] A particular embodiment of the present invention is that R 37 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, and relates to a compound of formula (I).

[0184] A particular embodiment of the present invention is that R 38 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, and relates to a compound of formula (I).

[0185] A particular embodiment of the present invention is that R 39 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, and relates to a compound of formula (I).

[0186] A particular embodiment of the present invention is that R 40 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, and relates to a compound of formula (I).

[0187] A particular embodiment of the present invention is that R 41 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, and relates to a compound of formula (I).

[0188] A particular embodiment of the present invention is that R 42 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, and relates to a compound of formula (I).

[0189] A particular embodiment of the present invention is that R 43 is hydrogen or C 1-7 -alkyl, in particular, hydrogen or methyl, and relates to a compound of formula (I).

[0190] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 44 is hydrogen or C 1-7 -alkyl, particularly hydrogen or methyl.

[0191] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 45 is hydrogen or C 1-7 -alkyl, particularly hydrogen or methyl.

[0192] Certain embodiments of the present invention relate to compounds of formula (I) wherein one of R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , or R 45 is other than hydrogen.

[0193] Certain embodiments of the present invention relate to compounds of formula (I) wherein at least one of R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , or R 45 is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino.

[0194] Certain embodiments of the present invention relate to A 1 which is selected from the group consisting of

Chemical formula

[0195] Certain embodiments of the present invention relate to a compound of formula (I) wherein s is 0.

[0196] Certain embodiments of the present invention relate to a compound of formula (I) wherein s is 1 or 2.

[0197] Certain embodiments of the present invention relate to a compound of formula (I) wherein A 1 is selected from the group consisting of.

Chemical formula

[0198] Certain embodiments of the present invention are A 1 as follows,

Chemical formula

[0199] Certain embodiments of the present invention are such that R 46 is hydrogen or C 1-7-alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0200] Certain embodiments of the present invention relate to R 47 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0201] Certain embodiments of the present invention relate to R 48 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0202] Certain embodiments of the present invention relate to R 49 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0203] Certain embodiments of the present invention relate to R 50 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0204] Certain embodiments of the present invention relate to R 51 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0205] Certain embodiments of the present invention relate to R 52 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0206] Certain embodiments of the present invention relate to R 53 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0207] Certain embodiments of the present invention relate to R 54 being hydrogen or C 1-7 -alkyl, especially hydrogen or methyl, of the compound of formula (I).

[0208] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 55 is hydrogen or C 1-7 -alkyl, particularly hydrogen or methyl.

[0209] Certain embodiments of the present invention relate to compounds of formula (I) wherein one of R 37 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , or R 55 is other than hydrogen.

[0210] Certain embodiments of the present invention relate to compounds of formula (I) wherein at least one of R 37 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 , or R 55 is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino.

[0211] Certain embodiments of the present invention relate to compounds of formula (I) wherein A 1 is selected from the group consisting of

Chemical formula

[0212] A particular embodiment of the present invention relates to a compound of formula (I) wherein t is 0.

[0213] A particular embodiment of the present invention relates to a compound of formula (I) wherein t is 1 or 2.

[0214] A particular embodiment of the present invention relates to a compound of formula (I) wherein A 1 is selected from the group consisting of the following.

Chemical formula

[0215] A particular embodiment of the present invention relates to a compound of formula (I) wherein A 1 is hydrogen, deuterium, C 1-7-Alkyl (e.g., methyl, ethyl, propyl, isopropyl, isobutyl, etc.), C 3-8 -Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxyl, formyl, acetyl, methoxyacetyl, 2-hydroxyacetyl, tert-butylacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, dimethylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, N,N-dimethylamino, 1,1,1-trifluoro-2-hydroxybutyl, 5,5,5-trifluoro-2-oxopentyl, or hydroxycyclobutyl, particularly, tert-butylacetyl, methoxyacetyl, isopropyl, isobutyl, 1,1,1-trifluoro-2-hydroxybutyl, 5,5,5-trifluoro-2-oxopentyl, dimethylsulfonyl, or hydroxycyclobutyl, and relates to a compound of formula (I) selected from the group consisting of

[0216] Certain embodiments of the present invention are A 2 is as follows,

Chemical formula

[0217] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 28 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0218] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 29 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0219] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 30 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0220] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 31 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0221] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 75 is hydrogen or C 1-7-alkyl, especially hydrogen or methyl, relates to a compound of formula (I).

[0222] Certain embodiments of the present invention relate to a compound of formula (I) in which R 28 , R 29 , R 30 , R 31 , or R 75 is other than hydrogen.

[0223] Certain embodiments of the present invention relate to a compound of formula (I) in which at least one of R 28 , R 29 , R 30 , R 31 , or R 75 is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino.

[0224] Certain embodiments of the present invention relate to a compound of formula (I) in which A 2 is selected from the group consisting of

Chemical formula

[0225] A particular embodiment of the present invention relates to a compound of formula (I) wherein u is 0.

[0226] A particular embodiment of the present invention relates to a compound of formula (I) wherein u is 1 or 2.

[0227] A particular embodiment of the present invention relates to a compound of formula (I) wherein A 2 is selected from the group consisting of

Chemical formula

[0228] A particular embodiment of the present invention is A 2 is as follows,

Chemical formula

[0229] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 32 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0230] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 33 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0231] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 34 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0232] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 35 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0233] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 36 is hydrogen or a C 1-7 -alkyl, particularly hydrogen or methyl.

[0234] Certain embodiments of the present invention relate to compounds of formula (I) wherein one of R 32 , R 33 , R 34 , R 35 , or R 36 is other than hydrogen.

[0235] Certain embodiments of the present invention relate to compounds of formula (I) wherein at least one of R 32 , R 33 , R 34 , R 35 , or R 36 is deuterium, a C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), a C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino.

[0236] Certain embodiments of the present invention relate to compounds of formula (I) wherein A 2 is selected from the group consisting of

Chemical formula

[0237] A particular embodiment of the present invention relates to a compound of formula (I) wherein v is 0.

[0238] A particular embodiment of the present invention relates to a compound of formula (I) wherein v is 1 or 2.

[0239] A particular embodiment of the present invention relates to a compound of formula (I) wherein A 2 is selected from the group consisting of:

Chemical formula

[0240] A particular embodiment of the present invention is wherein A 2 is as follows,

Chemical formula

[0241] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 56 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0242] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 57 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0243] A particular embodiment of the present invention relates to a compound of formula (I) wherein R 58 is hydrogen or C 1-7 -alkyl, especially hydrogen or methyl.

[0244] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 59 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0245] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 60 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0246] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 61 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0247] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 62 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0248] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 63 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0249] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 64 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0250] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 , or R 64 is other than hydrogen.

[0251] Certain embodiments of the present invention relate to compounds of formula (I) wherein R 56 , R 57 , R 58 , R 59, R 60 , R 61 , R 62 , R 63 , or R 64 wherein at least one of them is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino, relates to a compound of formula (I).

[0252] In a particular embodiment of the present invention, A 2 is selected from the group consisting of

Chemical formula

[0253] A particular embodiment of the invention relates to a compound of formula (I) wherein w is 0.

[0254] A particular embodiment of the invention relates to a compound of formula (I) wherein w is 1 or 2.

[0255] A particular embodiment of the invention relates to a compound of formula (I) wherein A 2 is selected from the group consisting of:

Chemical formula

[0256] A particular embodiment of the invention wherein A 2 is as follows:

Chemical formula

[0257] Particular embodiments of the present invention relate to compounds of formula (I) wherein R 65 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0258] Particular embodiments of the present invention relate to compounds of formula (I) wherein R 66 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0259] Particular embodiments of the present invention relate to compounds of formula (I) wherein R 67 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0260] Particular embodiments of the present invention relate to compounds of formula (I) wherein R 68 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0261] Certain embodiments of the present invention relate to compounds of formula (I) in which R 69 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0262] Certain embodiments of the present invention relate to compounds of formula (I) in which R 70 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0263] Certain embodiments of the present invention relate to compounds of formula (I) in which R 71 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0264] Certain embodiments of the present invention relate to compounds of formula (I) in which R 72 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0265] Certain embodiments of the present invention relate to compounds of formula (I) in which R 73 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0266] Certain embodiments of the present invention relate to compounds of formula (I) in which R 74 is hydrogen or C 1-7 -alkyl, in particular hydrogen or methyl.

[0267] Certain embodiments of the present invention relate to compounds of formula (I) in which R 56 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , or R 74 is other than hydrogen.

[0268] Certain embodiments of the present invention relate to compounds of formula (I) in which R 56 , R65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 , or R 74 wherein at least one of them is deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodo), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino, relates to the compound of formula (I).

[0269] In a particular embodiment of the present invention, A 2 is selected from the group consisting of

[0270]

Chemical formula

[0271] A particular embodiment of the invention relates to a compound of formula (I) wherein y is 0.

[0272] A particular embodiment of the invention relates to a compound of formula (I) wherein y is 1 or 2.

[0273] A particular embodiment of the invention relates to a compound of formula (I) wherein A 2 is selected from the group consisting of

Chemical formula

[0274] A particular embodiment of the invention relates to a compound of formula (I) wherein A 2 is hydrogen.

[0275] A particular embodiment of the invention relates to a compound of formula (I) wherein A 2 is tert-butyl.

