Pyridazinone-derived compounds for modulation of MYC and for medical use

Abstract

Described herein are compositions, systems, and methods for modulating, and in particular reducing or inhibiting the expression or activity of MYC in a cellular, animal, or human subject. Such compositions, systems, and methods are useful for preventing, ameliorating, or treating diseases, including cell proliferative diseases and conditions, such as cancer, particularly MYC-driven cancer. Compositions comprising a compound of formula (I), as well as pharmaceutical compositions or medicaments thereof, are described. Also described are methods of treating, preventing, or ameliorating diseases, including cell proliferative diseases and conditions, such as cancer, in particular MYC-driven cancer, using such compositions. Compositions comprising conjugates and complexes of compounds of Formula (I) are also described, which are also useful in the methods described herein. Methods are described including the use of compounds of Formula (I), or pharmaceutical compositions thereof, for reducing or inhibiting MYC expression or activity, and / or for achieving one or more desired phenotypic outcomes, such as, for example, 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 survival rate in animals or humans, or other desirable outcomes with respect to a particular phenotype (e.g., weight, metabolism, etc. Related medicaments, kits, and methods of delivering such compositions are described. Methods of developing, making and / or synthesizing the compounds of formula (I) and pharmaceutical compositions thereof are also described. In addition, methods including diagnostics and assays for detecting levels of MYC expression or activity, and compositions including kits for diagnostics and assays, are described.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 352,514 (filed on June 15, 2022), the disclosure of which is incorporated by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy, created on June 9, 2023, is named 20230609-MYC.xml and is 23,426 kilobytes in size. Technical Field

[0005] The present invention relates to compositions, systems and methods for regulating, and in particular reducing or inhibiting, the expression and / or activity of MYC in cells, animals or human subjects. Such compositions, systems and methods can be used to treat, prevent or ameliorate diseases, including cell proliferation diseases and conditions, such as cancer, in particular MYC-driven cancers. Background Art

[0006] In the following discussion, certain terms and procedures will be described for background and introduction purposes. Nothing contained herein should be construed as an "admission" of prior art. Applicants expressly reserve the right to demonstrate, where appropriate, that the terms and procedures cited herein do not constitute prior art under applicable statutory provisions.

[0007] The MYC family of proto-oncogenes consists of C-MYC (otherwise known as MYC, MYCC, V-Myc myelocytomatosis viral oncogene homolog, BHLHe39 or MRTL), N-MYC (otherwise known as MYCN, BHLHe37, V-Myc myelocytomatosis viral oncogene neuroblastoma derived homolog, MYCNOT, MODED or ODED) and L-MYC (otherwise 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 a specific embodiment, MYC refers to C-MYC. In another specific embodiment, MYC refers to N-MYC. In some embodiments, MYC refers to a polymorph, isoform, homolog, pseudogene or mutant form of MYC. As used herein, MYC may refer to a gene, RNA transcript or protein product obtained from the expression of a nucleic acid encoding MYC, unless otherwise specified or indicated.

[0008] The MYC family of genes encoding transcription factors plays an important role in regulating cell proliferation, cell cycle, cell growth, differentiation, angiogenesis, apoptosis, immunity, stress response and tumorigenesis. Some examples of the role 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)), the disclosures of which are incorporated herein by reference in their entirety along with their references.

[0009] The MYC family contributes to the pathogenesis of nearly all cancers. Gain of function of MYC is commonly observed in cancer, which can be the result of mutation, chromosomal rearrangement, gene amplification or increased expression, among others. Some examples of the various mechanisms and pathways by which DMYC can lead to the pathogenesis of cancer 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)), the disclosures of which are incorporated herein by reference in their entirety along with their references.

[0010] The MYC family is known to be a driving factor for a variety of different cancer types. Known C-MYC drives cancers such as, for example, breast cancer, Burkitt's 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's lymphoma, medullary thyroid cancer, 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, etc. N-MYC is known to drive cancers such as, for example, astrocytomas, lower grade gliomas 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, etc. L-MYC is known to drive cancers such as, for example, small cell lung cancer, etc.Different types of cancer driven by C-MYC, N-MYC and L-MYC are described by 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)), the disclosures of which are incorporated herein by reference in their entirety along with their references.

[0011] Due to its wide range of pathogenic significance, MYC is an important target for cell proliferation diseases and conditions, such as cancer and other diseases characterized by MYC gain of function. Studies have shown that for many cancer types, such as MYC-driven cancers, reducing the expression and / or activity of MYC leads to a significant slowing of tumor growth, a reduction in tumor size (i.e., tumor regression) and / or a reduction in metastasis in a variety of models (e.g., cancer cell lines, animal models, such as cell line-derived xenografts (CDX) models and patient-derived xenografts (PDX) models, etc.). Therefore, it is necessary to find modulators that can reduce or inhibit MYC expression and / or activity, which can be used as therapeutic agents and research tools.

[0012] Compared to other types of modulators (e.g., nucleic acids, siRNA, antisense oligonucleotides, CRISPR, gene therapy, antibodies), small molecule compounds offer unique advantages, such as, for example, ease of administration (most are orally administrable), ability to cross cell membranes to reach intracellular targets, tunability to allow systemic distribution with or without distribution in the central nervous system (CNS), ability to engage biological targets via various modes of action, and / or lower development and manufacturing costs in most cases. However, MYC has been a challenging target and is currently considered "undruggable" by small molecule compounds because the MYC protein lacks a pocket or groove that can serve as a good binding site for small molecules. Small molecule compounds targeting MYC known in the art typically target MYC indirectly (e.g., inhibitors of MYC-MAX protein-protein interactions) and lack potency and appropriate pharmacokinetic properties for in vivo applications.

[0013] Therefore, there is a need in the art for better methods of reducing MYC expression and / or activity, as well as more effective treatments for treating, preventing or ameliorating cell proliferative diseases and conditions, such as cancer. The present disclosure addresses this and other unmet needs in the art. A series of small molecule compounds and pharmaceutical compositions thereof for reducing the expression and / or activity of MYC in cells, animals or human subjects, as well as methods of use thereof, are disclosed. Such compositions, systems and methods can be used to treat, prevent or ameliorate diseases, particularly cell proliferative diseases and conditions, such as cancer, and other diseases characterized by MYC gain of function. Summary of the invention

[0014] The present invention relates to compounds of formula (I):

[0015]

[0016] Among them A 1 , A 2 , R 1 , R 2、 R B , Z, d, h, i, j, k and m are as described herein.

[0017] Compositions comprising compounds of formula (I) disclosed herein, and pharmaceutical compositions or medicaments thereof are described, which can be used to treat, prevent or ameliorate diseases, including cell proliferative diseases and conditions, such as cancer, particularly MYC driven cancers. Methods of using such compositions to treat, prevent or ameliorate diseases, including cell proliferative diseases and conditions, such as cancer, particularly MYC driven cancers are also described. Compositions comprising conjugates and complexes of compounds of formula (I) are also described, which can also be used in the methods described herein.

[0018] Methods comprising using a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to reduce or inhibit MYC expression or activity are described. Methods comprising using a compound of formula (I) disclosed herein or a pharmaceutical composition thereof are also described for achieving one or more phenotypic results, such as, for example, reduced cancer cell growth or proliferation, reduced cancer cell viability, reduced apoptosis, reduced tumor volume (i.e., tumor regression), reduced cancer metastasis, increased survival of animals or human subjects, or other desired results with respect to a particular phenotype (e.g., body weight, metabolism, etc.). Related drugs, kits, and methods for delivering such compositions are described.

[0019] Also described are methods of developing, manufacturing and / or synthesizing compounds of formula (I) disclosed herein and pharmaceutical compositions thereof. In addition, described herein are methods including diagnostics and tests for detecting MYC expression or activity levels, and compositions including kits for diagnostics and tests.

[0020] Other features and advantages of the present invention will become apparent from the following detailed description and examples. DETAILED DESCRIPTION

[0021] The following description is presented to enable those of ordinary skill in the art to make and use the present invention, and is provided in the context of a patent application and its requirements. Various modifications to exemplary embodiments and genetic principles and features as described herein will be apparent. The exemplary embodiments are mainly described according to the specific processes and systems provided in a specific implementation. However, these processes and systems will be effectively operated in other specific implementations. Phrases such as "exemplary embodiments", "an embodiment" and "another embodiment" may refer to identical or different embodiments.

[0022] Exemplary embodiments will be described with respect to methods and compositions having certain components. However, the methods and compositions may include more or fewer components than shown, and the arrangement and types of components may be varied without departing from the scope of the invention.

[0023] The exemplary embodiments will also be described in the context of methods having certain steps. However, the methods and compositions operate effectively with additional steps and steps in a different order that are inconsistent with the exemplary embodiments. Therefore, the present invention is not intended to be limited to the embodiments shown, but is intended to reach the broadest scope consistent with the principles and features described herein, and is defined solely by the appended claims.

[0024] Unless expressly stated, the terms used herein are intended to have their ordinary and common meanings as understood by those of ordinary skill in the art. The following definitions are intended to aid the reader in understanding the present invention but are not intended to alter or limit the meanings of such terms unless expressly stated. All publications mentioned herein are incorporated by reference for the purpose of describing and disclosing the formulations and processes described in the publications and which may be used with the presently described invention.

[0025] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments of the invention described herein in the detailed description and accompanying drawings. Such equivalents are intended to be encompassed by the claims.

[0026] For simplicity, in this document, certain embodiments are described with respect to the use of certain methods. Upon reading this disclosure, it will become apparent to those skilled in the art that the present invention is not intended to be limited to a specific use, but can be used in a variety of specific implementations.

[0027] For clarity of the disclosure, and not in a limiting manner, the detailed description of the present invention is divided into sub-sections that describe or illustrate certain features, embodiments, or applications of the present invention.

[0028] General Definition

[0029] 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 belong.

[0030] All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0031] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0032] It should be noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to the effect of "a compound" may refer to the effect of one or more compounds, and reference to "a method" includes reference to equivalent steps and processes known to those skilled in the art, etc.

[0033] Where a range of values ​​is provided, it is to be understood that each intervening value between the upper and lower limits of the range and any other stated or intervening value in the range are encompassed within the present invention. Where stated ranges include upper and lower limits, ranges excluding any of those limits are also encompassed within the present invention.

[0034] "Nucleobase" or "base" are used interchangeably and refer to nitrogenous compounds that form nucleosides, which in turn are components of nucleotides. The five primary or natural nucleobases are adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U). Other nucleic acid bases, such as synthetic or modified nucleic acid bases, are included herein and described in detail below.

[0035] "Nucleotide" refers to a compound comprising a nucleoside and a linking group, typically a phosphate linking group. Nucleotides include both natural and modified nucleotides.

[0036] "Motif" refers to a region or subsequence in an oligonucleotide or polypeptide sequence that has a specific function or biological significance. Examples of motifs include nucleobase sequences in oligonucleotides, such as DNA or RNA, that are recognized by DNA or RNA binding proteins or functional RNAs (e.g., miRNAs). Other examples of motifs include nucleobase sequences in RNA that are responsible for the specific function of the RNA, or amino acid sequences in a polypeptide that are responsible for the specific function of the polypeptide. A motif may also refer to a target site for a modulator on a DNA, RNA, or polypeptide target.

[0037] "Nucleic acid sequence", "nucleobase sequence", "nucleotide sequence" or simply "sequence" are used interchangeably and refer to the sequence of nucleobases on a nucleic acid molecule or oligonucleotide. A nucleic acid molecule may refer to a deoxyribonucleic acid (DNA) molecule or a ribonucleic acid (RNA) molecule.

[0038] 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 functional RNA but not translated into a polypeptide.

[0039] As used herein, the term "RNA" refers to a ribonucleic acid molecule. The transcription process initially results in the formation of a precursor mRNA (pre-mRNA). In the case of a protein-coding gene, the pre-mRNA is subsequently processed into a mature mRNA by splicing to remove introns and add a 5' end cap and a poly-A tail. Mature mRNA is used as a template for translation into a polypeptide by ribosomes. As used herein, the term "RNA" includes pre-mRNA (sometimes also referred to as heterogeneous nuclear RNA), mature mRNA, and RNA at any processing stage. As used herein, the term "RNA" includes coding RNA and non-coding RNA (e.g., miRNA, tRNA, rRNA, etc.) that are translated into a polypeptide.

[0040] "Polypeptide," "oligopeptide," "peptide," and "protein" are used interchangeably and refer to a polymer of two or more amino acids.

[0041] "Oligonucleotide" refers to a polymer composed of two or more nucleotides.

[0042] "Allele", also known as "variant" or "polymorphism", refers to one nucleotide sequence variation among at least two different nucleotide sequence variations at a given position (locus) in a genome. Thus, a specific allele of a polymorphic site refers to a specific version of the sequence for the polymorphic site. "Variant" or "polymorphism" may also refer to a specific allele of a polymorphic site that is different from a reference genome.

[0043] "Polymorphic marker", also referred to as "polymorphic site" or simply "marker", refers to a genomic site with at least two sequence variants or at least two alleles. Therefore, the genetic association with a polymorphic marker refers to the association with at least one specific allele of the polymorphic marker. "Marker" may also refer to the specific allele of the polymorphic marker. Polymorphic markers may refer to any type of sequence variation found in the genome, including but not limited to single nucleotide polymorphisms (SNPs), selected SNPs (csnp), insertions, deletions, copy number variations (CNVs), codon amplifications, methylation states, translocations, duplications, repeat amplifications, rearrangements, multi-base polymorphisms, splice variants, microsatellite polymorphisms, etc. "Marker" may also refer to a "biomarker".