[0276] Certain compounds of formula (I) of the present invention are 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 2-[[1-(7-fluoroquinazolin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(6-methylpyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methylpyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(7H-purin-6-yl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(6-fluoroquinazolin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[[1-(1,6-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)azetidin-3-yl]methyl]-6-pyridin-4-ylpyridazin-3-one, 2-[1-(1,6-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)azetidin-3-yl]-6-pyridin-4-ylpyridazin-3-one, 6-pyrazol-1-yl-2-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methyl]pyridazin-3-one, 6-(1,2,4-triazol-1-yl)-2-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(7H-purin-6-yl)azetidin-3-yl]methyl]-6-pyridin-4-ylpyridazin-3-one, 2-[[1-(6-methylpyrazin-2-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(3-methyl-[1,2,4]triazolo[4,3-b](3-Pyridazin-6-yl)azetidin-3-yl]methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(3-methylimidazo[4,5-b]pyridin-2-yl)piperidin-4-yl]pyridazin-3-one, 2-((1-(5H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrazolo[1,5-a]pyrimidin-5-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methylpyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-propan-2-ylpyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(9-methylpurin-6-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(6-ethyl-5-fluoropyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-thieno[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(imidazo[1,2-b]pyridazin-6-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-4-carbonitrile, 6-[4-[[3-(2,4-dimethyl-1,3-(Thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-3-carbonitrile, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-thieno[3,2-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-3-carbonitrile, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(5-methylpyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrimidin-2-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrazolo[1,5-a]pyrazin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-[[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 6-(2,4-dimethyl-1,3-(Thiazol-5-yl)-2-[[1-(4-methylpyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(5,6,7,8-tetrahydroquinazolin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-quinoxalin-2-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 5-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carbonitrile, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methylpyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyrimidine-4-carbonitrile, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(4-methoxypyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-(piperidin-4-ylmethyl)pyridazin-3(2H)-one, 4-((3-(2,4-dimethylthiazol-5-yl)-6-oxopyridazin-1(6H)-yl)methyl)piperidine-1-carboxylic acid tert-butyl, 3-(4-((3-(2,4-dimethylthiazol-5-yl)-6-oxopyridazin-1(6H)-yl)methyl)piperidin-1-yl)pyridazine-2-carbonitrile, 4-[[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]methyl]benzonitrile, 6-(2,(4-Dimethylthiazol-5-yl)-2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-((1-(3-chlorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(3-methylquinoxalin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 2-((1-(3,5-difluorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-[[1-[(3,4-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-[[1-[(2-chloro-6-fluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-[[1-[(2,5-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-[[1-[(2,4-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-Thiazol-5-yl)pyridazin-3-one, 2-[[1-(6-fluoroquinazolin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(7-fluoroquinazolin-4-yl)azetidin-3-yl]methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(6-fluoroquinazolin-4-yl)azetidin-3-yl]methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol, 1-(1-ethylpiperidin-4-yl)-2-(1-pyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-(1-quinolin-4-ylpiperidin-4-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-(1-quinolin-2-ylpiperidin-4-yl)pyridazin-3-one, 2-[[1-(7-fluoroquinazolin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(2,6-dimethylpyrimidin-4-yl)piperidin-4-yl]pyridazin-3-one, 2-[1-(2-cyclopropylpyrimidin-4-yl)piperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(1-methyl-6-oxopyrimidin-4-yl)piperidin-4-yl]pyridazin-3-one, 2-[4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidin-1-yl]quinoline-3-carbonitrile, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(5,6-dimethylpyrimidin-4-yl)piperidin-4-yl]pyridazin-3-one, 2-[[1-(6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidin-1-yl]quinoline-4-carbonitrile, 6-[4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidin-1-yl]pyridine-2-carbonitrile, 6-[4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidin-1-yl]-3-methyl-1H-pyrimidine-2,4-dione, 6-(3,5-dimethylpyrazol-1-yl)-2-(1-thieno[3,2-d]pyrimidin-4-ylpiperidin-4-yl)pyridazin-3-one, 6-(3,5-(Dimethylpyrazol-1-yl)-2-(1-thieno[2,3-d]pyrimidin-4-ylpiperidin-4-yl)pyridazin-3-one, 2-[[1-(7H-purin-6-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)azetidin-3-yl]methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(3-methylquinoxalin-2-yl)piperidin-4-yl]pyridazin-3-one, 2-[1-(6-cyclobutylpyrimidin-4-yl)piperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(9-methylpurin-6-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-[2-methyl-6-(trifluoromethyl)pyrimidin-4-yl]piperidin-4-yl]pyridazin-3-one, 2-[4-[(6-oxo-3-pyrazol-1-ylpyridazin-1-yl)methyl]piperidin-1-yl]pyrido[1,2-a]pyrimidin-4-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(5-fluoropyrimidin-4-yl)azetidin-3-yl]methyl]pyridazin-3-one, 6-pyrazol-1-yl-2-[(1-thieno[3,2-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-pyrazol-1-yl-2-[(1-thieno[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 2-[[1-(1-methylpyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-pyrazol-1-yl-2-[[1-[6-(trifluoromethyl)pyrimidin-4-yl]piperidin-4-yl]methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[(1-thieno[3,2-d]pyrimidin-4-ylazetidin-3-yl)methyl]pyridazin-3-one, 6-(3,5-(Dimethylpyrazol-1-yl)-2-[[1-(7H-purin-6-yl)azetidin-3-yl]methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-[6-(trifluoromethyl)pyrimidin-4-yl]azetidin-3-yl]methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[(1-thieno[2,3-d]pyrimidin-4-ylazetidin-3-yl)methyl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(5,6-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(5-methylpyrazolo[1,5-a]pyrimidin-7-yl)azetidin-3-yl]methyl]pyridazin-3-one, 2-[[1-(1,6-dimethylpyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-yl)azetidin-3-yl]methyl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 2-[4-[(6-oxo-3-pyrazol-1-ylpyridazin-1-yl)methyl]piperidin-1-yl]pyridine-3-carbonitrile, 2-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(4-methoxypyrimidin-2-yl)piperidin-4-yl]pyridazin-3-one, 2-[[1-(3-chloropyridin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 3-[3-[[3-(3,5-(Dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]methyl]azetidin-1-yl]pyrazine-2-carbonitrile, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(1-methylbenzimidazol-2-yl)piperidin-4-yl]pyridazin-3-one, 2-[4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidin-1-yl]pyridine-4-carbonitrile, 2-[3-[[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]methyl]azetidin-1-yl]pyrido[1,2-a]pyrimidin-4-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(2-methylpyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(2-fluorophenyl)sulfonylpiperidin-4-yl]pyridazin-3-one, N-(2-chlorophenyl)-4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidine-1-carboxamide, N-(2,6-difluorophenyl)-4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidine-1-carboxamide, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(1-methylpyrazolo[3,4-d]pyrimidin-4-yl)azetidin-3-yl]methyl]pyridazin-3-one, 2-[3-[[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]methyl]azetidin-1-yl]pyridine-3-carbonitrile, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-[3-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl]methyl]pyridazin-3-one, 6-(3,5-(Dimethylpyrazol-1-yl)-2-[[1-(3-methylquinoxalin-2-yl)azetidin-3-yl]methyl]pyridazin-3-one, 2-[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]-N-(2-phenylethyl)piperidine-1-carboxamide, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-[2-(4-fluorophenoxy)acetyl]piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-piperidin-4-ylpyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[[1-(5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)azetidin-3-yl]methyl]pyridazin-3-one, 2-[1-(3-cyclopropyl-1,2,4-thiadiazol-5-yl)piperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]-N-[(4-fluorophenyl)methyl]piperidine-1-carboxamide, 2-[1-(1,3-benzoxazol-2-yl)piperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(2-pyridin-3-ylacetyl)piperidin-4-yl]pyridazin-3-one, 6-[3-[[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]methyl]azetidin-1-yl]pyridine-3-carbonitrile, 2-[1-[2-(2-chloro-6-fluorophenyl)acetyl]piperidin-4-yl]-6-(3,5-(dimethylpyrazol-1-yl)pyridazin-3-one, N-(3,4-dimethylphenyl)-4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidine-1-carboxamide, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(1,3-thiazol-2-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-[2-(2-fluorophenoxy)propanoyl]piperidin-4-yl]pyridazin-3-one, , 2-[1-(3,4-dimethylphenyl)sulfonylpiperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 3-[4-[(6-oxo-3-pyrazol-1-ylpyridazin-1-yl)methyl]piperidin-1-yl]pyrazine-2-carbonitrile, 6-[4-[(6-oxo-3-pyrazol-1-ylpyridazin-1-yl)methyl]piperidin-1-yl]pyridine-3-carbonitrile, 6-pyrazol-1-yl-2-[[1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(6-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[1-[2-(2-chlorophenyl)acetyl]piperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-[2-(1-methylindol-3-yl)acetyl]piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(isoquinoline-1-carbonyl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-[(E)-3-phenylprop-2-enyl]piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(4,4,4-trifluorobutanoyl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(2-methoxyacetyl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(4-fluoro-1,3-benzothiazol-2-yl)piperidin-4-yl]pyridazin-3-one, 6-(3,5-dimethylpyrazol-1-yl)-2-[1-(2-phenylethylsulfonyl)piperidin-4-yl]pyridazin-3-one, 2-[(1-quinolin-4-ylpiperidin-4-yl)methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one,2-[[1-[(2,5-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(5-fluoropyrimidin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 6-pyrazol-1-yl-2-[[1-[3-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(2-methylpyrimidin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[[1-(6-tert-butylpyridazin-3-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(2-phenylethyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(2-indol-1-ylacetyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(6-methylpyrimidin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[[1-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-[6-(dimethylamino)pyrimidin-4-yl]piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[(1-imidazo[1,2-b]pyridazin-6-ylpiperidin-4-yl)methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-((1-(3aH-indole-6-carbonyl)piperidin-4-yl)methyl)-6-(1H-pyrazol-1-yl)pyridazin-3(2H)-one,2-[(1-Thieno[3,2-d]pyrimidin-4-ylpiperidin-4-yl)methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[(1-propan-2-ylpiperidin-4-yl)methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(1-phenylethyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[4-[[6-oxo-3-(1,2,4-triazol-1-yl)pyridazin-1-yl]methyl]piperidin-1-yl]pyrido[1,2-a]pyrimidin-4-one, 2-[[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[(1-thieno[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[[1-(2-hydroxycyclohexyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-[2-(2-fluorophenyl)acetyl]piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[(1-cyclopentylpiperidin-4-yl)methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(2-hydroxyethyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-[(1-hydroxycyclohexyl)methyl]piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-[(1-hydroxycyclopentyl)methyl]piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(5-bromopyrimidin-2-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-((1-(5H-indole-4-carbonyl)piperidin-4-yl)methyl)-6-(1H-pyrazol-1-yl)pyridazin-3(2H)-one, 2-[[1-(cyclopentylmethyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one,2-[[1-(2-Piperidin-1-ylethyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-pyrazol-1-yl-2-[[1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(2-methylpropyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[(1-benzylpiperidin-4-yl)methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-pyrazol-1-yl-2-[[1-(quinoline-2-carbonyl)piperidin-4-yl]methyl]pyridazin-3-one, 2-((1-(2H-benzo[d]imidazole-5-carbonyl)piperidin-4-yl)methyl)-6-(1H-pyrazol-1-yl)pyridazin-3(2H)-one, 2-[[1-(2-cyclopropyl-6-methylpyrimidin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 6-pyrazol-1-yl-2-[[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-pyrazol-1-yl-2-[[1-(3,3,3-trifluoro-2-hydroxypropyl)piperidin-4-yl]methyl]pyridazin-3-one, 2-(piperidin-4-ylmethyl)-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(oxan-2-ylmethyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(2-fluorobenzoyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-[(4-hydroxyoxan-4-yl)methyl]piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(2-hydroxycyclobutyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one,2-[[1-(7H-Purin-6-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[[1-[2-(4-chlorophenyl)acetyl]piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 4-[[4-[(6-oxo-3-pyrazol-1-ylpyridazin-1-yl)methyl]piperidin-1-yl]methyl]benzonitrile, 2-[4-[(6-oxo-3-pyrazol-1-ylpyridazin-1-yl)methyl]piperidin-1-yl]-5,6,7,8-tetrahydroquinoline-3-carbonitrile, 2-[[1-(oxan-4-ylmethyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-pyrazol-1-yl-2-[[1-(quinoxaline-6-carbonyl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-(isoquinoline-1-carbonyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-[2-(2-chlorophenyl)acetyl]piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(6-cyclopropylpyrimidin-4-yl)piperidin-4-yl]methyl]-6-(1,2,4-triazol-1-yl)pyridazin-3-one, 2-[(1-methylsulfonylpiperidin-4-yl)methyl]-6-pyrazol-1-ylpyridazin-3-one, 2-[[1-(4-fluorobenzoyl)piperidin-4-yl]methyl]-6-pyrazol-1-ylpyridazin-3-one, 6-(1,2,4-triazol-1-yl)-2-[[1-[6-(trifluoromethyl)pyrimidin-4-yl]piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(pyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(7-fluoroquinazolin-4-yl)piperidin-4-yl)methyl)-6-(1H-pyrazol-1-yl)pyridazin-3(2H)-one,6-(2,4-Dimethylthiazol-5-yl)-2-((1-(6-methylpyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(2-methylpyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(9H-purin-6-yl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-((1-(6-fluorobenzo[d]thiazol-4-yl)piperidin-4-yl)methyl)-6-(1H-1,2,4-triazol-1-yl)pyridazin-3(2H)-one, , 2-((1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)azetidin-3-yl)methyl)-6-(pyridin-4-yl)pyridazin-3(2H)-one, 2-(1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)azetidin-3-yl)-6-(pyridin-4-yl)pyridazin-3(2H)-one, 6-(1H-pyrazol-1-yl)-2-((1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(1H-1,2,4-triazol-1-yl)-2-((1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(9H-purin-6-yl)azetidin-3-yl)methyl)-6-(pyridin-4-yl)pyridazin-3(2H)-one, 2-((1-(6-methylpyrazin-2-yl)piperidin-4-yl)methyl)-6-(1H-1,2,4-triazol-1-yl)pyridazin-3(2H)-one, 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-((1-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)azetidin-3-yl)methyl)pyridazin-3(2H)-one, 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(1-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-4-yl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-[(5-methyl-1,2-oxazol-3-yl)methyl]piperidin-4-yl]methyl]pyridazin-3-one, N-[2-(7-cyclohexyl-6-imino-13-methyl-2-oxo-1,7,9-triazatricyclo[8.4.0.03,8]tetradeca-3(8),4,9,11,13-pentaen-5-yl)-4-phenyl-1,3-thiazol-5-yl]-4-methoxybenzamide, 2-[[1-(1,3-benzoxazol-2-yl)piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-Thiazol-5-yl)pyridazin-3-one, 2-(3-cyclopropyl-6-oxopyridazin-1-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(6-fluorobenzo[d]oxazol-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-2-(4-oxoquinazolin-3-yl)acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-2-(1-methyltetrazol-5-yl)sulfanylacetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]thiophene-2-sulfonamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-2,3-dihydro-1,4-benzodioxine-6-sulfonamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3,5-dimethyl-1,2-oxazole-4-sulfonamide, 2-(benzimidazol-1-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-1-methylsulfonylpiperidine-4-carboxamide, 3-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]propanamide, 2-(1,2-benzoxazol-3-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide, 2-(1,3-benzothiazol-2-ylsulfanyl)-N-[2-[3-(2,4-dimethyl-1,N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3-thiazol-5-yl)-6-oxopyridazin-1-yl]acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-4-methylthiadiazole-5-carboxamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-1-thiophen-2-ylcyclopentane-1-carboxamide, 3-(benzenesulfonyl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]propenamide, 1-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3-(naphthalen-1-ylmethyl)urea, 1-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3-(2-methoxyphenyl)urea, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]furan-2-carboxamide, a pharmaceutically acceptable salt thereof.,

[0277] Certain compounds of formula (I) of the present invention are 2-((1-(5H-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(7H-purin-6-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(6-methylpyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methylpyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrazolo[1,5-a]pyrimidin-5-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methylpyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-propan-2-ylpyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(9-methylpurin-6-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(6-methyl-3H-pyrrolo[3,2-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(6-ethyl-5-fluoropyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-thieno[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(imidazo[1,2-b](2,4-Dimethyl-1,3-thiazol-5-yl)-6-oxo-1,6-dihydropyridazine-3-carbonitrile, 2-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-4-carbonitrile, 6-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-3-carbonitrile, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-[(1-thieno[3,2-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-3-carbonitrile, 6-(2,4-Dimethylthiazol-5-yl)-2-((1-(6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-Dimethylthiazol-5-yl)-2-((1-(4-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-[[1-(5-methylpyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrimidin-2-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-Dimethylthiazol-5-yl)-2-((1-(5-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-[[1-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrazolo[1,5-a]pyrazin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,(4-Dimethylthiazol-5-yl)-2-((1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-[[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(4-methylpyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methyl]pyridazin-3-one, 2-[[1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-[(5-methyl-1,2-oxazol-3-yl)methyl]piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(5,6,7,8-tetrahydroquinazolin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[(1-quinoxalin-2-ylpiperidin-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(5-fluoropyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 5-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyridine-2-carbonitrile, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methylpyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]pyrimidine-4-carbonitrile, 6-(2,4-dimethyl-1,3-(Thiazol-5-yl)-2-[[1-(4-methoxypyrimidin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(piperidin-4-ylmethyl)pyridazin-3-one, N-[2-(7-cyclohexyl-6-imino-13-methyl-2-oxo-1,7,9-triazatricyclo[8.4.0.03,8]tetradeca-3(8),4,9,11,13-pentaen-5-yl)-4-phenyl-1,3-thiazol-5-yl]-4-methoxybenzamide, 3-(4-((3-(2,4-dimethylthiazol-5-yl)-6-oxopyridazin-1(6H)-yl)methyl)piperidin-1-yl)pyridazine-2-carbonitrile, 4-[[4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidin-1-yl]methyl]benzonitrile, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-((1-(4-chlorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-((1-(3-chlorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(3-methylquinoxalin-2-yl)piperidin-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-[[1-(2-methyl-6,7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one, 2-[[1-[(2,5-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-[[1-[(2,4-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-[[1-[(3,4-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-((1-(3,5-difluorobenzyl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-[[1-[(2-chloro-6-fluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-[[1-(1,3-benzoxazol-2-yl)piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one, 2-(3-cyclopropyl-6-oxopyridazin-1-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide, 4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidine-1-carboxylic acid tert-butyl, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(6-fluorobenzo[d]oxazol-2-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-2-(4-oxoquinazolin-3-yl)acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-2-(1-methyltetrazol-5-yl)sulfanylacetamide, N-[2-[3-(2,4-dimethyl-1,3-Thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]thiophene-2-sulfonamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-2,3-dihydro-1,4-benzodioxine-6-sulfonamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3,5-dimethyl-1,2-oxazole-4-sulfonamide, 2-(benzimidazol-1-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide, N-[2-[3-(2,4-dimethyl-1,3-, (Thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-1-methylsulfonylpiperidine-4-carboxamide, 3-(3,5-dimethyl-1,2-oxazol-4-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]propanamide, 2-(1,2-benzoxazol-3-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide, 2-(1,3-benzothiazol-2-ylsulfanyl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-4-methylthiadiazole-5-carboxamide, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-1-thiophen-2-ylcyclopentane-1-carboxamide, 3-(benzenesulfonyl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]propanamide, 1-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3-(naphthalen-1-ylmethyl)urea, 1-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3-(2-methoxyphenyl)urea, N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]furan-2-carboxamide, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable solvate thereof.

[0278] Specific compounds of formula (I) of the present invention are 6-(2,4-dimethylthiazol-5-yl)-2-((1-(pyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(7-fluoroquinazolin-4-yl)piperidin-4-yl)methyl)-6-(1H-pyrazol-1-yl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(6-methylpyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazol-5-yl)-2-((1-(2-methylpyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(9H-purin-6-yl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one, 2-((1-(6-fluoroquinazolin-4-yl)piperidin-4-yl)methyl)-6-(1H-1,2,4-triazol-1-yl)pyridazin-3(2H)-one, 2-((1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)azetidin-3-yl)methyl)-6-(pyridin-4-yl)pyridazin-3(2H)-one, 2-(1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)azetidin-3-yl)-6-(pyridin-4-yl)pyridazin-3(2H)-one, 6-(1H-pyrazol-1-yl)-2-((1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 6-(1H-1,2,4-triazol-1-yl)-2-((1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(9H-purin-6-yl)azetidin-3-yl)methyl)-6-(pyridin-4-yl)pyridazin-3(2H)-one, 2-((1-(6-methylpyrazin-2-yl)piperidin-4-yl)methyl)-6-(1H-1,2,4-triazol-1-yl)pyridazin-3(2H)-one, 6-(3,Those selected from the group consisting of 5-dimethyl-1H-pyrazol-1-yl)-2-((1-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)azetidin-3-yl)methyl)pyridazin-3(2H)-one, 6-(3,5-dimethyl-1H-pyrazol-1-yl)-2-(1-(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-4-yl)pyridazin-3(2H)-one, and pharmaceutically acceptable salts thereof.,

[0279] A specific embodiment of the present invention is formula (II),

Chemical formula

[0280] Certain embodiments of the present invention [Chemical formula] relate to compounds of formula (II) selected from the group consisting of: [Chemical formula]

[0281] Certain compounds of formula (I) of the present invention 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(3-fluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(3,3-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(2-fluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(2,2-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(2,3-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazol-5-yl)-2-(2,4-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-(2,5-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-(2,6-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-(3,4-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, 6-(2,4-Dimethyl-1,3-thiazol-5-yl)-2-(3,5-difluoro-1-pyrido[2,3-d]pyrimidin-4-ylpiperidin-4-yl)methylpyridazin-3-one, selected from the group consisting of, and pharmaceutically acceptable salts thereof.

[0282] The formulas of the compounds disclosed herein are to be interpreted to include all possible stereoisomers, enantiomers, or epimers of the compounds, unless a specific stereoisomer, enantiomer, or epimer is indicated by the formula. The formulas of the compounds disclosed herein are to be interpreted to include salts, esters, amides, or solvates of the compounds.

[0283] In certain embodiments, compounds similar to the compounds of formula (I) disclosed herein are provided herein. The similarity between small molecules can be determined using methods well known in the art, such as those that derive, for example, the Tanimoto index, Dice index, Cosine coefficient, or Soergel distance. Such methods are described in Bajusz et al. (Bajusz et al., Journal of Cheminformatics, 7: Article number 20 (2015)), which is hereby incorporated by reference in its entirety together with the references cited therein. In some embodiments, compounds having a Tanimoto index of at least 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 0.96, 0.97, 0.98, 0.99, or 1.00 are provided herein as compared to the compounds of formula (I) disclosed herein.

[0284] The compounds of formula (I) disclosed herein can be developed and generated by any number of methods known to those of skill in the art (see below for specific methods).