[0044] "Single nucleotide polymorphism" or "SNP" is a type of DNA variation in which a single nucleotide at a specific location in the genome differs between two or more individuals or two or more populations. Most SNPs have two alleles; in this case, an individual or at the polymorphic site is homozygous for one allele, or heterozygous for both alleles.

[0045] An "insertion" or "deletion" is a variant having additional nucleotides or fewer nucleotides, respectively, compared to a reference DNA sequence.

[0046] A "microsatellite" is a type of polymorphic marker in which there are multiple small repeats of bases 2-8 nucleotides in length.

[0047] The term "associated with" means and may be used interchangeably with "in" or "related to" or "linkage disequilibrium with" or "functionally related to" or any combination of these terms. "Linkage disequilibrium" refers to the non-random association of alleles at different loci in a given population.

[0048] "Susceptibility" refers to an individual's tendency, predisposition, or risk of developing a particular phenotype (e.g., a trait or disease), or being more or less resistant to developing a particular phenotype. The term includes reduced susceptibility to a disease, reduced risk of disease, or prevention of a disease. The term also encompasses increased susceptibility to a disease or increased risk of disease.

[0049] The term "and / or" means "one or the other or both." In other words, the term means both items or any one of the items involved.

[0050] The term "biomarker" refers to a biological molecule, such as a protein, peptide, small molecule, metabolite, or nucleic acid sequence, that is associated with a phenotype, such as a disease, and whose measurement can be used to determine susceptibility to the disease, or the prognosis of the disease, or the diagnosis of the disease, or to determine the response to treatment for the disease.

[0051] The term "lookup table" is a table that links one form of data to another form of data, or links one or more forms of data to a predicted outcome (e.g., a trait, disease, or other phenotype). A lookup table can contain information about the expression or activity levels of one or more targets or one or more polymorphic markers, as well as correlations between the expression or activity levels of one or more targets or between alleles of a polymorphic marker and a particular phenotype (e.g., a trait or disease).

[0052] "Computer readable media" is 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.

[0053] "Nucleic acid sample" refers to a DNA or RNA sample obtained from an individual. The nucleic acid sample can be obtained from any source containing DNA or RNA, such as blood, saliva, tissue samples, cerebrospinal fluid, amniotic fluid, etc.

[0054] "Sample" generally refers to any sample obtained from an individual, such as a biological sample.

[0055] "Subject" is interchangeable with "patient" or "individual," and refers to a living multicellular vertebrate organism, including both humans and non-human mammals, unless otherwise indicated.

[0056] A "subject in need of treatment" may include a subject having a disease, condition, or disorder responsive to treatment with the compounds disclosed herein. For example, a "subject in need of treatment" may include a subject having a cell proliferative disease, condition, or disorder, such as a cancer described herein. A "subject in need of treatment" may include a subject having a cell proliferative disease, condition, or disorder, such as cancer, associated with MYC expression or activity.

[0057] The term "therapeutic agent" refers to an agent that can be used to prevent, treat, or ameliorate symptoms associated with a disease.

[0058] The terms "response to a treatment method," "response to therapy," or "response to administration of a modulator" refer to the results of any kind of treatment performed on an individual and include beneficial, neutral, and adverse effects.

[0059] The term "therapeutically effective amount" refers to an amount of a therapeutic agent that, when administered alone or in combination with one or more additional therapeutic agents, induces a desired response, such as a reduction in the signs and symptoms associated with a disease. Typically, a therapeutically effective amount provides the desired response without causing significant side effects to the subject to which it is administered. An effective amount of a drug administered to a particular subject under a particular circumstances is not always effective in treating the conditions / diseases described herein, even if such dosage is considered a therapeutically effective amount by one skilled in the art.

[0060] The term "modulator" refers to a compound (also referred to as a "modulator") that affects the signal transduction, activity or expression of a polypeptide or nucleic acid sequence, and includes both activators and inhibitors. Regulators that increase or upregulate the signal transduction, activity or expression of a polypeptide or nucleic acid sequence are referred to as "activators". Regulators that inhibit, reduce, reduce or downregulate the signal transduction, activity or expression of a polypeptide or nucleic acid sequence are referred to as "inhibitors". "Regulate" refers to the regulatory behavior as defined above, and can be performed with a regulator. Unless otherwise indicated, "regulate" or "modulation" refers to the regulatory behavior as defined above, including increasing or upregulating the signal transduction, activity or expression of a polypeptide or nucleic acid sequence, and inhibiting, reducing, reducing or downregulating the signal transduction, activity or expression of a polypeptide or nucleic acid sequence.

[0061] The term "antisense modulator" refers to a modulator that affects the signal transduction, activity or expression of at least one nucleic acid sequence by binding or hybridizing to a certain form of complementary nucleic acid molecules. Common forms of antisense modulators include antisense oligonucleotides (ASOs) and nucleic acids used in RNAi mechanisms for gene regulation, including but not limited to miRNA, siRNA and short hairpin RNA (shRNA).

[0062] The term "amplification" refers to increasing the number of copies of a nucleotide sequence. An example of amplification is the "polymerase chain reaction," in which 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. The process is repeated to increase the number of copies of the nucleotide sequence. Other methods can be used for amplification and are known to those of ordinary skill in the art.

[0063] 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 to increase its purity.

[0064] The term "tissue" refers to an aggregate of cells that performs a specific physiological function in an organism.

[0065] 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, cells in culture, an animal or human subject or patient.

[0066] "Carrier", also known as "vehicle" or "excipient", when used in the context of a drug, medicament or pharmaceutical composition, is one or more molecules used to facilitate the delivery of one or more other molecules. Examples of carriers include, but are not limited to, gelatin, cellulose, cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose, polyethylene glycol, and the like.

[0067] "Cancer" refers to the abnormal growth of cells that tend to proliferate in an uncontrolled manner and, in some cases, tend to metastasize. The term "cancer" or "cancers" includes, but is not limited to, astrocytoma, breast cancer, low-grade glioma of the brain, Burkitt's 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's lymphoma, medullary thyroid carcinoma, medulloblastoma, melanoma (e.g., cutaneous melanoma, uveal melanoma), mesothelioma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, paraganglioma, pheochromocytoma, prostate cancer, retinoblastoma, renal cancer (e.g., clear cell renal cell carcinoma) and retinoblastoma, rhabdomyosarcoma and testicular cancer, etc.

[0068] "Improvement" refers to a reduction in the severity of a disease, as measured by at least one indicator of the disease. The indicator may be a symptom of the disease, or a marker associated with the disease, and may be assessed objectively or subjectively. In certain embodiments, "improvement" may refer to slowing, stopping, or reversing the progression of a disease.

[0069] A "dose" is a designated unit of a pharmaceutical composition for administration. In some embodiments, a dose may refer to a designated amount of a pharmaceutical composition administered over a period of time. A dose may refer to the total amount of a pharmaceutical composition administered, or the amount of a pharmaceutical composition administered per unit time.

[0070] Chemical Definition

[0071] New chemical entities and uses of chemical entities are disclosed herein.Chemical entities can be described using terms known in the art and are discussed further below.