[0285] Targets, target regions, target segments, and nucleic acid base sequences In certain embodiments, the compounds of formula (I) disclosed herein may target nucleic acids, and the target nucleic acid is RNA encoding MYC or a part thereof. RNA-targeting small molecules are useful because they combine the advantages of small molecule drugs (see the background art) with the advantages of targeting RNA, for example, enabling an extended target range that includes non-coding regulatory RNAs beyond protein-coding genes, and enabling the targeting of "undruggable" proteins that lack deep binding pockets. In certain embodiments, the target nucleic acid may comprise a nucleotide sequence encoding MYC, including but not limited to RefSeq accession number NC_000008.11 (incorporated herein as SEQ ID NO: 1) truncated at nucleotides 127735434-127742951, RefSeq accession NM_002467.6 (incorporated herein as SEQ ID NO: 2), and RefSeq accession NM_001354870.1 (incorporated herein as SEQ ID NO: 3), or a part thereof, where the adenine base (A) is exchangeable with the uracil base (U). In some embodiments, the compounds of formula (I) disclosed herein may also target certain other RNA variants encoding MYC or a part thereof.

[0286] In certain embodiments, the compounds of formula (I) disclosed herein can target at least one target region within a target nucleic acid. A target region is a structurally or functionally defined region of a target nucleic acid. Examples of target regions include exons, introns, exon-intron junctions, intron-exon junctions, exon-exon junctions, 3'untranslated regions (3'UTRs), 5'untranslated regions (5'UTRs), translation initiation regions, translation termination regions, 5'donor splice sites, 3'acceptor splice sites, start codons, upstream open reading frames (ORFs), repetitive regions, hexanucleotide repeat expansions, splice enhancer regions, exonic splicing enhancers (ESEs), splice suppressor regions, exonic splicing silencers (ESSs), intronic splicing enhancers (ISEs), intronic splicing silencers (ISSs), RNA destabilization motifs, RNA stabilization motifs, miRNA binding sites, RNA-binding protein (RBP) sites, or other defined nucleic acid regions, but are not limited thereto. Information regarding such structurally or functionally defined target regions in RNAs such as MYC RNA can be obtained in part by accession numbers from databases such as NCBI, GENBANK, and ENSEMBL, and references therein, and such information is hereby incorporated by reference in its entirety.

[0287] The target region may include one or more overlapping or non-overlapping target segments. In certain embodiments, the target segments within the target region are less than 10,000, 5,000, 2,500, 1,000, 500, 250, 100, or 50 nucleotides in length. In some embodiments, the compounds of formula (I) disclosed herein may target one target segment within the target region. In some embodiments, the compounds of formula (I) disclosed herein may target two or more overlapping or non-overlapping target segments within the same target region. In other embodiments, the compounds of formula (I) disclosed herein may target two or more target segments derived from different target regions.

[0288] Suitable target segments may particularly include certain structurally or functionally defined target regions (e.g., start codons or stop codons). Determination of suitable target segments can include comparison of the nucleobase sequence of the target segment with other sequences across the transcriptome. For example, the BLAST algorithm can be used to identify regions of similarity between different sequences. This comparison can enable the selection of unique target segments in order to develop compounds that specifically target the target nucleic acid while minimizing non-specific targeting (i.e., off-targeting) of other nucleic acids.

[0289] In some embodiments, targeting involves determining at least one target segment within a target nucleic acid with which a compound can interact to produce a desired effect. The desired effect can be a decrease in the stability of the target nucleic acid, resulting in a decrease in RNA levels and a corresponding decrease in the level of the encoded protein. The desired effect can be an increase in the stability of the target nucleic acid, resulting in an increase in RNA levels and a corresponding increase in the level of the encoded protein. The desired effect can also be a change in translation efficiency from the target nucleic acid, resulting in no change in its RNA levels but an increase or decrease in the level of its encoded protein. The desired effect can also be a phenotypic change associated with a change in the RNA level of the target nucleic acid or a change in the level of the protein encoded by the target nucleic acid. In certain embodiments, the desired effect of using a compound of formula (I) disclosed herein to target at least one target segment within a target nucleic acid encoding MYC is a reduction in MYC RNA levels. In other embodiments, the desired effect of using a compound of formula (I) disclosed herein to target at least one target segment within a target nucleic acid encoding MYC is a reduction in MYC protein levels. In yet other embodiments, the desired effect of using a compound of formula (I) disclosed herein to target at least one target segment within a target nucleic acid encoding MYC is a phenotypic change associated with a reduction in MYC RNA or protein levels.

[0290] Accordingly, some embodiments provide a compound of formula (I) disclosed herein that can inhibit or reduce the expression or activity of MYC. In one embodiment, the compound of formula (I) disclosed herein targets a nucleic acid encoding MYC and can inhibit its transcription. In one embodiment, the compound can target a nucleic acid encoding MYC and can degrade or destabilize it. In one embodiment, the compound targets a nucleic acid encoding MYC and can inhibit its translation. In yet another embodiment, the compound targets a nucleic acid encoding MYC and can regulate its splicing, thereby decreasing the expression or activity of MYC.

[0291] In certain embodiments, inhibition or reduction of MYC RNA or MYC protein can be achieved by targeting MYC-related genes or pathways. Thus, in certain embodiments, provided herein are compounds of formula (I) that can reduce or inhibit MYC expression, activity, or signaling by targeting and inhibiting at least one gene or pathway that positively regulates or increases MYC expression, activity, or signaling. In other embodiments, provided herein are compounds of formula (I) that can reduce or inhibit MYC expression, activity, or signaling by targeting and increasing the expression or activity of at least one gene or pathway that negatively regulates or inhibits MYC expression.

[0292] Conjugates and Complexes In certain embodiments, the compounds of formula (I) disclosed herein are conjugated or bound to, or complexed with, at least one other molecule, such as a peptide or polypeptide, antibody, lipid, sugar, nucleotide or oligonucleotide, other polymer, cleaving agent, transporting agent, inserting agent, molecular beacon, hybridization-induced cross-linking agent, lipophilic agent, or hydrophilic agent. These conjugates or complexes can provide the compound with numerous benefits, including, but not limited to, increased efficacy or activity, improved delivery to specific tissues or cells, increased oral bioavailability or absorption, enhanced cellular uptake, reduced toxicity, resistance to nuclease degradation, increased half-life or residence time, enhanced pharmacodynamic or pharmacokinetic properties, and / or improved selectivity for a particular target. Certain embodiments can include one or more combinations of the conjugates or complexes described herein.

[0293] In some embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with a protein or other polyamide, amine, or similar molecule. In other embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with a lipid, phospholipid, cholesterol or thiolcholesterol, cholic acid, aliphatic chain, hexylamino-carbonyl-oxy cholesterol, or another similar molecule. In yet other embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with another organic molecule such as an ether or thioether, steroid, biotin, phenazine, folic acid, phenanthridine, anthraquinone, acridine, adamantane acetic acid, palmitoyl, fluorescein, rhodamine, coumarin, a dye or other marker molecule, or another polymer (e.g., polyethylene glycol). In other embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with another compound having special electromagnetic or optical properties such as a photo-labile protecting group.

[0294] In some embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with another drug or agent described herein for use in treating, preventing or ameliorating cancer. In other embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with another drug, such as another drug that alleviates pain or other symptoms, or improves uptake or delivery, such as an anticoagulant (e.g., aspirin, warfarin), an anti-inflammatory and pain reliever such as a COX inhibitor, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, pranoprofen, carprofen, indomethacin, folic acid, taioprofenic acid, diclofenac, niflumic acid, a diazepine or benzodiazepine, a barbiturate; or an antibacterial, antiviral, antibiotic, or other drug that promotes at least one benefit in a therapeutic setting including a therapeutic effect, symptom alleviation, drug resistance, or side effect mediation.

[0295] In some embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with an antibody or nanobody that recognizes a specific antigen characteristic of a particular cell type (e.g., a cancer cell) or tissue, to enable delivery of the compounds of formula (I) to a particular cell type or tissue. In some embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with a nanobody or nanocarrier, thereby enabling targeted delivery of the compounds of formula (I) to a particular cell type or tissue. In other embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with another agent that promotes transport across the cell membrane or another agent that promotes transport across the blood-brain barrier. In some embodiments, the compounds of formula (I) disclosed herein are conjugated to or complexed with one or more GalNAc residues, which are recognized by the asialoglycoprotein receptor and result in efficient uptake into cells.

[0296] In some embodiments, the conjugates described herein are prodrugs that are converted, after administration, into a pharmacologically active drug, such as a compound of formula (I) disclosed herein, for example, by an enzyme in the body. Prodrugs are useful, for example, for improving stability, improving solubility, increasing permeability, increasing drug absorption, extending the duration of action, or achieving selective delivery of a pharmacologically active drug. Currently, approximately 10% of the drugs approved worldwide are administered as prodrugs. Prodrugs are described by Hajnal et al. (Hajnal et al., Acta Medica Marisiensis, 62(3):356 - 362(2016)), Rautio et al. (Rautio et al., Nature Reviews Drug Discovery, 17:559 - 587(2018)), and Rautio et al (Rautio et al., Wiley - VCH Verlag GmbH & Co. KGaA, Prodrugs and Targeted Delivery: Towards Better ADME Properties, Volume 47(2011)), which are hereby incorporated by reference in their entirety along with the references cited therein.

[0297] In some embodiments, the compounds of formula (I) disclosed herein can be conjugated to ribonucleases such as RNase L to induce the degradation of target RNA. Such bivalent compounds are known as RIBOTACs (ribonuclease-targeting chimeras) and are described by Dey et al. (Dey et al., Cell Chemical Biology, 26(8):1047-1049(2019)), which is incorporated herein in its entirety along with the references cited therein. In other embodiments, the compounds of formula (I) disclosed herein can be conjugated to a ligand of an E3 ubiquitin ligase to induce ubiquitination of the target protein and subsequent degradation by the proteasome. Such bivalent compounds are known as PROTACs (proteolysis-targeting chimeras) and are described by Toure et al. (Toure et al., Angew. Chem. Int. Ed., 55:1966-1973(2016)), which is incorporated herein in its entirety along with the references cited therein.

[0298] Pharmaceutical Compositions and Delivery Methods Some embodiments of the invention provide pharmaceutical compositions or medicaments comprising a compound of formula (I) disclosed herein together with a pharmaceutically acceptable carrier, diluent, and / or other substances. Another embodiment relates to a method of using a compound of formula (I) disclosed herein for preparing such a pharmaceutical composition or medicament. The carrier, diluent, and / or other substances of the pharmaceutical composition must be "acceptable" in the sense of being compatible with the other components of the composition and not harmful to its recipient. In one embodiment, the carrier, diluent, and / or other substances are therapeutically inert. The terms "pharmaceutical composition" and "medicament" are used interchangeably herein.

[0299] A pharmaceutical composition or a medicament is formulated, dosed, and administered in accordance with good medical practice. A general list of practices is described by Wu & Chen (U.S. Patent Application Publication No. 2018 / 0112272 (A1)), which is incorporated herein in its entirety, together with the references cited therein. In some embodiments, the pharmaceutical composition or the medicament can include a formulation prepared by mixing at least one compound of formula (I) disclosed herein with a carrier or an excipient. Suitable carriers and excipients are described in more detail by Ansel et al. (Ansel et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia), Gennaro et al. (Gennaro et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia), and Rowe et al. (Rowe et al., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago), which are incorporated herein in their entirety, together with the references cited therein.

[0300] In some embodiments, the pharmaceutical composition or medicament can comprise at least one compound of formula (I) disclosed herein together with one or more substances common in pharmaceutical preparations such as, for example, adjuvants, anesthetics, antioxidants, buffers, carriers, colorants, diluents, emulsifiers, flavoring agents, glidants, lubricants, masking agents, opaquing agents, perfumes, pH adjusters, preservatives, processing aids, salts for changing osmotic pressure, solubilizing agents, stabilizers, surfactants, suspending agents, sweetening agents, and wetting agents. The pharmaceutical composition or medicament may also contain one or more substances for improving the sedation of the pharmaceutical product and / or for assisting in its manufacture. The pharmaceutical composition or medicament may also contain further therapeutically valuable substances. For example, the pharmaceutical composition or medicament may comprise a mixture of two or more compounds that are each therapeutically beneficial, at least one of which is a compound of formula (I) disclosed herein.

[0301] In some embodiments, the aforementioned pharmaceutical composition or medicament is prepared in unit dosage form for ease of administration and uniformity of dosage. As used herein, unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of the active ingredient, i.e., a compound of formula (I) disclosed in the present invention, calculated to produce the desired therapeutic effect in association with the carrier and / or other substances in the pharmaceutical composition. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, cachets, suppositories, injectable solutions or suspensions, etc., and multiple subdivisions thereof.

[0302] The dosage at which the compounds of formula (I) disclosed herein are administered can vary within a wide range and needs to be adjusted according to the individual requirements of each case. For example, in some embodiments, the daily dosage can range from about 0.01 mg to about 1000 mg per person for compounds administered orally, although the upper and lower limits may be exceeded as necessary.

[0303] In certain embodiments, the pharmaceutical composition or medicament can be administered by any suitable means including, for example, enteral, epidural, inhalation, intra-arterial, intracerebral, intraventricular, intradermal, intralesional (if local treatment is desired), intramuscular, intranasal, intraocular, intraperitoneal, intrapulmonary, intrathecal, intravenous, intravitreal, oral, parenteral, percutaneous, rectal, subcutaneous, topical (including buccal and sublingual), transdermal, transmucosal, and vaginal administration.

[0304] In some embodiments, the pharmaceutical composition or medicament can be in any suitable form convenient for administration, such as, for example, capsules, conjugates, creams, crystals, dispersions, elixirs, emulsions, nanoparticles, ointments, gels, patches, pills, powders, solutions, sprays, suppositories, suspensions, syrups, or tablets.

[0305] The following are examples of pharmaceutical compositions suitable for different routes of administration and methods for their preparation. In certain embodiments, pharmaceutical compositions for oral administration in liquid form, such as suspensions, syrups, elixirs, emulsions, and solutions, can include a liquid carrier or diluent such as water, glycol, oil, alcohol, etc. In other embodiments, pharmaceutical compositions for oral administration in solid form, such as powders, pills, capsules, and tablets, can include a solid carrier such as sugar (e.g., mannitol, lactose, sucrose, glucose, sodium saccharin, etc.), magnesium carbonate, kaolin, diluent, lubricant (e.g., silicon dioxide, stearic acid, magnesium stearate, talcum, etc.), binder, disintegrant (e.g., starch, clay, cellulose, algining, gum, and polymer, etc.) that facilitates dissolution of the solid. Tablets and capsules are the most advantageous oral dosage forms for easy administration, and in this case, a solid pharmaceutical carrier is naturally used.

[0306] In some embodiments, for example, a pharmaceutical composition administered parenterally in the form of an injectable solution or suspension may contain a carrier such as sterile water, but other components may be included, for example, to assist solubility. The carrier can be used to prepare an injectable solution containing physiological saline, a glucose solution, or a mixture of physiological saline and a glucose solution. The injectable solution can be formulated in oil for sustained action. Oils suitable for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long-chain fatty acids, and mixtures of these and other oils. The injectable suspension can be prepared using a suitable liquid carrier, a suspending agent, and the like. In certain embodiments, the pharmaceutical composition for parenteral administration can be a sterile solution, emulsion, or suspension prepared from a solid or lyophilized form prior to administration. In other embodiments, the pharmaceutical composition may contain certain adjuvants, anesthetics, buffers, or wetting agents that promote more effective distribution of the composition, facilitate administration of the composition, or improve the patient's response or health status.

[0307] Certain embodiments provide a pharmaceutical composition for transdermal administration (e.g., percutaneous, or topical), wherein the carrier optionally contains a penetration enhancer and / or a suitable wetting agent, and optionally is combined in a small proportion with a suitable additive of any nature that does not cause significant harmful effects on the skin. The additive can facilitate administration through the skin and / or can be useful in preparing the desired composition. The pharmaceutical composition can be administered in various ways, for example, as a transdermal patch, as a spot-on, cream, gel, or ointment.

[0308] Some embodiments provide pharmaceutical compositions that can be administered transmucosally, such as in the form of sprays or suppositories. Other embodiments provide pharmaceutical compositions that can be administered by nasal administration (e.g., inhalants), and / or can be administered via an aerosol delivery device such as an atomizer, nebulizer, or vaporizer. The aerosol delivery devices referred to herein, and other aerosol delivery devices, are well known to those of skill in the art and are included in the various embodiments herein.

[0309] Certain embodiments of the present invention provide a method of delivering a compound of formula (I) or a pharmaceutical composition thereof, disclosed herein, to a cell, tissue, animal or human subject. In some embodiments, the compound of formula (I) or a pharmaceutical composition thereof, disclosed herein, is delivered using one of the above routes of administration, or other routes of administration known to those of skill in the art. In some embodiments, the compound of formula (I) or a pharmaceutical composition thereof, disclosed herein, is delivered via a targeting method that directly introduces or targets the compound or pharmaceutical composition to a specific cell or tissue involved in a disease, such as a cancerous cell or tumor. Manish and Vimukta (Manish and Vimukta, Research Journal of Chemical Sciences, 1(2):135-138(2011)) describe some methods for targeted drug delivery, which are hereby incorporated by reference in their entirety, along with the references cited therein.

[0310] In some embodiments, the method of delivering a compound of formula (I) or a pharmaceutical composition thereof disclosed herein includes naked delivery to a cell, animal, or human subject. In some embodiments, the delivery method is electroporation or permeabilization. In other embodiments, the delivery method includes the use of liposome-based or amine-based transfection reagents. In other embodiments, the delivery method includes other forms of lipid-mediated transport. In another embodiment, the delivery method includes the use of membrane fusion. In another embodiment, the delivery method includes the use of a solution of colloids or nanoparticles containing polymer particles. The nanoparticles may include specific properties (such as electromagnetic properties) that assist in targeting a specific region for delivery or otherwise facilitate delivery. In another embodiment, the delivery method includes the use of chemical-mediated transport, including the use of calcium phosphate. In another embodiment, the delivery method includes peptide-mediated transport, including the use of polylysine. In another embodiment, the delivery method includes the use of endocytosis. In other embodiments, the delivery method may include direct microinjection into a cell. These delivery methods can be used with or without the aforementioned complexes or conjugates of the compounds of formula (I) disclosed herein. Certain complexes or conjugates can improve the delivery rate or stability of the compound and are included in these embodiments. Other delivery methods are known to those skilled in the art and include standard practices incorporated into certain embodiments herein.

[0311] Analysis of the Activity of Compounds and Pharmaceutical Compositions The compounds of formula (I) disclosed herein, or pharmaceutical compositions thereof, may have variable activity, as defined, for example, by percent reduction in target RNA level, percent reduction in target protein level, or percent reduction in activity of a target protein. In some embodiments, the target is MYC. In certain embodiments, a decrease in MYC RNA level, including but not limited to RNA from transcription of the MYC gene and RNA translated into MYC protein, indicates a reduction or inhibition of MYC expression. In particular embodiments, a decrease in the level of one or more MYC transcripts disclosed by SEQ ID NOs: 1-3 herein indicates a reduction or inhibition of MYC expression. In some embodiments, a decrease in the level of MYC protein indicates a reduction or inhibition of MYC expression. In particular embodiments, a decrease in the level of one or more MYC proteins that are translation products of one or more MYC transcripts disclosed by SEQ ID NOs: 1-3 herein indicates a reduction or inhibition of MYC expression.

[0312] In other embodiments, a decrease in the activity of MYC protein, which is a translation product of one or more MYC transcripts disclosed by SEQ ID NOs: 1-3 herein, indicates a reduction or inhibition of MYC activity. The activity of MYC refers to one or more activities normally performed by the MYC transcripts or proteins described herein, such as regulation of, for example, cell proliferation, cell cycle, cell growth, differentiation, angiogenesis, apoptosis, immunity, stress response, or tumor formation. In certain embodiments, the compounds of formula (I) disclosed herein or pharmaceutical compositions thereof selectively target the levels or activities of one or more specific MYC transcript variants and the proteins encoded thereby and can reduce them, and a decrease in the level or activity of such one or more MYC transcript variants or proteins indicates a reduction in MYC expression or activity.

[0313] In yet other embodiments, certain phenotypic changes resulting from the administration of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein to a cell, animal or human subject may indicate a reduction or inhibition of MYC expression or activity, such as, for example, cell cycle arrest, decreased cancer cell growth or proliferation, decreased cancer cell viability, decreased cancer cell migration, decreased cancer cell invasion, decreased cancer cell metastasis, decreased angiogenesis, or decreased or increased apoptosis.

[0314] In certain embodiments, changes to other genes, mRNAs, proteins, or pathways within a cell that result from and are well known to those of skill in the art to be associated with a reduction or inhibition of MYC expression or activity are incorporated herein as indicative of a reduction or inhibition of MYC expression or activity.

[0315] RNA Level Analysis In certain embodiments, the reduction or inhibition of MYC expression by a compound of formula (I) or a pharmaceutical composition thereof disclosed herein can be evaluated by measuring a decrease in the level of MYC RNA transcripts. RNA analysis can be performed on poly(A)+ mRNA or total cellular RNA. Methods of RNA isolation are well known in the art and include, for example, using TRIzol reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's recommended protocol, or using an RNA extraction kit (Qiagen). Target RNA levels can be quantified using methods well known in the art, including, for example, Northern blot analysis, competitive polymerase chain reaction (PCR), or quantitative real-time PCR using an ABI PRISM 7600, 7700, or 7900 Sequence Detection System (PE-Applied Biosystems, Foster City, CA) after reverse transcription according to the manufacturer's instructions.

[0316] Prior to quantitative real-time PCR, the isolated RNA is first subjected to a reverse transcription reaction to generate complementary DNA (cDNA), which is then used as a substrate for the real-time PCR amplification reaction. Reagents for reverse transcription and real-time PCR are commercially available (e.g., Invitrogen, Carlsbad, CA). The reverse transcription reaction and the real-time PCR reaction can be performed sequentially in the same sample well or in different sample wells. The levels of the target gene or RNA obtained by real-time PCR can be normalized using, for example, the total RNA level quantified by RIBOGREEN (Invitrogen, Carlsbad, CA), or the expression levels of genes such as cyclophilin A or β-actin, whose expression in cells is more or less stable. The method of RNA quantification using RIBOGREEN is described in Jones et al. (Jones et al., Analytical Biochemistry, 265:368-374 (1998)), and is hereby incorporated by reference in its entirety, together with the references cited therein. RIBOGREEN fluorescence can be measured using a CYTOFLUOR 4000 instrument (PE Applied Biosystems). The expression levels of cyclophilin A or β-actin can be quantified by real-time PCR in the same well as the well used to quantify the level of the target RNA (i.e., by performing a multiplex reaction), or by performing it in a separate well. Probes and primers that hybridize to the target nucleic acid encoding MYC can be designed using methods well known in the art, including, for example, the use of software such as PRIMER EXPRESS software (Applied Biosystems, Foster City, CA). A further method for measuring a decrease in the level of MYC RNA is described in Example 2, which is included in the embodiments of this specification.

[0317] Analysis at the protein level In certain embodiments, the reduction or inhibition of MYC expression by a compound of formula (I) or a pharmaceutical composition thereof disclosed herein can be evaluated by measuring a decrease in the level of MYC protein. Several methods for quantifying or measuring the protein level of MYC are well known in the art, including Western blot analysis, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, immunocytochemistry, fluorescence activated cell sorting (FACS), immunohistochemistry, protein activity assays, quantitative protein assays, and the bicinchoninic acid assay (BCA assay), also known as the Smith assay. Antibodies specific for target proteins such as MYC can be generated using conventional monoclonal or polyclonal antibody production methods well known in the art, or identified and commercially obtained from various sources such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, MI). Antibodies for the detection of mouse, rat, monkey, and human MYC are commercially available. Further methods for measuring a decrease in the level of MYC protein are described in Example 1, which is included in some embodiments of this specification.

[0318] In Vitro Testing of Compounds The compounds of formula (I) or pharmaceutical compositions thereof disclosed herein can be administered to cultured cells in vitro to evaluate their effects on the expression or activity of a target gene (e.g., MYC), or on one or more phenotypes such as, for example, cell growth or proliferation, cell viability, cell morphology, cell cycle arrest, cell migration, cell invasion, and apoptosis. In some embodiments, administration of the compounds of formula (I) or pharmaceutical compositions thereof disclosed herein to cultured cells results in a reduction or inhibition of the expression of MYC protein (see, e.g., Example 1). In other embodiments, administration of the compounds of formula (I) or pharmaceutical compositions thereof disclosed herein to cultured cells results in a reduction or inhibition of the expression of MYC RNA (see, e.g., Example 2). In some embodiments, administration of the compounds of formula (I) or pharmaceutical compositions thereof disclosed herein to cultured cells results in one or more phenotypes such as, for example, a decrease in cancer cell growth or proliferation, a decrease in cancer cell viability, and an increase in apoptosis (see, e.g., Examples 3-5).

[0319] In certain embodiments, the cultured cells for testing a compound in vitro are cancer-derived cells from animals or humans, such as breast cancer cells (e.g., MCF7, MDA-MB-231, MDA-MB-468, HS 578T, BT-549, and T-47D, etc.), Burkitt lymphoma cells (e.g., BL-2, CA-46, etc.), colon cancer cells (e.g., COLO 205, HCC-2998, HCT-116, HCT-15, HT29, KM12, and SW-620, etc.), CNS cells (e.g., SF-268, SF-295, SF-539, SNB-19, SNB-75, and U251, etc.), glioblastoma cells (e.g., U-87, etc.), leukemia cells (e.g., CCRF-CEM, HL-60, K-562, MOLT-4, RPMI-8226, and SR, etc.), liver cancer cells (e.g., HepG2, etc.), melanoma cancer cells (e.g., LOX IMVI, MALME-3M, M14, MDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, and UACC-62, etc.), multiple myeloma cells (e.g., MM.1S cells), non-small cell lung cancer cells (e.g., A549, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460, and NCI-H522, etc.), ovarian cancer cells (e.g., IGR-OV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI / ADR-RES, and SK-OV-3, etc.), prostate cancer cells (e.g., DU-145 and PC-3, etc.), renal cancer cells (e.g., 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, and UO-31, etc.), and small cell lung cancer cells (e.g., H2171, H82, etc.). In certain embodiments, the cultured cells are derived from MYC-promoted cancers. Examples of cancer-derived cells including MYC-promoted cancer cells are described in the catalogs of commercial suppliers, such as Clonetics Corporation, Walkersville, MD, American Type Culture Collection, Manassas, VA, Zen-Bio, Inc., Research Triangle Park, NC, etc., and are incorporated herein by reference.Such cells are cultured according to the supplier's instructions using commercially available reagents (e.g., Invitrogen Life Technologies, Carlsbad, CA). The cells can be cultured and tested in multi-well plates, such as 6-well, 24-well, 48-well, 96-well, 384-well plates, etc.

[0320] One or more phenotypes resulting from the administration of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein to cultured cells, such as a decrease in cell growth and proliferation, a decrease in cell viability, or a decrease or increase in apoptosis, can be evaluated using any method known to those skilled in the art. Examples of assays for evaluating cell growth and proliferation, or cell viability, include colorimetric assays utilizing dyes such as MTT, XTT, MTS, and CCK-8, fluorescence-based assays such as ApoTox-Glo, and luminescence-based assays such as CellTiter-Glo. Examples of assays for evaluating apoptosis include ApoTox-Glo, Caspase-Glo (3 / 7, 8, and 9), Annexin V, etc. In certain embodiments, the disclosed compound has less than about 10 μM, 5 μM, 1 μM, 0.5 μM, 0.25 μM, 0.1 μM, 0.05 μM, 0.01 μM or less in a selected assay. In other embodiments, the disclosed compound reduces the growth or viability of cancer cells, such as MYC-promoting cancer cells, by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% at a concentration of about 500 μM, 100 μM, 50 μM, 20 μM, 10 μM, 1 μM, 0.1 μM, 0.05 μM, 0.01 μM or less. In some embodiments, the disclosed compound reduces the growth or viability of healthy (non-cancer) cells by 50%, 40%, 30%, 20%, 10%, 5% or less at a concentration of about 100 μM, 50 μM, 20 μM, 10 μM, 1 μM, 0.1 μM, 0.05 μM, 0.01 μM or less.

[0321] In Vivo Testing of Compounds The compounds of formula (I) disclosed herein, or pharmaceutical compositions thereof, are administered in vivo to an animal or human subject to evaluate their properties such as, for example, pharmacokinetic profiles, safety, maximum tolerated dose (MTD), ADME (absorption, distribution, metabolism, and excretion), pharmacodynamics, effects on the expression or activity of target genes (e.g., MYC), or effects on one or more phenotypes such as, for example, survival, cancer cell growth, cancer metastasis, behavior, body weight, metabolism, etc. In some embodiments, administration of the compounds of formula (I) disclosed herein or pharmaceutical compositions thereof to an animal or human subject results in a reduction or inhibition of the expression and / or activity of MYC protein and / or RNA. In some embodiments, administration of the compounds of formula (I) disclosed herein or pharmaceutical compositions thereof to an animal or human subject results in one or more phenotypes such as, for example, a decrease in tumor volume (i.e., tumor regression), a decrease in cancer cell growth or proliferation, a decrease in cancer metastasis, an increase in animal or human subject survival, or other desired outcomes related to a particular phenotype (e.g., body weight, metabolism, etc.). In some embodiments, the tests can be conducted in healthy animal or human subjects. In other embodiments, the tests can be conducted in disease animal models (e.g., cell line-derived xenograft (CDX), patient-derived xenograft (PDX) models, syngeneic models, orthotopic models, humanized models, spontaneous or induced cancer models, etc.), or in human subjects diagnosed with cancer.

[0322] In certain embodiments, the compounds of formula (I) disclosed herein are formulated for administration to animals in a pharmaceutically acceptable diluent such as phosphate buffered saline. Administration includes any route of administration described herein, such as, for example, oral, intrathecal, intraperitoneal, intravenous, and subcutaneous, among others. Methods for calculating appropriate dosages and dosing frequencies for the compounds disclosed herein are well known in the art and depend on factors such as the weight of the animal and the route of administration. After administering the compounds or pharmaceutical compositions thereof disclosed herein to an animal, the animal is monitored at defined time points for effects on the expression levels of target genes such as MYC, and other phenotypes such as, for example, survival, cancer cell growth, cancer metastasis, behavior, body weight, metabolism, and the like. The levels of MYC RNA or MYC protein are known in the art in various tissues derived from animals such as, for example, CSF, plasma, brain, spinal cord, lung, liver, kidney, and the like, and can be measured using the methods described herein. Other modifications are known to those skilled in the art and are considered to be included in the embodiments of this specification.

[0323] In certain embodiments, administration of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein results in a decrease in MYC RNA of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or in a range defined by any two of these values. In certain embodiments, administration of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein results in a decrease in MYC protein of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or in a range defined by any two of these values. In certain embodiments, administration of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein results in a decrease in tumor size of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or in a range defined by any two of these values. In certain embodiments, administration of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein results in a decrease in tumor metastasis. In certain embodiments, administration of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein results in an increase in survival of an animal or human subject of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, or 99%, or in a range defined by any two of these values.

[0324] Methods of Use and Treatment Some embodiments provide a method of reducing the expression of MYC in a cell or tissue, the method comprising administering to the cell, animal, or human a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein such that the expression of MYC is reduced. Other embodiments provide a method of reducing the activity of MYC in a cell or tissue, the method comprising administering to the cell, animal, or human a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein such that the activity of MYC is reduced. Other embodiments provide a method of achieving one or more phenotypic outcomes such as, for example, a decrease in cancer cell growth or proliferation, a decrease in cancer cell viability, a decrease in apoptosis, a decrease in tumor volume (i.e., tumor regression), a decrease in cancer metastasis, an increase in animal or human subject survival, or other desired outcomes related to a particular phenotype (e.g., body weight, metabolism, etc.), the method comprising administering to the cell, animal, or human a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein. Still other embodiments provide a method for treating a disease such as cancer, the method comprising administering to an animal or human an effective amount of a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein. In certain embodiments, the cancer is a MYC-driven cancer.

[0325] In certain embodiments, provided herein is a method of treating a human subject diagnosed with cancer, such as a MYC-driven cancer, the method comprising administering to the human individual a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein. In certain embodiments, provided herein is a method of prophylactically reducing MYC expression or activity in a human subject at risk of developing cancer, such as a MYC-driven cancer, in order to prevent a disease such as cancer. In other embodiments, a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein is administered to a human subject to treat or ameliorate the symptoms of cancer.