[0072] The nomenclature used herein is based on the IUPAC systematic nomenclature, or other nomenclature commonly used and understood by those of ordinary skill in the art.

[0073] Unless otherwise stated, any open valencies appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicate the presence of hydrogen.

[0074] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on the parent molecule.

[0075] The term "substituted" means that the specified group carries one or more substituents. When any group may carry multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and can be, but need not be, the same. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents independently selected from possible substituents.

[0076] When indicating the number of substituents, the term "one or more" refers to a range from one substituent to the highest possible number of substituents, ie, replacement of one hydrogen up to replacement of all hydrogens by substituents.

[0077] The term "moiety" refers to an atom or group of chemically bonded atoms that is attached to another atom or molecule by one or more chemical bonds, thereby forming a part of a molecule. For example, variable A of formula (I) 1 , A 2 , R 1 , R 2 R B and Z refer to moieties attached to the core structure of formula (I) via one or more covalent bonds.

[0078] As used herein, an asterisk "*", a plus sign "+", or a dashed line may be used to indicate the point of attachment of any radical group, moiety, and / or substituent group.

[0079] The term "alkyl" refers to straight or branched chain saturated hydrocarbon groups in all isomeric forms thereof. In particular embodiments, alkyl refers to straight or branched chain groups 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, which are also referred to herein 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. Some specific examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and the like.

[0080] The term "alkylene" refers to the diradical of an alkyl group (e.g., -(CH2) n —wherein n is an integer, such as an integer between 1 and 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.

[0081] The terms "halo", "halogen" and "halide" are used interchangeably herein and refer to fluorine, chlorine, bromine or iodine. A specific example of a halogen is fluorine.

[0082] The term "haloalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by the same or different halogens. Examples of haloalkyl include monofluoromethyl (—CH2F), difluoromethyl (—CHF2), trifluoromethyl (—CF3), 2,2,2-trifluoroethyl (—CH2CF3), etc. "Perhaloalkyl" refers to an alkyl group in which all hydrogen atoms of the alkyl group have been replaced by the same or different halogens.

[0083] As used herein, the term "heteroalkyl" refers to an "alkyl" group in which at least one carbon atom has been replaced by a heteroatom (eg, an O, N, or S atom). An example of a heteroalkyl group is an "alkoxy" group.

[0084] The term "alkenyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2 to 12, 2 to 10, 2 to 8, 2 to 7, 2 to 6, or 2 to 4 carbon atoms, which are also referred to herein as C 2-12 -Alkenyl, C 2-10 -Alkenyl, C 2-7 -Alkenyl, C 2-6 -alkenyl or C 2-4 -alkenyl.

[0085] The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms, which are also referred to herein as C 2-12 -Alkynyl, C 2-10 -Alkynyl, C 2-8 -Alkynyl, C 2-6 -alkynyl or C 2-4 -alkynyl.

[0086] The terms "amine" and "amino" refer to an amino group of the formula -NR a R c A group in which R a and Rc is independently hydrogen, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl or another group. a and R c Together with the nitrogen to which they are attached, they may form a heterocycloalkyl group. a and R c The term "secondary amino" refers to a group in which R a is hydrogen and R c The term "tertiary amino group" means a group in which R a and R c A radical which is neither hydrogen. Examples of secondary and tertiary amino groups include methylamino, ethylamino, propylamino, isopropylamino, phenylamino, benzylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, and the like.

[0087] The term "alkoxy", "alkoxyl" or "-O-alkyl" refers to an alkyl group as defined above, which is attached to the rest of the molecule through an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, etc. Wherein other moieties, such as alkenyl, alkynyl, heteroalkyl, etc., are attached to the rest of the molecule through an oxygen atom, which can be represented by -O-alkenyl, -O-alkynyl, -O-heteroalkyl, etc., respectively.

[0088] The term "ether" refers to two hydrocarbons covalently linked by an oxygen atom.

[0089] As used herein, the term "carbonyl" refers to the free radical -C(O)-.

[0090] The term "oxo" refers to an oxygen atom doubly bonded to carbon or another element.

[0091] As used herein, the term "carboxamido" refers to the free radical -C(O)NRR f , where R and R f The substituents may be the same or different. For example, R and R f They may independently be alkyl, aryl, aralkyl, cycloalkyl, formyl, haloalkyl, heteroaryl or heterocyclic.

[0092] As used herein, the term "carboxy" or "carboxyl" refers to the free radical -COOH or its corresponding salt, such as -COONa and the like.

[0093] As used herein, the term "amide" or "amido" or "amidyl" refers to a group of the form -R g C(O)N(R d )—、—Rg C(O)N(R d )R e —, —C(O)NR d R e or -C(O)NH2 free radical, where R g , R d and R e For example, each is independently alkoxy, alkyl, alkenyl, alkynyl, amide, amido, aryl, aralkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic, hydrogen, hydroxyl, ketone, or nitro.

[0094] The term "bicyclic ring system" may refer to two rings fused to each other via a common single or double bond (annealed bicyclic ring system), or alternatively two rings fused together via a sequence of three or more common atoms (bridged bicyclic ring system), or alternatively two rings fused together via a common single atom (spirocyclic bicyclic ring system). The bicyclic ring system may be saturated, partially unsaturated, unsaturated or aromatic. The bicyclic ring system may include rings in which one or more carbon atoms are substituted by the same or different heteroatoms selected from N, O and S.

[0095] The term "cycloalkyl" refers to a saturated cyclic, bicyclic or bridged ring (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 carbon atoms per ring, which are also referred to herein 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. Unless otherwise indicated, the cycloalkyl group is optionally substituted at one or more ring positions by, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, aralkyl, azido, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halo, haloalkyl, heteroaryl, heterocyclic radical, hydroxyl, imino, ketone, nitro, phosphate, phosphonic acid, phosphinic acid, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the cycloalkyl group is unsubstituted, i.e., it is unsubstituted.

[0096] The term "partially unsaturated carbocyclic group" refers to a cyclic hydrocarbon containing at least one double bond between ring atoms, wherein at least one ring of the carbocyclic group is not aromatic. Partially unsaturated carbocyclic groups can be characterized according to the number of ring carbon atoms. For example, partially unsaturated carbocyclic groups can contain 5 to 14, 5 to 12, 5 to 10, 5 to 8 or 5 to 6 ring carbon atoms, and are therefore referred to as 5-14-, 5-12-, 5-10-, 5-8- or 5-6-membered partially unsaturated carbocyclic groups. Partially unsaturated carbocyclic groups can be in the form of monocyclic carbocyclic rings, bicyclic carbocyclic rings, tricyclic carbocyclic rings, bridged carbocyclic rings, spirocyclic carbocyclic rings or other carbocyclic ring systems. The example of partially unsaturated carbocyclic groups also includes partially unsaturated cycloalkenyl groups and bicyclic carbocyclic groups. Unless otherwise indicated, part of the unsaturated carbocyclic radical is optionally replaced at one or more ring positions by, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, aralkyl, azido, carbamate, carbonate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic radical, hydroxyl, imino, ketone, nitro, phosphate, phosphonic acid, phosphinic acid, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, part of the unsaturated carbocyclic radical is not substituted, i.e., it is not substituted.