[0326] In certain embodiments, MYC-promoting cancers include C-MYC-promoting cancers such as breast cancer, Burkitt lymphoma, cervical cancer, colorectal cancer (e.g., colon adenocarcinoma, rectal adenocarcinoma), esophageal cancer, gastric cancer (e.g., gastric adenocarcinoma), glioblastoma (e.g., glioblastoma multiforme), head and neck squamous cell carcinoma, leukemia (e.g., myeloid leukemia), liver cancer, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, lung squamous cell carcinoma), non-Burkitt lymphoma, medulloblastoma, melanoma (e.g., cutaneous melanoma, uveal melanoma), mesothelioma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer (e.g., clear cell renal cell carcinoma), and rhabdomyosarcoma. In certain embodiments, MYC-promoting cancers include N-MYC-promoting cancers such as astrocytoma, low-grade glioma of the brain, breast cancer, glioblastoma, lung cancer e.g., small cell lung cancer, medullary thyroid cancer, medulloblastoma, neuroblastoma, ovarian cancer, pancreatic cancer, pheochromocytoma and paraganglioma, prostate cancer, retinoblastoma, rhabdomyosarcoma (e.g., alveolar rhabdomyosarcoma), and testicular cancer.

[0327] Other embodiments provide for the use of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein for reducing the expression or activity of MYC. Still other embodiments provide for the use of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein for achieving one or more phenotypic outcomes such as, for example, a decrease in cancer cell growth or proliferation, a decrease in cancer cell viability, a decrease in apoptosis, a decrease in tumor volume (i.e., tumor regression), a decrease in cancer metastasis, an increase in survival time of an animal or human subject, or other desired outcomes related to a particular phenotype (e.g., body weight, metabolism, etc.). Still other embodiments provide for the use of a compound of formula (I) or a pharmaceutical composition thereof disclosed herein for treating, preventing, or ameliorating a cancer such as a MYC-promoting cancer.

[0328] Certain embodiments provide a compound of formula (I) disclosed herein or a pharmaceutical composition thereof for use in reducing the expression or activity of MYC. Certain other embodiments provide the use of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof for use in achieving one or more phenotypic outcomes such as, for example, a decrease in cancer cell growth or proliferation, a decrease in cancer cell viability, an increase in apoptosis, a decrease in tumor volume (i.e., tumor regression), a decrease in cancer metastasis, an increase in survival time of an animal or human subject, or other desired outcomes related to a particular phenotype (e.g., body weight, metabolism, etc.). Certain other embodiments provide a compound of formula (I) disclosed herein or a pharmaceutical composition thereof for use in the treatment, prevention or amelioration of cancer such as MYC-driven cancer.

[0329] Some embodiments provide the use of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof in the manufacture of a medicament for reducing the expression or activity of MYC. Certain other embodiments provide that a compound of formula (I) disclosed herein or a pharmaceutical composition thereof is used in the manufacture of a medicament for achieving one or more phenotypic outcomes such as, for example, a decrease in cancer cell growth or proliferation, a decrease in cancer cell viability, an increase in apoptosis, a decrease in tumor volume (i.e., tumor regression), a decrease in cancer metastasis, an increase in survival time of an animal or human subject, or other desired outcomes related to a particular phenotype (e.g., body weight, metabolism, etc.). In certain embodiments, a compound of formula (I) disclosed herein or a pharmaceutical composition thereof is used in the manufacture of a medicament for treating, preventing or ameliorating cancer in a patient diagnosed with cancer such as MYC-driven cancer or a patient at risk of developing cancer.

[0330] In other embodiments, provided herein are methods of preventing, treating, or ameliorating other diseases that are not cancer, including administering a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein to a cell, tissue, animal, or human subject. In certain embodiments, such diseases are associated with MYC expression or activity, and targeting MYC to reduce or inhibit its expression or activity can provide a therapeutic benefit. Examples of such diseases include inflammatory diseases, autoimmune diseases, metabolic diseases, age-related diseases, and the like. Specific examples include asthma, renal cystic diseases (e.g., polycystic kidney disease), Crohn's disease, lipid metabolism diseases, autoimmune encephalomyelitis, and the like. Madden et al. have described examples of such diseases (Madden et al., Mol. Cancer, 20, Article 3 (2021)), the disclosure of which, together with that reference, is incorporated herein by reference in its entirety.

[0331] In certain embodiments, provided herein is a method of treating a human subject in need thereof by administering to the human individual a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein, which can target one or more MYC nucleic acids or portions thereof as disclosed herein. In some embodiments, administration of a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof as disclosed herein is accompanied by monitoring MYC RNA levels, protein levels, or activity in the individual to determine the individual's response to the administration of the compound or pharmaceutical composition. The response of a human subject to the administration of the compound can be used by a physician to determine the dosage, schedule, and duration of the therapeutic intervention.

[0332] The treatment methods involving the administration of the compounds of formula (I) disclosed herein, or their pharmaceutical compositions or medicaments, to cell, tissue, animal or human subjects can vary with respect to the composition, the amount of administration, and the schedule of administration. A unit dose is a predetermined therapeutically effective amount of the compounds of formula (I) disclosed herein, or their pharmaceutical compositions and medicaments, to be administered. The unit dose can vary depending on various factors including, but not limited to, body weight, age, gender, severity of symptoms, medical history, and treatment aggressiveness. The schedule is the frequency of administration of the unit dose. The size of the unit dose and the schedule of administration of the compound or its pharmaceutical compositions and medicaments can be determined by those skilled in the art and incorporated into certain embodiments herein.

[0333] In certain embodiments, the compounds of formula (I) disclosed herein, or pharmaceutical compositions or medicaments thereof, are co-administered with one or more other agents. The compounds, pharmaceutical compositions, or medicaments described herein may be formulated in a single formulation together with one or more other agents or may be formulated separately. In some embodiments, the one or more other agents are designed to treat different diseases, disorders, symptoms, or conditions compared to the compounds, pharmaceutical compositions, or medicaments described herein. In other embodiments, the one or more other agents are designed to treat the same diseases, disorders, symptoms, or conditions as the compounds, pharmaceutical compositions, or medicaments described herein. In some embodiments, the one or more other agents are co-administered with the compounds, pharmaceutical compositions, or medicaments described herein to provide an additive effect. In certain embodiments, the one or more other agents are co-administered with the compounds, pharmaceutical compositions, or medicaments described herein to provide a synergistic effect or an effect that exceeds an additive effect, such that the co-administration of both provides an effect greater than the sum of the effects of administering each alone. In other embodiments, the one or more other agents are co-administered with the compounds, pharmaceutical compositions, or medicaments described herein to treat undesirable side effects of the compounds, pharmaceutical compositions, or medicaments described herein. In certain embodiments, the compounds, pharmaceutical compositions, or medicaments described herein are co-administered with one or more other agents to prevent or delay the onset of symptoms, to slow disease progression, to reduce side effects, to improve therapeutic efficacy, or otherwise to improve the patient outcome. Co-administration, as used herein, can refer to the case where one or more other agents are administered simultaneously with the compounds, pharmaceutical compositions, or medicaments described herein, as well as the case where one or more other agents are administered before or after (e.g., within hours, days, or weeks, etc.) the compounds, pharmaceutical compositions, or medicaments described herein are administered.

[0334] In certain embodiments, one or more other agents co-administered with the compounds, pharmaceutical compositions, or medicaments described herein can include, for example, antisense oligonucleotides, other oligonucleotides (e.g., siRNA, ribozymes, deoxyribozymes, or aptamers), antibodies, peptides, small molecule compounds, nucleic acid vectors, cell therapies (e.g., CAR-T), or gene therapy agents. In certain embodiments, one or more agents co-administered with the compounds, pharmaceutical compositions, or medicaments described herein are drugs typically administered to treat or ameliorate symptoms in cancer, such as alkylating agents (e.g., altretamine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, melphalan, temozolomide, and trabectedin, etc.), antimetabolites (e.g., azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, 6-mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil, etc.), antitumor antibiotics (e.g., bleomycin, daunorubicin, doxorubicin, doxorubicin liposome, epirubicin, idarubicin, mitoxantrone, and valrubicin, etc.), biological response modifiers that enhance the body's immune system to fight cancer growth or disrupt processes necessary for cancer growth or metastasis (e.g., avastin, erbitux, herceptin, and rituxan, etc.), corticosteroid hormones (e.g., dexamethasone, and prednisone, etc.), nitrosoureas (e.g., carmustine, and lomustine, etc.), plant alkaloids and natural products (e.g., docetaxel, etoposide, irinotecan, paclitaxel, teniposide, topotecan, vinblastine, vincristine, and vinorelbine, etc.), and sex hormones (e.g., leuprolide, and tamoxifen, etc.).In certain embodiments, one or more agents co-administered with the compounds, pharmaceutical compositions, or medicaments described herein include drugs that relieve pain, inflammation, or other symptoms (e.g., COX inhibitors, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, pranoprofen, carprofen, indomethacin, folic acid, tiaprofenic acid, diclofenac, niflumic acid, diazepine or benzodiazepine (e.g., diazepam), and barbiturates, etc.), drugs that improve absorption or delivery, such as anticoagulants (e.g., aspirin, and warfarin, etc.), antibacterial agents, antiviral agents, antibiotics, or other drugs that provide at least one benefit including therapeutic efficacy, symptom relief, drug resistance, or side effect modulation in a therapeutic setting.

[0335] In certain embodiments, one or more agents that can be co-administered with the compounds, pharmaceutical compositions, or medicaments described herein include additional modulators that can reduce the expression or activity of MYC. In certain embodiments, the dosage of the co-administered agent is lower than the dosage that would be administered if the co-administered agent were administered alone.

[0336] Methods of development In certain embodiments, methods for developing small molecule compounds that target MYC, or its related genes or pathways, thereby reducing the expression or activity of MYC are provided herein. In certain embodiments, the method for developing the compound is entirely computer-based. In some embodiments, the method for developing the compound includes biochemical or cell-based methods such as screening and selection. In some embodiments, the method for developing the compound includes a combination of computer-based methods and biochemical or cell-based methods. Such development methods are known to those skilled in the art and include standard techniques incorporated into specific embodiments herein.

[0337] In some embodiments, the computer-implemented method may include artificial intelligence or machine learning software, may rely on large molecular databases, may utilize high-throughput analysis, or may include any combination thereof. The computational methods described by Manigrasso et al. (Manigrasso et al., Chem, 7(11):2965-2988(2021)), Mendez-Lucio et al. (Mendez-Lucio et al., Nature Communications, 11, 10(2020)), Dallakyan and Olson (Dallakyan and Olson, Hempel et al. (ed.) Chemical Biology: Methods and Protocols, Chapter 19, Methods in Molecular Biology pg 243-250(2015)), Zoete et al. (Zoete et al., Journal of Chemical Information and Modeling, 56:1399-1404(2016)), and Merk et al. (Merk et al., Molecular Informatics, 37:1700153(2018)) represent some of the available computer-implemented methods, and together with the references cited therein, are incorporated herein by reference in their entirety. In some embodiments, the structure of a target RNA such as MYC or a portion thereof is predicted by a computer. Thereafter, a computer library of small molecule compounds is computationally docked individually to the target, and the binding energy of each small molecule compound to the target is determined using a computer-implemented method. Small molecule compounds predicted to have a favorable binding energy to the target RNA are prioritized for further analysis and development. In some embodiments, new small molecule compounds are created for computer screening from the fusion of existing molecules or atoms from one or more databases. Other computer-implemented methods are well known to those skilled in the art and are included in various embodiments herein.

[0338] In certain embodiments, methods for developing small molecule compounds include high-throughput biochemical or cell-based screening methods known to those of skill in the art. Physical libraries of small molecules are either constructed or obtained from commercial sources. These libraries are screened against selected target molecules such as MYC, which is done by introducing small molecules to the selected target molecule and then performing washing or separation methods to determine binding affinity and / or specificity. An example of such a method is the affinity selection mass spectrometry (ALIS) described by Rizvi et al. (Rizvi et al., Methods, 167:28-38 (2019)), which is incorporated by reference in its entirety along with the references cited therein. In some embodiments, binding of small molecule compounds to target molecules can be detected and measured using biophysical methods such as, for example, NMR, X-ray crystallography, small-angle X-ray scattering, microscale thermophoresis, surface plasmon resonance, fluorescence-based methods, isothermal titration calorimetry, and the like. In other embodiments, cells are treated with a library of small molecule compounds, followed by detecting the levels of target RNA (e.g., using RT-qPCR or RNA-seq) and / or protein (e.g., using Western blot, ELISA, AlphaScreen, or homogeneous time-resolved fluorescence (HTRF), etc.) to identify compounds that can modulate the expression or activity of targets such as MYC using cell-based methods. Biochemical or cell-based assays or a series of biochemical or cell-based assays can be used to determine the structural and chemical properties of the molecular complexes formed between small molecules or between small molecules and selected target molecules. A control or negative selection step can be used to screen for small molecules that have off-target binding activity to other molecules that are not the selected target molecule. Further, screening at different concentrations of small molecules against the selected target molecule is used to determine the IC 50, other properties such as EC50 and potency are determined. Further descriptions of methods and procedures for developing low molecular weight compounds are described by Falese et al. (Falese et al., Chem. Soc. Rev., 50:2224 (2021)) and Cronk (Cronk, Drug Discovery and Development (Second Edition) Chapter 8, pp. 95 - 117 (2013)), which are incorporated herein by reference in their entirety along with the references cited therein. Other biochemical or cell - based screening methods are well known to those skilled in the art and are included in various embodiments of the present specification.

[0339] In certain embodiments, methods for developing small molecule modulators include fragment - based discovery techniques known to those skilled in the art. These methods include screening a library of small molecule fragments that contain one or more binding epitopes for binding affinity and / or specificity to a target molecule (e.g., MYC). Typically, small molecule fragments have a molecular weight of about 120 - 250 daltons. In certain cases, these fragment - based discovery methods are combined with computer - based methods, some of which are described below. Examples of fragment - based discovery techniques include lead identification by fragment evolution, lead identification by fragment linking, lead identification by fragment self - assembly, and lead progression by fragment optimization, which are described herein. In many cases, the evaluation of the target molecule binding site, the development of fragment complexes, and the subsequent determination of binding efficacy or specificity are informed by structural, morphological, and chemical data obtained from evaluation tools such as nuclear magnetic resonance spectroscopy, mass spectrometry, or X - ray crystallography.

[0340] In lead identification by fragment evolution, a library of fragments is applied to a selected target molecule, and the strength and specificity of binding are determined. Fragments with higher binding specificity are then reacted with or evolved against various other fragments to form fragment complexes that are screened for having even higher binding specificity.

[0341] In lead identification by fragment linking, a fragment library is screened through multiple binding sites of a target molecule selected for binding specificity. Two or more fragments having high binding specificity for two or more adjacent binding sites on the selected target molecule are chemically linked together.

[0342] In lead identification by fragment self-assembly, also called combinatorial chemistry, a library of self-assembling fragments is introduced into a selected target molecule. The fragments can bind to the selected target molecule in a manner that produces a complex that inhibits the expression or activity of the selected target molecule. The various fragments can be assembled together while binding to the selected target molecule via complementary reactive groups. Once assembled, these fragment complexes can then be isolated and their chemical and structural properties can be evaluated.

[0343] In lead progression by fragment optimization, a library of fragments is used to modify the properties of an existing modulator or fragment complex. Typically, this method is used to address the optimization of specific properties such as selectivity, solubility, stability, or efficacy.

[0344] Examples of methods and procedures for the development of small molecule modulators through fragment-based discovery, and further considerations, are described by Rees et al. (Rees et al., Nature Reviews Drug Discovery, 3(8):660(2004)), Erlanson et al. (Erlanson et al., Journal of Medicinal Chemistry, 47(14):3463-3482(2004)), and Congreve et al. (Congreve et al., Journal of Medicinal Chemistry, 51(13):3661-3680(2008)), all of which are hereby incorporated by reference in their entirety, together with the references cited therein. Other methods are well known to those skilled in the art and are included in various embodiments of the present specification.