[0097] 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 carbon atoms per ring, wherein one or more of the ring-forming atoms is a heteroatom, such as, for example, N, O or S. Cycloheteroalkyl or heterocycloalkyl may include spirocyclic rings. Examples of monocyclic saturated cycloheteroalkyl or heterocycloalkyl groups include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, Oxazolidinyl, isocyanate oxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl-4-yl, azepanyl, diazaazepanyl, homopiperazinyl, oxazepanyl, etc. 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, etc. Examples of partially unsaturated cycloheteroalkyl or heterocycloalkyl groups include dihydrofuranyl, imidazolinyl, dihydrofuranyl, Also included in the definition of cycloheteroalkyl or heterocycloalkyl are moieties having one or more aromatic rings fused (i.e., having a common bond) to a non-aromatic heterocycle, such as phthalimido, naphthoyl, and benzo derivatives of heterocycles, such as, for example, 2,3-dihydrobenzofuranyl, 1,3-benzo ... Azoles, 1,4-benzodioxadiazoles Alkane etc. have one or more condensed aromatic rings.Cycloheteroalkyl or heterocycloalkyl group can be connected by aromatic or non-aromatic part.The definition of cycloheteroalkyl or heterocycloalkyl also includes the part in which one or more ring atoms are replaced by 1 or 2 oxo or thio groups.In some embodiments, cycloheteroalkyl or heterocycloalkyl group has between 1 to 6, 1 to 5, 1 to 4, 1 to 3 or 1 to 2 heteroatoms (for example, N, O or S).In some embodiments, cycloheteroalkyl or heterocycloalkyl group includes 0,1,2,3,4 or 5 double bonds.In some embodiments, cycloheteroalkyl or heterocycloalkyl group includes 0,1 or 2 triple bonds.

[0098] The term "N-heterocycloalkyl" refers to a heterocycloalkyl group containing at least one nitrogen ring atom, and wherein the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through the nitrogen ring atom. Examples of N-heterocycloalkyl groups include 1,4-diazazepanyl, hexahydropyrrolo[1,2-a]pyrazinyl, piperidinyl, piperazinyl, pyrrolidinyl, and the like, wherein the point of attachment of the heterocycloalkyl radical to the rest of the molecule is through the nitrogen ring atom.

[0099] The term "cycloalkylene" refers to a cycloalkyl group that is unsaturated in one or more of the ring bonds.

[0100] The term "aryl" refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, etc. The term "aryl" also includes a polycyclic system with two or more carbocyclic rings, wherein two or more carbons are shared by two adjacent rings (these rings are "fused rings"), wherein at least one ring in these rings is aromatic, and other rings may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocycloalkyl and / or aryl. Unless otherwise indicated, aromatic rings may be substituted by, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy, amino, nitro, sulfydryl, imino, amido, carboxylic acid, -C (O) alkyl, -CO2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaryl moiety, -CF3, -CN, etc. at one or more ring positions. In certain embodiments, the aromatic ring is substituted by halogen, alkyl, hydroxyl or alkoxy at one or more ring positions. In certain other embodiments, the aromatic ring is unsubstituted, i.e., it is unsubstituted. In certain embodiments, the aryl group is a 6 to 10 membered ring structure.

[0101] The terms "heterocyclyl" and "heterocyclic" 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, wherein one or more of the ring-forming atoms is a heteroatom, such as, for example, N, O, or S. As used herein, "heterocyclyl" includes "aryl" groups, wherein at least 1 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 specifying the number of ring atoms. For example, C 3-6 A heterocyclyl group refers to a saturated or partially unsaturated 3- to 6-membered ring structure in which one or more of the ring atoms is a heteroatom (eg, N, O, or S). 3-6 ” indicates that the heterocyclic ring contains a total of 3 to 6 ring atoms, including any heteroatoms that are ring atoms.

[0102] It is contemplated that the terms described herein may be attached to form chemically related combinations, such as, for example, "carboxyheterocycloalkyl," "arylalkylheteroaryl," or "aminoalkylheterocyclyl." Regardless of whether the terms in question appear alone or in combination, the definitions described herein apply. The last member of the bond is the radical, which is attached to the rest of the molecule. The other members of the bond are attached to the bonded radical in the reverse order of the literal sequence. For example, the combination "aminoalkylheterocyclyl" refers to a heterocyclyl radical substituted by an alkyl group, which is substituted by an amino group.

[0103] The terms "compound(s) of this invention," "compound(s) of this disclosure," "compound(s) of the disclosure," and "compound(s) of the present invention" refer to compounds as disclosed herein and stereoisomers, tautomers, solvates, and salts (e.g., pharmaceutically acceptable salts) thereof.

[0104] When the compounds of the present invention are solid, those skilled in the art will appreciate that these compounds and their solvates and salts may exist in different solid forms, particularly different crystalline forms, all of which are within the scope of the present invention and the specified formula.

[0105] The term "chiral center" refers to a carbon atom bonded to four non-identical substituents. The term "chiral" refers to an embodiment that is non-superimposable with its mirror image, while the term "achiral" refers to an embodiment that is repositionable with its mirror image. Chiral molecules are optically active, i.e., they have the ability to rotate the plane of plane-polarized light.

[0106] The stereochemical definitions and conventions used herein generally follow those of SP 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. In describing optically active compounds, the prefixes D and L, or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The substituents attached to the chiral center under consideration are ordered according to the order rules 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 rotation of plane polarized light by the compound, where (-) or L indicates that the compound is levorotatory. Compounds prefixed with (+) or D are dextrorotatory.

[0107] The compounds of the present invention may have one or more chiral centers and / or double bonds, and therefore exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. Whenever there are chiral centers and / or double bonds in the chemical structure, all stereoisomers associated with the chiral centers and / or double bonds are encompassed in the present invention. The term "stereoisomer" as used herein encompasses all geometric isomers, enantiomers or diastereomers and mixtures thereof.

[0108] The compounds of the invention may exist in the form of optically pure enantiomers or mixtures of enantiomers, such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. Compositions comprising, consisting essentially of, or consisting of enantiomerically pure compounds are also contemplated herein, and the compositions may 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 a compound of formula (I) disclosed herein.

[0109] It should be understood that graphic depictions of chemical structures, such as generic chemical structures, encompass all stereoisomeric forms of a given compound unless otherwise indicated. The skilled artisan will recognize that structures may implicitly represent chiral centers. Thus, throughout this specification, the compounds of the present disclosure include all enantiomers, stereoisomers, racemic mixtures, and optically pure isomeric forms.