[0345] Diagnosis and Kits In some embodiments, measuring and detecting an increase in the expression or activity of MYC, or an increase in signaling through a pathway associated with MYC, can be used to diagnose or determine an increased risk or increased susceptibility to cancers such as the MYC-promoted cancers disclosed herein. In some embodiments, measuring and detecting a decrease in the expression or activity of MYC, or a decrease in signaling through a pathway associated with MYC, can be used to determine a decreased risk or decreased susceptibility to cancers such as the MYC-promoted cancers disclosed herein. In some embodiments, a method for determining the susceptibility of a subject to cancers such as the MYC-promoted cancers disclosed herein includes obtaining a sample comprising a tissue, body fluid, or other biological sample from the subject, detecting the expression level of at least one MYC RNA transcript associated with the sequences described by SEQ ID NOs: 1-3, (wherein different expression levels of the transcript are associated with different susceptibilities to the disease), and determining the susceptibility to the disease. In certain embodiments, a method for detecting the expression of MYC, the activity of MYC, or signaling through a pathway associated with MYC includes the use of a compound of formula (I) or a conjugate thereof disclosed herein.

[0346] In certain embodiments, a method for determining the risk or susceptibility to the above-described disease, or a method for diagnosing the disease, can be applied to predict the prognosis of a human individual diagnosed with or experiencing symptoms associated with a cancer such as MYC-driven cancer. In other aspects, a method for determining the risk or susceptibility to the above-described disease, or a method for diagnosing the disease, can be used to evaluate the likelihood of response of a human individual to a treatment method and / or modulator used to treat, prevent, or ameliorate symptoms associated with a cancer such as MYC-driven cancer. In one embodiment, such a method can be used to select a treatment method or modulator to be used when treating a subject diagnosed with the disease.

[0347] Some embodiments also relate to kits and devices for determining the susceptibility of a human individual to a disease; or for diagnosing a disease; or for predicting the prognosis of a human individual diagnosed with or experiencing symptoms associated with the disease; or for evaluating the likelihood of response of a human individual to a treatment method and / or modulator used to treat, prevent or ameliorate symptoms associated with the disease. In some aspects, the disease is a cancer such as MYC-driven cancer described herein.

[0348] A kit useful for any of the methods described herein may include, but is not limited to, probes (e.g., hybridization probes, allele-specific oligonucleotides), enzymes (e.g., for RFLP analysis, for activity assays), reagents for nucleic acid amplification, reagents for direct analysis of at least one allele of at least one polymorphic marker within or related to MYC, reagents for indirect analysis of at least one allele of at least one polymorphic marker within or related to MYC, reagents for detecting the expression or activity of MYC, reagents for detecting signal transduction through a pathway related to MYC, and any other component useful for any of the methods described herein. In one embodiment, the kit can include the necessary buffers. In another embodiment, the kit can further provide reagents for other disease-specific diagnostic methods known in the art to be practiced in conjunction with the methods described herein.

[0349] In certain embodiments, the reagents in the kit can include at least one compound of formula (I) disclosed herein, or a complex or conjugate thereof, that can interact with MYC or otherwise detect the expression of MYC, the activity of MYC, or signal transduction through a pathway related to MYC. In another embodiment, the kit includes at least one labeled compound of formula (I) disclosed herein and reagents for detection of the label. Suitable labels can include, but are not limited to, radioisotopes, fluorescent labels, enzyme labels, enzyme cofactor labels, magnetic labels, spin labels, or epitope labels.

[0350] In certain embodiments, the kit and the device include a lookup table containing correlation data between the expression levels of at least one transcript related to the sequences described by SEQ ID NOs: 1-3 selectively evaluated by the kit, and the susceptibility to a disease, or the prognosis of a disease, or the response to at least one treatment for a disease. Another series of embodiments relates to methods of using the compounds of formula (I) disclosed herein in the manufacture of reagents for diagnosing or assessing susceptibility to a disease, or the prognosis of a disease, or the response to treatment of a disease in a human individual. In one embodiment, the kit further includes a set of instructions for using the reagents that make up the kit. In another embodiment, the kit includes a set of instructions or guidelines for interpreting the results of a test using the reagents that make up the kit.

[0351] A further series of embodiments provides a kit (also referred to as a pharmaceutical pack and used interchangeably) comprising a compound of formula (I) disclosed herein, or a pharmaceutical composition and medicament thereof, and a set of instructions for administering the compound or its pharmaceutical composition and medicament to a human. In some embodiments, an individual identified as a carrier of at least one allele of at least one polymorphic marker associated with MYC-promoted cancer is instructed to ingest a prescribed dose of the compound of formula (I) disclosed herein, or a pharmaceutical composition and medicament thereof. In other embodiments, an individual at high risk of cancer or highly susceptible to cancer, such as MYC-promoted cancer, is instructed to ingest a prescribed dose of the compound of formula (I) disclosed herein or a pharmaceutical composition and medicament thereof. In other embodiments, an individual diagnosed with cancer, such as MYC-promoted cancer, is instructed to ingest a prescribed dose of the compound of formula (I) disclosed herein, or a pharmaceutical composition and medicament thereof.

[0352] Computer-readable media and devices The compositions, methods, and kits described herein may be implemented, in whole or in part, as computer-executable instructions on a computer-readable medium. As will be understood by those skilled in the art, the various steps of the compositions, methods, and kits described herein can be implemented as various blocks, operations, routines, tools, modules, and techniques, which can then be implemented in hardware, firmware, software, or any combination of hardware, firmware, and / or software. In certain embodiments, hardware implementations may include, but are not limited to, custom integrated circuits (ICs), application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), programmable logic arrays (PLAs), and the like. In other embodiments, when implemented as software, the software can be stored on any computer-readable medium known in the art, including but not limited to solid state disks, magnetic disks, optical disks, or other storage media, the RAM or ROM or flash memory of a computer, a processor, a hard disk drive, a thumb drive, an optical disk drive, a tape drive, and the like. In one embodiment, the software can be distributed to a user or a computing system via any delivery method known in the art, including but not limited to communication channels such as the Internet, wireless connections, satellite connections, telephone lines, computer-readable disks, or other portable computer storage mechanisms.

[0353] A series of embodiments provides a suitable computing system environment known in the art for implementing the compositions, methods, and kits described herein, including, but not limited to, a cellular phone, laptop, personal computer, server computer, multiprocessor system, microprocessor-based system, set-top box, programmable household appliance, network PC, minicomputer, mainframe computer, cloud computing environment, and distributed computing environments including any of the above systems or devices. In some embodiments, the steps of the compositions, methods, or kits described herein are implemented via computer-executable instructions, such as, but not limited to, routines, programs, objects, components, data structures, etc., that perform a particular task or implement a particular abstract data type. In one embodiment, the method and apparatus are implemented in a distributed computing environment where tasks are performed by remote processing devices linked via a communication network. In one embodiment, the method and apparatus are implemented in an integrated computing environment. In both integrated and distributed computing environments, program modules can be located on both local and / or remote computer storage media, including memory storage devices.

[0354] Accordingly, a series of embodiments provides a computer-readable medium having computer-executable instructions for determining the effect of administering a compound of formula (I) or a pharmaceutical composition and medicament thereof disclosed herein to a cell, animal, or human subject, the computer-readable medium comprising data indicative of the level of at least one protein, RNA, biomarker, or other phenotype, and a routine stored on the computer-readable medium and adapted to be executed by a processor to determine the effect of administering the compound or its composition from the data. In certain embodiments, the effect determined is a change in the level of MYC RNA, or a change in the level of MYC protein, or a change in one or more phenotypes such as, for example, cell growth or proliferation, cell viability, cell morphology, cell cycle arrest, cell migration, cell invasion, apoptosis, survival, cancer cell growth, cancer metastasis, behavior, body weight, metabolism, and the like. In one embodiment, the computer-readable medium is used to determine the progression of a disease such as cancer and the response thereof to administration of a compound of formula (I) or a pharmaceutical composition and medicament thereof to a human subject disclosed herein.

[0355] Another series of embodiments provides a computer-readable medium having computer-executable instructions for developing a compound of formula (I) disclosed herein using at least one computational method described herein or other computational methods known to those of skill in the art, which is also included in the embodiments of this specification. The computer-readable medium can include data related to a specific nucleotide sequence, sequence number, or a portion thereof disclosed herein, and any polypeptide sequence resulting from transcription and translation of the nucleotide sequence. The computer-readable medium can also be adapted to be executed by a processor to develop a compound of formula (I) disclosed herein from the data.

[0356] Without departing from the spirit and scope of the present invention, many modifications and variations can be made to the compositions, methods, and kits described herein. Accordingly, it should be understood that the compositions, methods, and kits described herein are merely exemplary and do not limit the scope of the present invention.

Examples

[0357] The following examples are presented to provide a complete disclosure and description of how to practice and use the present invention to those skilled in the art, and are not intended to limit the scope of what the inventors regard as their invention, nor are they intended to represent or imply that the examples are all or the only experiments that were performed. Those skilled in the art will understand that numerous modifications and / or corrections can be made to the present invention as shown in the specific embodiments without departing from the broadly described spirit or scope of the present invention. It should also be understood that the examples are provided to give possible guidance regarding the use of the combined features of this disclosure for applying such compositions, methods, and systems to other uses. Accordingly, this embodiment should be considered exemplary in all respects and not limiting.

[0358] In certain embodiments, these examples can be implemented by a computer or other processing device that incorporates and / or executes software, in which case the methods and functions, software, and processors utilize special methods for analyzing data.

[0359] Efforts have been made to ensure accuracy with respect to the numerical values used (e.g., amounts, strengths, temperatures, etc.), but some experimental errors and deviations need to be taken into account.

[0360] Example 1: Regulation of MYC Protein Expression by Test Compounds Using the MYC homogeneous time-resolved fluorescence (HTRF) assay kit (CisBio / Perkin Elmer 63ADK053PEG), the level of MYC protein in human cell lines (e.g., A549, HepG2) after treatment with test compounds was quantified according to the following protocol. Human cells cultured in DMEM-10% FBS medium were seeded in 96-well plates at 20,000 cells per well. After 1 day, the cells were treated with test compounds at a final concentration of approximately 20 μM. After a 2-day incubation period, the supernatant was removed from the wells and the HTRF assay was performed according to the kit manufacturer's protocol. Briefly, lysis buffer #4 was added to prepare cell lysates. 10 μL of the cell lysate was added to 10 μL of a pre-mixed antibody solution (anti-human Myc-Eu cryptate antibody and anti-human Myc-d2 antibody) prepared in detection buffer #3 in a 384-well low-volume white-wall plate. After a 3-hour incubation, fluorescence readings were taken at the emission wavelengths of the donor and acceptor fluorophores (620 nm and 665 nm, respectively) using an HTRF-compatible plate reader. The ratio of the acceptor fluorescence emission signal to the donor fluorescence emission signal for each sample was calculated by dividing the fluorescence signal at 665 nm by the signal at 620 nm, and further normalized by dividing by the concentration of total protein in that sample determined by the BCA assay. The values thus obtained were expressed as a percentage relative to the values of samples treated with no compound and solvent only (DMSO). The lower the percentage of MYC protein in the sample relative to the DMSO-treated sample, the greater the percentage reduction in MYC protein level by the test compound, and vice versa.

[0361] Table 1 provides the percentage reduction in MYC protein level by specific test compounds when tested using the above HTRF assay protocol. Specific compounds of formula (I) disclosed herein reduce the MYC protein level by 10%, 20%, 30%, 40%, 50%, 60%, or 70% relative to samples treated with solvent only (DMSO).

[0362] The reduced levels of MYC protein after treatment with the test compound are also evaluated by Western blot according to the following protocol. Human cancer cell lines (e.g., A549 or HepG2) are seeded in a 96-well plate at 20,000 cells / well. After 1 day, the cells are treated with the test compound at a final concentration of approximately 10 μM. After a 2-day incubation period, the supernatant is removed from the wells and RIPA buffer is added to prepare cell lysates. The lysates are analyzed by Western blot and probed with a MYC-specific antibody (e.g., Proteintech 10828-1-AP) together with a GAPDH-specific antibody (e.g., Proteintech 10494-1-AP) that functions as a loading control. The intensity of the Western blot bands is quantified by FIJI (Image J). The relative expression value of MYC after treatment with the test compound is calculated by dividing the intensity of the MYC band of the sample by the intensity of its own GAPDH band. The value thus obtained is expressed as a percentage relative to the value of the sample treated with no compound and solvent only (DMSO). The lower the percentage of MYC protein in the sample relative to the DMSO-treated sample, the greater the percentage reduction in MYC protein level by the test compound, and vice versa.

[0363] Table 2 provides the percentage reduction in MYC protein level by specific test compounds when tested using the Western blot assay described above. Specific compounds of formula (I) disclosed herein reduce the MYC protein level by 10%, 20%, 30%, 40%, 50%, or 60% relative to samples treated with solvent only (DMSO).

[0364] Example 2: Regulation of MYC RNA Expression by Test Compounds The reduction level of MYC RNA after treatment with the test compound is evaluated using RT-qPCR according to the following protocol. Human cancer cell lines (e.g., A549, HepG2) are seeded in a 96-well plate at 20,000 cells / well. After 1 day, the cells are treated with the test compound at a final concentration of approximately 10 μM. After a 1-day incubation period, the supernatant is removed from the wells, and a lysis solution from the Cells-to-CT 1-Step Power SYBR Green Kit (Invitrogen A25599) is added to prepare cell lysates according to the kit manufacturer's protocol. Then, according to the kit manufacturer's protocol, a pair of MYC-specific primers for detecting MYC RNA (e.g., SEQ ID NO: 4 and SEQ ID NO: 5), and a pair of β-actin-specific primers for detecting β-actin RNA that functions as a loading control (e.g., SEQ ID NO: 6 and SEQ ID NO: 7) are used to perform RT-qPCR for each sample. The relative expression levels of MYC and β-actin RNA are calculated using a standard curve generated from a dilution series of untreated cell lysates. The normalized level of MYC RNA after treatment with the test compound is calculated by dividing the relative expression level of MYC in the sample by the relative expression level of β-actin in the same sample. The values thus obtained are expressed as a percentage relative to the values of samples treated with no compound and only the solvent (DMSO). The lower the percentage of MYC RNA in the sample relative to the DMSO-treated sample, the greater the percentage reduction in the MYC RNA level by the test compound, and vice versa.

[0365] Table 3 provides the percentage reduction in MYC RNA levels by specific test compounds when tested using the above RT-qPCR assay. Specific compounds of formula (I) disclosed herein reduce the MYC RNA level by 10%, 20%, 30%, or 40% relative to samples treated with only the solvent (DMSO).

[0366] Example 3: Effect of Test Compounds on Cell Viability Determined Using the CCK-8 Assay The effect of the test compound on cell viability is determined according to the following protocol using a CCK-8 assay kit (Dojindo CK04-1000). Human cancer cell lines (e.g., A549, HepG2, JeKo-1, MDA-MB-231, etc.) and non-cancer human cell lines (e.g., HEK-293, HaCaT, etc.) are seeded in 96-well plates at 20,000 cells / well. After 1 day, the cells are treated with the test compound at various final concentrations (e.g., 10 nM, 31.6 nM, 100 nM, 316 nM, 1 μM, 3.16 μM, 10 μM, 20 μM, etc.). After an incubation period of 2 or 3 days, 10 μL of CCK-8 solution containing the WST-8 dye is added to each well according to the kit manufacturer's protocol. After incubating for 1 - 4 hours, the absorbance at 450 nm is measured using a microplate reader. The absorbance at 450 nm measures the amount of WST-8 reduced to WST-8 formazan by cellular dehydrogenase, which is directly proportional to the number of live cells. The cytotoxic effect of the test compound at various concentrations is calculated by subtracting from 1 the ratio of the absorbance of the compound-treated sample at 450 nm to the absorbance of the compound-free, solvent-only (DMSO) treated sample. A higher number indicates a greater cytotoxic effect of the test compound on the cells (corresponding to a greater reduction in cellular dehydrogenase activity), and vice versa. The IC 50 value for the cytotoxic effect of each test compound in A549, HepG2, JeKo-1, and / or MDA-MB-231 cells is determined by plotting the dose-response curve and calculating the concentration of the test compound that produces half of the maximum cytotoxic effect. The cytotoxic effect and IC 50 of the test compound are also measured in non-cancer human cell lines (e.g., HEK-293 and / or HaCaT) as a surrogate for healthy cells to determine the therapeutic concentration range of the test compound (i.e., the concentration range at which the test compound selectively kills cancer cells rather than healthy cells). The therapeutic index of the test compound is the ratio of its IC 50 in HEK-293 cells to its IC 50As defined herein, it is divided by. The higher the therapeutic index, the more selective the test compound is in killing cancer cells rather than healthy cells, and thus the safer and more useful as an anticancer drug.

[0367] Table 4 shows the IC of a specific test compound when tested using the above CCK-8 assay 50 is provided. When a specific compound of formula (I) is tested using the above CCK-8 assay, it shows an IC of less than 10 μM, less than 1 μM, or less than 0.5 μM. 50 When a specific compound of formula (I) is tested using the above CCK-8 assay, it shows a therapeutic index greater than 1, greater than 10, or greater than 100. As a benchmark, sAJM589, one of the most well-known inhibitors of MYC, acts to inhibit the MYC-MAX protein-protein interaction, but shows ICs of 28.4 μM, 20.5 μM, and 34.2 μM when tested in A549, HepG2, and HEK-293 cells, respectively 50 (therapeutic index 1.67). Therefore, the results of the CCK-8 assay indicate that one or more compounds of formula (I) disclosed herein are more potent in killing cancer cells compared to sAJM589. In addition, one or more compounds of formula (I) disclosed herein have a higher therapeutic index compared to sAJM589 (and thus are safer drugs).

[0368] Example 4: Effect of test compounds on cell viability determined using the CellTiter-Glo 2.0 assay The effect of the test compound on cell viability is also determined using the CellTiter-Glo 2.0 assay kit (Promega G9241) according to the following protocol. Human cancer cell lines (e.g., HepG2) and non-cancer human cell lines (e.g., HEK-293) are seeded in 96-well plates at 20,000 cells / well. After 1 day, the cells are treated with the test compound at various concentrations (e.g., 10 nM, 31.6 nM, 100 nM, 316 nM, 1 μM, 3.16 μM, 10 μM, 20 μM, etc.). After a 2-day incubation period, the CellTiter-Glo 2.0 assay is performed according to the kit manufacturer's protocol. Briefly, an equal volume of CellTiter-Glo 2.0 reagent is added to each well (e.g., 100 μL of CellTiter-Glo 2.0 reagent is added to 100 μL of medium containing the cells). The contents are mixed on an orbital shaker for 2 minutes to induce cell lysis, incubated at room temperature for 10 minutes, and then the luminescence signal is measured using a microplate reader. The intensity of the luminescence signal is directly proportional to the amount of ATP present, which in turn is directly proportional to the number of metabolically active cells. The cytotoxic effect of the test compound at different concentrations is calculated by subtracting the ratio of the luminescence signal of the sample treated with the compound to the luminescence signal of the sample treated with no compound or solvent only (DMSO) from 1. Higher values indicate a greater cytotoxic effect of the test compound on the cells (corresponding to a greater reduction in metabolically active cells), and vice versa. The IC 50 value for the cytotoxic effect of each test compound in HepG2 cells is determined by plotting the dose-response curve and calculating the concentration of the test compound that produces half of the maximum cytotoxic effect. The cytotoxic effect and IC 50 of the test compound are also measured in non-cancer human cell lines (e.g., HEK-293) as a substitute for healthy cells to determine the therapeutic concentration range of the test compound (i.e., the concentration range at which the test compound selectively kills cancer cells rather than healthy cells). The therapeutic index of the test compound is the ratio of its IC 50 in HEK-293 cells to its IC 50As defined herein, it is divided by. The higher the therapeutic index, the more the test compound selectively kills cancer cells and is safer and more useful as an anticancer drug that minimizes side effects on healthy cells.

[0369] Table 5 provides the IC 50 and therapeutic index of certain test compounds when tested using the CellTiter-Glo 2.0 assay described above. Certain compounds of formula (I) have an IC of less than 10 μM, less than 1 μM, or less than 0.2 μM when tested using the CellTiter-Glo 2.0 assay described above. 50 Certain compounds of formula (I) exhibit a therapeutic index greater than 1, greater than 10, or greater than 100 when tested using the CellTiter-Glo 2.0 assay described above. In comparison, sAJM589, one of the best-known inhibitors of MYC, acts to inhibit the MYC-MAX protein-protein interaction and has ICs of 13 μM and 12.2 μM, respectively, when tested in HepG2 and HEK-293 cells. 50 (Therapeutic index 0.94). Furthermore, paclitaxel (Taxol), one of the best-known anticancer drugs, kills dividing cells by interfering with the normal function of microtubule growth and has ICs of 7.5 μM and 27 μM, respectively, when tested in HepG2 and HEK-293 cells. 50 (Therapeutic index 3.6). Thus, the CellTiter-Glo 2.0 assay shows that one or more compounds of formula (I) disclosed herein are more potent in killing cancer cells compared to sAJM589. Furthermore, one or more compounds of formula (I) disclosed herein have a higher therapeutic index (and thus are safer drugs) compared to both sAJM589 and taxol.

[0370] Example 5: Effect of Test Compounds on Cell Viability and Apoptosis Determined Using the ApoTox-Glo Triplex Assay The effects of test compounds on cell viability and apoptosis are determined according to the following protocol using the ApoTox-Glo Triplex assay kit (Promega G6320). Human cancer cell lines (e.g., HepG2) and non-cancer human cell lines (e.g., HEK-293) are seeded in 96-well plates at 20,000 cells / well. After 1 day, the cells are treated with test compounds at various final concentrations (e.g., 10 nM, 31.6 nM, 100 nM, 316 nM, 1 μM, 3.16 μM, 10 μM, 20 μM, etc.). After a 2-day incubation period, the ApoTox-Glo Triplex assay is performed according to the kit manufacturer's protocol. Briefly, 20 μL of viability / cytotoxicity reagent containing both a GF-AFC substrate (a cell-permeable substrate for measuring viable cell protease activity) and a bis-AAF-R110 substrate (a cell-impermeable substrate for measuring dead cell protease activity) is added to each sample and mixed briefly by orbital shaking (about 30 seconds at 300 - 500 rpm). After incubation at 37 °C for 30 minutes, the fluorescence signal is measured at two wavelength sets (400 Ex / 505 Em ) and (485 Ex / 520 Em ) to evaluate viable cell protease activity and dead cell protease activity, respectively. Following the measurement of protease activity in viable and dead cells, 25 μl of Caspase-Glo 3 / 7 reagent containing a luminogenic DEVD-peptide substrate for caspase-3 / 7 and a thermostable luciferase is added to each sample and mixed briefly by orbital shaking (about 30 seconds at 1300 - 1500 rpm). After incubation at room temperature for 30 minutes, the luminescence signal is measured using a microplate reader. The luminescence signal is directly correlated with caspase-3 / 7 activity, an important indicator of apoptosis.

[0371] The cytotoxic effect of a test compound by the ApoTox-Glo Triplex assay is calculated as follows. The viability ratio is calculated by dividing the fluorescence signal of the live cell protease activity by the fluorescence signal of the dead cell protease activity. The cytotoxic effect of the test compound at different concentrations is calculated by dividing the viability ratio of the sample treated with the compound by the viability ratio of the sample treated without the compound and with solvent only (DMSO), and subtracting the result from 1. A higher value indicates a greater cytotoxic effect of the test compound on the cells (corresponding to a lower viability ratio, as evaluated by the live and dead cell protease activities), and vice versa. The IC 50 value for the cytotoxic effect of each test compound in HepG2 cells is determined by plotting the dose-response curve and calculating the concentration of the test compound that produces half of the maximum cytotoxic effect. The cytotoxic effect and IC 50 of the test compound are also measured in a non-cancer human cell line (e.g., HEK-293) as a substitute for healthy cells, in order to determine the therapeutic concentration range of the test compound (i.e., the concentration range in which the test compound selectively kills cancer cells rather than healthy cells). The therapeutic index of the test compound is defined herein as the ratio of its IC 50 in HEK-293 cells to its IC 50 in HepG2 cells. The higher the therapeutic index, the safer and more useful the test compound is as an anticancer drug that selectively kills cancer cells while minimizing side effects on healthy cells.

[0372] Table 6 provides the IC 50 and therapeutic index of certain test compounds when tested using the ApoTox-Glo Triplex assay described above. The specific compound of formula (I) has an IC 50is shown. Certain compounds of formula (I) exhibit a therapeutic index greater than 1, greater than 10, or greater than 100 when tested using the ApoTox-Glo Triplex assay described above. In comparison, sAJM589, one of the best-known inhibitors of MYC, acts to inhibit the MYC-MAX protein-protein interaction and exhibits IC 50 values of 3 μM and 13.6 μM, respectively, in HepG2 and HEK-293 cells (therapeutic index 4.53). Furthermore, paclitaxel (Taxol), one of the best-known anticancer drugs, kills dividing cells by interfering with the normal function of microtubule growth and exhibits IC 50 values of 2.6 μM and 6.9 μM, respectively, in HepG2 and HEK-293 cells (therapeutic index 2.65). Thus, the ApoTox-Glo Triplex assay indicates that one or more compounds of formula (I) disclosed herein are more potent in killing cancer cells compared to sAJM589. Furthermore, one or more compounds of formula (I) disclosed herein have a higher therapeutic index (and thus are safer drugs) compared to both sAJM589 and paclitaxel.

[0373] The results of the ApoTox-Glo Triplex assay showed an increase in the fold-change of caspase 3 / 7 activation in HepG2 cells with increasing concentrations of sAJM589 and taxol, indicating that the cytotoxic effects of sAJM589 and taxol are mediated through the apoptotic pathway. In contrast, an increase in the concentration of the compound of formula (I) disclosed herein resulted in a decrease in the fold-change of caspase 3 / 7 activation in HepG2 cells, indicating that the cytotoxic effect of the compound is mediated by a non-apoptotic pathway. Since MYC is known to upregulate caspase activity and MYC inhibition has been shown to result in non-apoptotic cancer cell death and growth arrest (Fornari et al., Biochem. Pharmacol., 51(7):931-940(1996)), these results are consistent with the effect of the compound of formula (I) disclosed herein to reduce the level of the MYC protein (see Example 1). The fold-change of caspase 3 / 7 activation was calculated by dividing the luminescence signal of the sample treated with the compound by the luminescence signal of the sample treated without the compound and with solvent only (DMSO). Table 7 reports the fold-change of caspase 3 / 7 activation after treating HepG2 cells with different concentrations of the test compound.

[0374] Example 6: In Vivo Efficacy of Test Compounds Against Cancer Cells Determined Using the Mouse Hollow Fiber Model The in vivo efficacy of a test compound against cancer cells (e.g., 6-(2,4-dimethylthiazol-5-yl)-2-((1-(pyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one) is determined using the mouse hollow fiber model established at the National Cancer Institute (NCI). Triple negative breast cancer (TNBC) (MDA-MB-231), pancreatic cancer (Mia-PaCa-2), and liver cancer (HepG2) cells are added to hollow fibers of different colors (KrosoFlo® Implant membrane, green: lot number: 20051617, blue: lot number: 20008858, white: lot number: 20051615), and both ends are sealed. Three hollow fibers, each containing a different cancer strain, are surgically implanted subcutaneously on both flanks of the mouse (a total of 6 hollow fibers per mouse). Drug treatment begins on day 0, which is 3 days after fiber implantation. Each treatment group has 2 mice (4 hollow fibers for each cancer type): Group 1: vehicle control; Group 2: gemcitabine control, administered intraperitoneally (i.p.) once every 3 days at 50 mg / kg; Group 3: test compound, administered orally once a day for 5 days at 50 mg / kg. At the end of the treatment on day 5, all animals are euthanized with an overdose of CO2. The fibers are excised from the mice, and the cytotoxicity of the compound against the cells within the hollow fibers is determined using a modified MTT assay. The average net cell growth % is calculated using the formula [(average OD (day 5) - average OD (day 0)) / (average OD (day 0)) × 100%]. The average % cell growth inhibition by treatment is calculated relative to the average net cell growth % of the vehicle control on day 5 for a specific cancer strain.

[0375] The results indicate that oral administration of the test compound at 50 mg / kg once daily for 5 days effectively inhibits the growth of MYC-driven cancers such as TNBC, pancreatic cancer, and liver cancer in vivo. The test compound showed the highest efficacy (88.2%) for TNBC growth inhibition, followed by pancreatic cancer (63.0%) and liver cancer (28.1%). This study shows that the test compound is effective in vivo against metastatic TNBC for which standard therapeutics are ineffective (MDA-MB-231 is derived from patients with metastatic TNBC and is commonly used to model advanced breast cancer). In a follow-up study motivated by the large difference in HepG2 efficacy in vitro versus in vivo, it was found that the efficacy of the test compound against the three cancers in the hollow fiber model was underestimated because the test compound interacts with the MTT assay used to evaluate efficacy in the hollow fiber study. In direct comparison with orthogonal cell viability assays (CCK-8, trypan blue, and CellTiter-Glo), MTT underestimated the potency of the test compound against MDA-MB-231, Mia PaCa-2, and HepG2 by 2-fold, 3-fold, and 21-fold, respectively. Thus, the true efficacy of the test compound against the growth inhibition of TNBC, pancreatic cancer, and liver cancer using the mouse hollow fiber model is predicted to be >90% for all three cancers.

[0376] Once-daily oral administration of the 50 mg / kg test compound did not result in a significant change in body weight relative to the vehicle-treated group, nor did it result in signs of toxicity in the treated mice due to gastrointestinal symptoms (e.g., abdominal distension, diarrhea, loose stools, bloody stools, constipation) and general clinical signs (e.g., lethargy, hunched posture, salivation, kyphosis, restlessness, dehydration, head tilt, recumbent position). This provides initial data confirming the safety of the test compound when administered once daily for 5 days at the therapeutically effective dose.

[0377] Example 7: In Vivo Efficacy of Test Compound Against Cancer Cells Determined Using a Mouse Xenograft Model of TNBC The in vivo efficacy of a test compound (e.g., 6-(2,4-dimethylthiazol-5-yl)-2-((1-(pyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methyl)pyridazin-3(2H)-one against cancer cells) is determined using a mouse xenograft model of TNBC (MDA-MB-231). 5×10 6 MDA-MB-231 cells (in 0.2 ml of serum-free medium containing 50% Matrigel) are injected subcutaneously into the tissue of each mouse. Treatment is initiated when the average tumor volume reaches 100 mm 3 (day 0). Mice bearing tumors are treated orally once daily for 3 weeks with vehicle and various doses of the test compound (15 mg / kg, 35 mg / kg, 50 mg / kg, and 100 mg / kg). Tumor volume mm 3 is measured once every 2 - 3 days throughout the study after cell transplantation. At the end of the treatment period, a portion of the tumor tissue is excised, homogenized, and the level of the MYC biomarker is analyzed using ELISA. Blood samples are collected 8 hours after the final dose from mice treated with the test compound.

[0378] The results show that treatment with the test compound results in a dose-dependent decrease in the average tumor volume when compared to the vehicle control on day 21 (Table 8). This correlates with a dose-dependent increase in the plasma concentration of the test compound and a dose-dependent decrease in the MYC biomarker level in the tumor after treatment with the test compound (Table 9). The tumor histopathology shows that treatment with the test compound results in a dose-dependent decrease in tumor cells, an increase in necrosis, and a decrease in angiogenesis compared to the vehicle. The decrease in the tumor cell population and blood vessels in the treatment groups compared to the vehicle control suggests tumor regression. The body weight and clinical signs of the animals are clearly normal throughout the study, confirming the safety of the test compound when administered once daily for 3 weeks at the therapeutically effective dose.