[0110] The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0111] The term "pharmaceutically acceptable acid addition salt" means those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes such as 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, aminobenzoic acid, benzoic acid, cinnamic acid, mandelic acid, enbernic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

[0112] The term "pharmaceutically acceptable base addition salt" refers to those pharmaceutically acceptable salts formed with organic 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, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine and polyamine resins.

[0113] Compound

[0114] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof:

[0115]

[0116] in

[0117] A 1 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0118] A 2 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0119] R 1 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0120] R 2 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0121] or A 2 and R 2 Together they form C 1-7 -alkylene or C 2-7 -alkenylene;

[0122] Z is for 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-;

[0123] h is 1, 2, or 3;

[0124] i is 0, 1, or 2;

[0125] j is 0, 1, 2, or 3;

[0126] k is 0, 1, 2, or 3;

[0127] m is 0 or 1;

[0128] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8- cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0129] Wherein R B Substituents, if any, are covalently attached to any ring atom in place of hydrogen, provided that no more than R B the maximized valence of the ring atom to which it is attached;

[0130] d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13;

[0131] Among them 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;

[0132] The prerequisite is that j and k are not both 0 in the same compound.

[0133] Particular embodiments of the present invention are compounds of formula (I) and pharmaceutically acceptable salts, tautomers, N-oxides and solvates thereof.

[0134] It should be understood that as disclosed herein, the 1 , A 2 , R 1 , R 2、 R B Each embodiment of A, Z, d, h, I, j, k and m can be combined with another embodiment of A as disclosed herein. 1 , A 2 , R 1 , R 2、 R B , Z, d, h, I, j, k and any other embodiment combination of m.

[0135] A specific embodiment of the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, tautomers, N-oxides and solvates thereof, wherein

[0136] A 1 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0137] A 2 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0138] R 1 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0139] R 2 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0140] or A 2 and R 2 Together they form C 1-7 -alkylene or C 2-7 -alkenylene;

[0141] Z is for 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-;

[0142] h is 1, 2, or 3;

[0143] i is 0, 1, or 2;

[0144] j is 0, 1, 2, or 3;

[0145] k is 0, 1, 2, or 3;

[0146] m is 0 or 1;

[0147] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8- cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0148] Wherein R B Substituents, if any, are covalently attached to any ring atom in place of hydrogen, provided that no more than R B the maximized valence of the ring atom to which it is attached;

[0149] d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13;

[0150] Among them 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;

[0151] The prerequisite is that j and k are not both 0 in the same compound.

[0152] A particular embodiment of the invention relates to compounds of formula (I) wherein R 1 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic radical, especially hydrogen or C 1-7 -alkyl.

[0153] A particular embodiment of the invention relates to compounds of formula (I) wherein R 2 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic radical, especially hydrogen or C 1-7 -alkyl.

[0154] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 and R 2 Together they form C 1-7 -alkylene or C 2-7 -alkenylene, in particular propylene or butylene.

[0155] A particular embodiment of the invention relates to compounds of formula (I) wherein R Bis bromine, chlorine, fluorine or iodine, especially fluorine.

[0156] A particular embodiment of the invention relates 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-, in particular -CH2-, -(CH2)2-, -C(=O)-, -C(=O)CH2- or -C(=O)NH-.

[0157] A particular embodiment of the invention relates to compounds of formula (I) wherein m is 0 or 1, in particular 0. For the avoidance of doubt, if m is 0, then in formula (I) the bridging A 1 and the Z part of N is A 1 Direct single covalent bond substitution between N and R.

[0158] A particular embodiment of the invention relates to compounds of formula (I), wherein m is 0 or 1, in particular 1.

[0159] A particular embodiment of the invention relates to compounds of formula (I), wherein d is 0, 1, 2, 3 or 4, in particular 0, 1 or 2.

[0160] A particular embodiment of the invention relates to compounds of formula (I), wherein h is 1, 2 or 3, in particular 1.

[0161] A particular embodiment of the invention relates to compounds of formula (I) wherein i is 0, 1 or 2, in particular 0. For the avoidance of doubt, wherein -[CH2] i Where i is 0, that particular —CH2— bond is replaced by a direct single covalent bond.

[0162] A particular embodiment of the invention relates to compounds of formula (I), wherein i is 0, 1 or 2, in particular 1.

[0163] A particular embodiment of the invention relates to compounds of formula (I), wherein j is 0, 1, 2 or 3, in particular 1.

[0164] A particular embodiment of the invention relates to compounds of formula (I), wherein j is 0, 1, 2 or 3, in particular 2.

[0165] A particular embodiment of the invention relates to compounds of formula (I), wherein k is 0, 1, 2 or 3, in particular 1.

[0166] A particular embodiment of the invention relates to compounds of formula (I), wherein k is 0, 1, 2 or 3, in particular 2.

[0167] A particular embodiment of the invention relates to compounds of formula (I), wherein h is 1, i is 1, j is 2, k is 2, and m is 0.

[0168] Particular embodiments of the invention relate to compounds of formula (I) wherein one or more hydrogens are replaced by deuterium, which may impart useful properties to the compound, such as, for example, prolonging the residence time of the active drug species in plasma to achieve greater efficacy, and / or avoiding adverse side effects.

[0169] A particular embodiment of the invention relates to compounds of formula (I),

[0170] Among them A 1 yes

[0171]

[0172] in

[0173] Each X is independently C or N;

[0174] R 3 , R 4 , R 5 , R 6 and R 7 Deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0175] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 3 , R 4 , R 5 , R 6 or R 7 ) is attached to that particular X.

[0176] A particular embodiment of the invention relates to compounds of formula (I) wherein R 3 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0177] A particular embodiment of the invention relates to compounds of formula (I) wherein R 4 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0178] A particular embodiment of the invention relates to compounds of formula (I) wherein R 5 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0179] A particular embodiment of the invention relates to compounds of formula (I) wherein R 6 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0180] A particular embodiment of the invention relates to compounds of formula (I) wherein R 7 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0181] A particular embodiment of the invention relates to compounds of formula (I) wherein R 3 , R 4 , R 5 , R 6 or R 7 One of the atoms is different from hydrogen.

[0182] A particular embodiment of the invention relates to compounds of formula (I) wherein R 3 , R 4 , R 5 , R 6 or R 7 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., bromine, chlorine, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamide, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamide, N-ethylformamide or N,N-dimethylamino.

[0183] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0184]

[0185] in

[0186] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0187] One or more of R B Substituents can be covalently attached to A in place of hydrogen 1 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0188] n is 0, 1, 2, 3, 4, 5 or 6.

[0189] A particular embodiment of the invention relates to compounds of formula (I), wherein n is 0.

[0190] A particular embodiment of the invention relates to compounds of formula (I), wherein n is 1 or 2.

[0191] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0192]

[0193] A particular embodiment of the invention relates to compounds of formula (I),

[0194] Among them A 1 yes

[0195]

[0196] in

[0197] Each X is independently C, N, O or S;

[0198] R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and R 14are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0199] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 ) is attached to that particular X.