[0379] Table Table 1: Percentage reduction of MYC protein by the test compound using the HTRF assay [Table 1]

[0380] Table 2: Percentage reduction of MYC protein by test compounds using Western blot [Table 2]

[0381] Table 3: Percentage reduction of MYC RNA by test compounds using RT-qPCR [Table 3]

[0382] Table 4: IC 50 and therapeutic index of test compounds using the CCK-8 assay [Table 4-1] [Table 4-2]

[0383] Table 5: IC 50 and therapeutic index of test compounds using the CellTiter-Glo 2.0 assay [Table 5]

[0384] Table 6: IC 50 and therapeutic index of test compounds using the ApoTox-Glo Triplex assay [Table 6]

[0385] Table 7: Fold change in caspase 3 / 7 activation in HepG2 determined using the ApoTox-Glo Triplex assay [Table 7]

[0386] Table 8: Tumor volume over time after treatment with vehicle and different doses of the test compound [Table 8]

[0387] Table 9: Plasma test compound concentration and tumor MYC biomarker levels after treatment with different doses of the test compound [Table 9]

Claims

1. A compound of formula (I), 【Chemistry 1】 During the ceremony, A 1 However, hydrogen, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Cycloalkyl, aryl, or heterocyclyl, A 2 However, hydrogen, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Cycloalkyl, aryl, or heterocyclyl, R 1 is hydrogen, halo, C 1-7 -alkyl, C 2-7 -alkenyl, C 3-8 -cycloalkyl, aryl, or heterocyclyl, and R 2 However, hydrogen, halo, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Whether it is a cycloalkyl, aryl, or heterocycline, Or A 2 and R 2 But together, C 1-7 - Alkylene, or C 2-7 - Forms alkenylenes, Z is C 1-7 - Alkylene, C 2-7 -Alkenylene, -CH 2 -, - (CH 2 ) 2 -ien-CH 2 (CH) 2 -, -C(=O)-, -C(=O)CH 2 -, -C(=O)(CH 2 ) 2 -, -C(=O)CH 2 O-, -C(=O)(CH 2 ) 2 O-, -C(=O)CH(CH 3 )O-, -C(=O)O-, -C(=O)OCH 2 -, -C(=O)O(CH 2 ) 2 -, -C(=O)NH-, -C(=O)NHCH 2 -, -C(=O)NH(CH 2 ) 2 -, -S (=O) 2 -, -S (=O) 2 CH 2 - or -S (=O) 2 (CH) 2 - and h is 1, 2, or 3, i is 0, 1, or 2, j is 0, 1, 2, or 3, k is 0, 1, 2, or 3, m is 0 or 1, R B However, each R represents a non-hydrogen substituent. B However, independently, deuterium, C 1-7 - Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino. The aforementioned R B If substituents are present, they are covalently bonded to one of the ring atoms instead of hydrogen, however, R B Provided that it does not exceed the maximum valence of the ring atom to which it is bonded, d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. C 1-7 - Alkyl, C 2-7 - Alkenil, C 1-7 - Alkylene, C 2-7 - Alkenylene, C 3-8 - Cycloalkyl, aryl, and heterocyclyl are each independently substituted or unsubstituted. However, this is subject to the condition that both j and k are not zero in the same compound. Furthermore, pharmaceutically acceptable salts, tautomers, N-oxides, and solvates thereof.

2. Equation (II), 【Chemistry 2】 During the ceremony, A 1 However, hydrogen, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Cycloalkyl, aryl, or heterocyclyl, A 2 However, hydrogen, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Cycloalkyl, aryl, or heterocyclyl, R 1 However, hydrogen, halo, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Cycloalkyl, aryl, or heterocyclyl, R 2 However, hydrogen, halo, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Whether it is a cycloalkyl, aryl, or heterocycline, Or A 2 and R 2 But together, C 1-7 - Alkylene, or C 2-7 - Forms alkenylenes, Z is C 1-7 -alkylene, C 2-7 -alkenylene, -CH 2 -, -(CH 2 ) 2 -, -CH 2 (CH) 2 -, -C(=O)-, -C(=O)CH 2 (CH) 2 (CH) 2 -, -C(=O)CH 2 O-, -C(=O)(CH 2 (CH) 2 O-, -C(=O)CH(CH 3 )(CH)O-, -C(=O)O-, -C(=O)OCH 2 -, -C(=O)O(CH 2 (CH) 2 -, -C(=O)NH-, -C(=O)NHCH 2 (CH) 2 (CH) 2 -, -S(=O) 2 -, -S(=O) 2 CH 2 -, or -S(=O) 2 (CH) 2 - and h is 1, 2, or 3, i is 0, 1, or 2, m is 0 or 1, R B However, each R represents a non-hydrogen substituent. B However, independently, deuterium, C 1-7 - Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino. The aforementioned R B If substituents are present, they are covalently bonded to one of the ring atoms instead of hydrogen, however, R B Provided that it does not exceed the maximum valence of the ring atom to which it is bonded, d is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9. C 1-7 - Alkyl, C 2-7 - Alkenil, C 1-7 - Alkylene, C 2-7 - Alkenylene, C 3-8 - The compound according to claim 1, represented by formula (II), wherein each of the cycloalkyl, aryl, and heterocyclyl is independently substituted or unsubstituted, and j is 2 and k is 2. Furthermore, pharmaceutically acceptable salts, tautomers, N-oxides, and solvates thereof.

3. A 1 However, hydrogen, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Cycloalkyl, aryl, or heterocyclyl, A 2 However, hydrogen, C 1-7 - Alkyl, C 2-7 - Alkenil, C 3-8 - Cycloalkyl, aryl, or heterocyclyl, R 1 However, hydrogen or C 1-7 -It is alkyl, R 2 However, hydrogen or C 1-7 -It is alkyl, h is 1, i is 1, m is 0, and A in equation (I) or (II) 1 The Z portion that bridges N is A 1 This is substituted by a direct single covalent bond between and N, R B However, it is bromo, chloro, fluoro, or iodine. The aforementioned R B If substituents are present, they are covalently bonded to one of the ring atoms instead of hydrogen, however, R B Provided that it does not exceed the maximum valence of the ring atom to which it is bonded, d is 0, 1, 2, 3, or 4, C 1-7 - Alkyl, C 2-7 - Alkenil, C 1-7 - Alkylene, C 2-7 - Alkenylene, C 3-8 - The compound according to claim 1 or 2, wherein the cycloalkyl, aryl, and heterocyclyl are each independently substituted or unsubstituted. Furthermore, pharmaceutically acceptable salts, tautomers, N-oxides, and solvates thereof. 【Request Item 4】 【Chemistry 3】 The compound according to claim 2, selected from the group consisting of the following. 【Chemistry 4】

5. A 1 However, the group is selected from the following: 【Transformation 5】 During the ceremony, R B However, each R represents a non-hydrogen substituent. B However, independently, deuterium, C 1-7 - Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino. One or more R B The substituent includes either or both of the six-membered rings, and instead of hydrogen, A 1 It can be covalently bonded to any of the ring atoms, however, R B Provided that it does not exceed the maximum valence of the ring atom to which it is bonded, The compound according to claim 1 or claim 2, wherein q is 0, 1, 2, 3, 4, 5, 6, 7, or 8.

6. A 1 The compound according to claim 1 or claim 2, selected from the group consisting of the following: 【Transformation 6】

7. A 2 However, the group is selected from the following: 【Transformation 7】 During the ceremony, R B However, each R represents a non-hydrogen substituent. B However, independently, deuterium, C 1-7 - Alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 -Cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromo, chloro, fluoro, or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamidyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylcarboxamide, N-ethylcarboxamide, or N,N-dimethylamino. One or more R B The substituent is A instead of hydrogen. 2 It can be covalently bonded to any of the ring atoms, however, R B Provided that it does not exceed the maximum valence of the ring atom to which it is bonded, The compound according to claim 1 or claim 2, wherein u is 0, 1, 2, 3, or 4.

8. A 2 The compound according to claim 1 or claim 2, selected from the group consisting of the following: 【Transformation 8】

9. 6-(2,4-dimethylthiazole-5-yl)-2-((1-(pyrido[2,3-d]pyrimidine-4-yl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(7-fluoroquinazolin-4-yl)piperidine-4-yl)methyl)-6-(1H-pyrazole-1-yl)pyridazine-3(2H)-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(6-methylpyrimidine-4-yl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(2-methylpyrido[3,4-d]pyrimidine-4-yl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(9H-purine-6-yl)piperidine-4-yl)methyl)-6-(2,4-dimethylthiazole-5-yl)pyridazine-3(2H)-one, 2-((1-(6-fluoroquinazolin-4-yl)piperidine-4-yl)methyl)-6-(1H-1,2,4-triazole-1-yl)pyridazine-3(2H)-one, 2-((1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)azetidine-3-yl)methyl)-6-(pyridine-4-yl)pyridazin-3(2H)-one, 2-(1-(1,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl)azetidine-3-yl)-6-(pyridine-4-yl)pyridazine-3(2H)-one, 6-(1H-pyrazole-1-yl)-2-((1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 6-(1H-1,2,4-triazol-1-yl)-2-((1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(9H-purine-6-yl)azetidine-3-yl)methyl)-6-(pyridine-4-yl)pyridazine-3(2H)-one, 2-((1-(6-methylpyrazine-2-yl)piperidine-4-yl)methyl)-6-(1H-1,2,4-triazole-1-yl)pyridazine-3(2H)-one, 6-(3,5-dimethyl-1H-pyrazole-1-yl)-2-((1-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)azetidine-3-yl)methyl)pyridazin-3(2H)-one, 6-(3,5-dimethyl-1H-pyrazole-1-yl)-2-(1-(3-methyl-3H-imidazo[4,5-b]pyridine-2-yl)piperidine-4-yl)pyridazine-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(3-fluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(3,3-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(2-fluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(2,2-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(2,3-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(2,4-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(2,5-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(2,6-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(3,4-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(3,5-difluoro-1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methylpyridazin-3-one, 2-((1-(5H-pyrazolo[3,4-d]pyrimidine-4-yl)piperidine-4-yl)methyl)-6-(2,4-dimethylthiazole-5-yl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(7H-purine-6-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(6-methylpyrimidine-4-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(2-methylpyrido[3,4-d]pyrimidine-4-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[(1-pyrazolo[1,5-a]pyrimidine-5-ylpiperidine-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(2-methylpyrimidine-4-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(2-propan-2-ylpyrimidine-4-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(9-methylpurine-6-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(6-methyl-3H-pyrrolo[3,2-d]pyrimidine-4-yl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(6-ethyl-5-fluoropyrimidine-4-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[(1-thieno[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(imidazo[1,2-b]pyridazin-6-yl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]methyl]piperidine-1-yl]pyridine-4-carbonitrile, 6-[4-[[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]methyl]piperidine-1-yl]pyridine-3-carbonitrile, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[(1-thieno[3,2-d]pyrimidine-4-ylpiperidine-4-yl)methyl]pyridazin-3-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]methyl]piperidine-1-yl]pyridine-3-carbonitrile, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(6-(trifluoromethyl)pyridine-2-yl)piperidine-4-yl)methyl)pyridazine-3(2H)-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(4-(trifluoromethyl)pyridine-2-yl)piperidine-4-yl)methyl)pyridazine-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(5-methylpyrimidine-2-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[(1-pyrimidine-2-ylpiperidine-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(5-(trifluoromethyl)pyridine-2-yl)piperidine-4-yl)methyl)pyridazine-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[(1-pyrazolo[1,5-a]pyrazine-4-ylpiperidine-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(3-(trifluoromethyl)pyridine-2-yl)piperidine-4-yl)methyl)pyridazine-3(2H)-one, 2-[[1-(5-chloropyrimidine-2-yl)piperidine-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazole-5-yl)pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(4-methylpyrimidine-2-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[(1-pyrido[2,3-d]pyrimidine-4-ylpiperidine-4-yl)methyl]pyridazin-3-one, 2-[[1-(4,6-dimethylpyrimidine-2-yl)piperidine-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazole-5-yl)pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-[(5-methyl-1,2-oxazole-3-yl)methyl]piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(5,6,7,8-tetrahydroquinazoline-4-yl)piperidine-4-yl)methyl)pyridazine-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[(1-quinoxaline-2-ylpiperidine-4-yl)methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(5-fluoropyrimidine-2-yl)piperidine-4-yl]methyl]pyridazin-3-one, 5-[4-[[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]methyl]piperidine-1-yl]pyridine-2-carbonilicate, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(2-methylpyrazolo[1,5-a]pyrazine-4-yl)piperidine-4-yl]methyl]pyridazin-3-one, 2-[4-[[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]methyl]piperidine-1-yl]pyrimidine-4-carbonitrile, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(4-methoxypyrimidine-2-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-(piperidine-4-ylmethyl)pyridazin-3-one, N-[2-(7-cyclohexyl-6-imino-13-methyl-2-oxo-1,7,9-triazatricyclo[8.4.0.03,8]tetradeca-3(8),4,9,11,13-pentaen-5-yl)-4-phenyl-1,3-thiazole-5-yl]-4-methoxybenzamide, 3-(4-((3-(2,4-dimethylthiazole-5-yl)-6-oxopyridazine-1(6H)-yl)methyl)piperidine-1-yl)pyridazine-2-carbonitrile, 4-[[4-[[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]methyl]piperidine-1-yl]methyl]benzonitrile, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(2-fluorobenzyl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(4-fluorobenzyl)piperidine-4-yl)methyl)pyridazine-3(2H)-one, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(3-fluorobenzyl)piperidine-4-yl)methyl)pyridazin-3(2H)-one, 2-((1-(2-chlorobenzyl)piperidine-4-yl)methyl)-6-(2,4-dimethylthiazole-5-yl)pyridazine-3(2H)-one, 2-((1-(4-chlorobenzyl)piperidine-4-yl)methyl)-6-(2,4-dimethylthiazole-5-yl)pyridazine-3(2H)-one, 2-((1-(3-chlorobenzyl)piperidine-4-yl)methyl)-6-(2,4-dimethylthiazole-5-yl)pyridazine-3(2H)-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(3-methylquinoxaline-2-yl)piperidine-4-yl]methyl]pyridazin-3-one, 6-(2,4-dimethyl-1,3-thiazole-5-yl)-2-[[1-(2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)piperidine-4-yl]methyl]pyridazin-3-one, 2-[[1-[(2,5-difluorophenyl)methyl]piperidine-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazole-5-yl)pyridazin-3-one, 2-[[1-[(2,4-difluorophenyl)methyl]piperidine-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazole-5-yl)pyridazin-3-one, 2-[[1-[(3,4-difluorophenyl)methyl]piperidine-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazole-5-yl)pyridazin-3-one, 2-((1-(3,5-difluorobenzyl)piperidine-4-yl)methyl)-6-(2,4-dimethylthiazole-5-yl)pyridazine-3(2H)-one, 2-[[1-[(2-chloro-6-fluorophenyl)methyl]piperidine-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazole-5-yl)pyridazin-3-one, 2-[[1-(1,3-benzoxazole-2-yl)piperidine-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazole-5-yl)pyridazin-3-one, 2-(3-cyclopropyl-6-oxopyridazine-1-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]acetamide, 4-[[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]methyl]piperidine-1-carboxylate tert-butyl, 6-(2,4-dimethylthiazole-5-yl)-2-((1-(6-fluorobenzo[d]oxazole-2-yl)piperidine-4-yl)methyl)pyridazine-3(2H)-one, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-2-(4-oxoquinazoline-3-yl)acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-2-(1-methyltetrazole-5-yl)sulfanylacetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]thiophen-2-sulfonamide, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-2,3-dihydro-1,4-benzodioxin-6-sulfonamide, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-3,5-dimethyl-1,2-oxazole-4-sulfonamide, 2-(benzimidazole-1-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-1-methylsulfonylpiperidine-4-carboxamide, 3-(3,5-dimethyl-1,2-oxazole-4-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]propanamide, 2-(1,2-benzoxazole-3-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]acetamide, 2-(1,3-benzothiazole-2-ylsulfanil)-N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]acetamide, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-4-methylthiadiazole-5-carboxamide, N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-1-thiophene-2-ylcyclopentan-1-carboxamide, 3-(benzenesulfonyl)-N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]propanamide, 1-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-3-(naphthalene-1-ylmethyl)urea, 1-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]-3-(2-methoxyphenyl)urea, A compound selected from the group consisting of N-[2-[3-(2,4-dimethyl-1,3-thiazole-5-yl)-6-oxopyridazine-1-yl]ethyl]furan-2-carboxamide, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, claim 2, or claim 9, wherein one or more hydrogen atoms are replaced by deuterium.

11. A pharmaceutical composition comprising a compound according to claim 1, claim 2, or claim 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

12. A method for reducing the expression or activity of MYC in cells, comprising contacting the cells with a pharmaceutical composition comprising the compound according to claim 1, claim 2, or claim 9, or the compound according to claim 1, claim 2, or claim 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents.

13. Use of a pharmaceutical composition comprising a compound according to claim 1, claim 2, or claim 9, or a compound according to claim 1, claim 2, or claim 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents, in the manufacture of a pharmaceutical for reducing the expression or activity of MYC in cells or tissues.

14. Use of a pharmaceutical composition comprising a compound according to claim 1, claim 2, or claim 9, or a compound according to claim 1, claim 2, or claim 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents, in the manufacture of a pharmaceutical for treating, preventing, or improving cancer.

15. The use according to claim 14, wherein the cancer is an MYC-promoting cancer.

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