[0200] A particular embodiment of the invention relates to compounds of formula (I) wherein R 8 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0201] A particular embodiment of the invention relates to compounds of formula (I) wherein R 9 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0202] A particular embodiment of the invention relates to compounds of formula (I) wherein R 10 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0203] A particular embodiment of the invention relates to compounds of formula (I) wherein R 11 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0204] A particular embodiment of the invention relates to compounds of formula (I) wherein R 12 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0205] A particular embodiment of the invention relates to compounds of formula (I) wherein R 13 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0206] A particular embodiment of the invention relates to compounds of formula (I) wherein R 14 is hydrogen or C1-7 - alkyl, in particular hydrogen or methyl.

[0207] A particular embodiment of the invention relates to compounds of formula (I) wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 One of the atoms is different from hydrogen.

[0208] A particular embodiment of the invention relates to compounds of formula (I) wherein R 8 , R 9 , R 10 , R 11 , R 12 , R 13 or R 14 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., bromine, chlorine, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamide, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamide, N-ethylformamide or N,N-dimethylamino.

[0209] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0210]

[0211]

[0212] in

[0213] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0214] One or more of R B Substituents can be covalently attached to A in place of hydrogen 1 any ring atom of R, including either or both of the 5-membered ring and the 6-membered ring, provided that no more than R B the maximized valence of the ring atom to which it is attached;

[0215] p is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0216] A particular embodiment of the invention relates to compounds of formula (I), wherein p is 0.

[0217] A particular embodiment of the invention relates to compounds of formula (I), wherein p is 1 or 2.

[0218] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0219]

[0220] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 yes

[0221]

[0222] in

[0223] Each X is independently C, N, O or S;

[0224] R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 and R 22 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0225] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 15 , R 16 , R 17, R 18 , R 19 , R 20 , R 21 or R 22 ) is attached to that particular X.

[0226] A particular embodiment of the invention relates to compounds of formula (I) wherein R 15 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0227] A particular embodiment of the invention relates to compounds of formula (I) wherein R 16 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0228] A particular embodiment of the invention relates to compounds of formula (I) wherein R 17 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0229] A particular embodiment of the invention relates to compounds of formula (I) wherein R 18 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0230] A particular embodiment of the invention relates to compounds of formula (I) wherein R 19 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0231] A particular embodiment of the invention relates to compounds of formula (I) wherein R 20 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0232] A particular embodiment of the invention relates to compounds of formula (I) wherein R 21 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0233] A particular embodiment of the invention relates to compounds of formula (I) wherein R 22 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0234] A particular embodiment of the invention relates to compounds of formula (I) wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20、 R 21 or R 22 One of the atoms is different from hydrogen.

[0235] A particular embodiment of the invention relates to compounds of formula (I) wherein R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 or R 22 , at least one of which 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., bromine, chlorine, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamide, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamide, N-ethylformamide or N,N-dimethylamino.

[0236] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0237]

[0238]

[0239] in

[0240] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0241] One or more of R B Substituents can be covalently attached to A in place of hydrogen 1 any ring atom of R, including any one or two 6-membered rings, provided that no more than R B the maximized valence of the ring atom to which it is attached;

[0242] q is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0243] A particular embodiment of the invention relates to compounds of formula (I), wherein q is 0.

[0244] A particular embodiment of the invention relates to compounds of formula (I), wherein q is 1 or 2.

[0245] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0246]

[0247] A particular embodiment of the invention relates to compounds of formula (I),

[0248] Among them A 1 yes

[0249]

[0250] in

[0251] Each X is independently C, N, O or S;

[0252] R 23 , R 24 , R 25 , R 26 and R 27 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0253] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 23 , R 24 , R 25 , R 26 or R 27 ) is attached to that particular X.

[0254] A particular embodiment of the invention relates to compounds of formula (I) wherein R 23 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0255] A particular embodiment of the invention relates to compounds of formula (I) wherein R24 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0256] A particular embodiment of the invention relates to compounds of formula (I) wherein R 25 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0257] A particular embodiment of the invention relates to compounds of formula (I) wherein R 26 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0258] A particular embodiment of the invention relates to compounds of formula (I) wherein R 27 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0259] A particular embodiment of the invention relates to compounds of formula (I) wherein R 23 , R 24 , R 25 , R 26 or R 27 One of the atoms is different from hydrogen.

[0260] A particular embodiment of the invention relates to compounds of formula (I) wherein R 23 , R 24 , R 25 , R 26 or R 27 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., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformyl, N-ethylformyl or N,N-dimethylamino.

[0261] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0262]

[0263] in

[0264] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7-alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0265] One or more of R B Substituents can be covalently attached to A in place of hydrogen 1 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0266] r is 0, 1, 2, 3, 4 or 5.

[0267] A particular embodiment of the invention relates to compounds of formula (I), wherein r is 0.

[0268] A particular embodiment of the invention relates to compounds of formula (I), wherein r is 1 or 2.

[0269] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0270]

[0271] A particular embodiment of the invention relates to compounds of formula (I),

[0272] Among them A 1 yes

[0273]

[0274] in

[0275] Each X is independently C, N, O or S;

[0276] R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 and R 45 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8- cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0277] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 or R 45 ) is attached to that particular X.

[0278] A particular embodiment of the invention relates to compounds of formula (I) wherein R 37 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0279] A particular embodiment of the invention relates to compounds of formula (I) wherein R 38 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0280] A particular embodiment of the invention relates to compounds of formula (I) wherein R 39 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0281] A particular embodiment of the invention relates to compounds of formula (I) wherein R 40 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0282] A particular embodiment of the invention relates to compounds of formula (I) wherein R 41 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0283] A particular embodiment of the invention relates to compounds of formula (I) wherein R 42 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0284] A particular embodiment of the invention relates to compounds of formula (I) wherein R 43 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0285] A particular embodiment of the invention relates to compounds of formula (I) wherein R 44 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0286] A particular embodiment of the invention relates to compounds of formula (I) wherein R 45 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0287] A particular embodiment of the invention relates to compounds of formula (I) wherein R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 or R 45 One of the atoms is different from hydrogen.

[0288] A particular embodiment of the invention relates to compounds of formula (I) wherein R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 or R 45 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., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformyl, N-ethylformyl or N,N-dimethylamino.

[0289] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0290]

[0291] in

[0292] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0293] One or more of R B Substituents can be covalently attached to A in place of hydrogen 1 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0294] s is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

[0295] A particular embodiment of the invention relates to compounds of formula (I), wherein s is 0.

[0296] A particular embodiment of the invention relates to compounds of formula (I), wherein s is 1 or 2.

[0297] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0298]

[0299] A particular embodiment of the invention relates to compounds of formula (I),

[0300] Among them A 1 yes

[0301]

[0302] in

[0303] Each X is independently C, N, O or S;

[0304] R 37 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 and R 55 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8- cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0305] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 37 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 or R 55 ) is attached to that particular X.

[0306] A particular embodiment of the invention relates to compounds of formula (I) wherein R 46 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0307] A particular embodiment of the invention relates to compounds of formula (I) wherein R 47 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0308] A particular embodiment of the invention relates to compounds of formula (I) wherein R 48 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0309] A particular embodiment of the invention relates to compounds of formula (I) wherein R 49 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0310] A particular embodiment of the invention relates to compounds of formula (I) wherein R 50 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0311] A particular embodiment of the invention relates to compounds of formula (I) wherein R 51 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0312] A particular embodiment of the invention relates to compounds of formula (I) wherein R 52 is hydrogen or C1-7 - alkyl, in particular hydrogen or methyl.

[0313] A particular embodiment of the invention relates to compounds of formula (I) wherein R 53 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0314] A particular embodiment of the invention relates to compounds of formula (I) wherein R 54 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0315] A particular embodiment of the invention relates to compounds of formula (I) wherein R 55 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0316] A particular embodiment of the invention relates to compounds of formula (I) wherein R 37 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 or R 55 One of the atoms is different from hydrogen.

[0317] A particular embodiment of the invention relates to compounds of formula (I) wherein R 37 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 53 , R 54 or R 55 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., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformyl, N-ethylformyl or N,N-dimethylamino.

[0318] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0319]

[0320] in

[0321] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0322] One or more of R B Substituents can be covalently attached to A in place of hydrogen 1 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0323] t is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0324] A particular embodiment of the invention relates to compounds of formula (I), wherein t is 0.

[0325] A particular embodiment of the invention relates to compounds of formula (I), wherein t is 1 or 2.

[0326] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the following groups:

[0327]

[0328] A particular embodiment of the invention relates to compounds of formula (I), wherein A 1 Selected from the group consisting of 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, hydroxy, formyl, acetyl, methoxyacetyl, 2-hydroxyacetyl, tert-butylacetyl, 2-hydroxypropanal, formyl, sulfonyl, methylsulfonyl, dimethylsulfonyl, ethylsulfonyl, 1-methylformylamino, N-ethylformylamino, N,N-dimethylamino, 1,1,1-trifluoro-2-hydroxybutyl, 5,5,5-trifluoro-2-oxopentyl or hydroxycyclobutyl, in particular tert-butylacetyl, methoxyacetyl, isopropyl, isobutyl, 1,1,1-trifluoro-2-hydroxybutyl, 5,5,5-trifluoro-2-oxopentyl, dimethylsulfonyl or hydroxycyclobutyl.

[0329] A particular embodiment of the invention relates to compounds of formula (I),

[0330] Among them A 2 yes

[0331]

[0332] in

[0333] Each X is independently C, N, O or S;

[0334] R 28 , R 29 , R 30 , R 31 and R 75 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0335] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 28 , R 29 , R 30 , R 31 or R 75 ) is attached to that particular X.

[0336] A particular embodiment of the invention relates to compounds of formula (I) wherein R 28 is hydrogen or C 1-7- alkyl, in particular hydrogen or methyl.

[0337] A particular embodiment of the invention relates to compounds of formula (I) wherein R 29 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0338] A particular embodiment of the invention relates to compounds of formula (I) wherein R 30 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0339] A particular embodiment of the invention relates to compounds of formula (I) wherein R 31 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0340] A particular embodiment of the invention relates to compounds of formula (I) wherein R 75 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0341] A particular embodiment of the invention relates to compounds of formula (I) wherein R 28 , R 29 , R 30 , R 31 or R 75 One of the atoms is different from hydrogen.

[0342] A particular embodiment of the invention relates to compounds of formula (I) wherein R 28 , R 29 , R 30 , R 31 or R 75 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., bromine, chlorine, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropanal, formamide, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamide, N-ethylformamide or N,N-dimethylamino.

[0343] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0344]

[0345] in

[0346] RB represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0347] One or more of R B Substituents can be covalently attached to A in place of hydrogen 2 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0348] u is 0, 1, 2, 3, or 4.

[0349] A particular embodiment of the invention relates to compounds of formula (I), wherein u is 0.

[0350] A particular embodiment of the invention relates to compounds of formula (I), wherein u is 1 or 2.

[0351] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0352]

[0353] A particular embodiment of the invention relates to compounds of formula (I),

[0354] Among them A 2 yes

[0355]

[0356] in

[0357] Each X is independently C, N, O or S;

[0358] R 32 , R 33 , R 34 , R 35 and R 36 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8- cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0359] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 32 , R 33 , R 34 , R 35 or R 36 ) is attached to the X.

[0360] A particular embodiment of the invention relates to compounds of formula (I) wherein R 32 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0361] A particular embodiment of the invention relates to compounds of formula (I) wherein R 33 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0362] A particular embodiment of the invention relates to compounds of formula (I) wherein R 34 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0363] A particular embodiment of the invention relates to compounds of formula (I) wherein R 35 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0364] A particular embodiment of the invention relates to compounds of formula (I) wherein R 36 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0365] A particular embodiment of the invention relates to compounds of formula (I) wherein R 32 , R 33 , R 34 , R 35 or R 36 One of the atoms is different from hydrogen.

[0366] A particular embodiment of the invention relates to compounds of formula (I) wherein R 32 , R 33 , R 34 , R 35 or R36 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., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformyl, N-ethylformyl or N,N-dimethylamino.

[0367] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0368]

[0369] in

[0370] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0371] One or more of R B Substituents can be covalently attached to A in place of hydrogen 2 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0372] v is 0, 1, 2, 3, 4, 5, or 6.

[0373] A particular embodiment of the invention relates to compounds of formula (I), wherein v is 0.

[0374] A particular embodiment of the invention relates to compounds of formula (I), wherein v is 1 or 2.

[0375] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0376]

[0377] A particular embodiment of the invention relates to compounds of formula (I),

[0378] Among them A 2 yes

[0379]

[0380] in

[0381] Each X is independently C, N, O or S;

[0382] R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 and R 64 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0383] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , R 63 or R 64 ) is attached to the X.

[0384] A particular embodiment of the invention relates to compounds of formula (I) wherein R 56 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0385] A particular embodiment of the invention relates to compounds of formula (I) wherein R 57 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0386] A particular embodiment of the invention relates to compounds of formula (I) wherein R 58 is hydrogen or C1-7 - alkyl, in particular hydrogen or methyl.

[0387] A particular embodiment of the invention relates to compounds of formula (I) wherein R 59 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0388] A particular embodiment of the invention relates to compounds of formula (I) wherein R 60 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0389] A particular embodiment of the invention relates to compounds of formula (I) wherein R 61 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0390] A particular embodiment of the invention relates to compounds of formula (I) wherein R 62 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0391] A particular embodiment of the invention relates to compounds of formula (I) wherein R 63 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0392] A particular embodiment of the invention relates to compounds of formula (I) wherein R 64 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0393] A particular embodiment of the invention relates 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 One of the atoms is different from hydrogen.

[0394] A particular embodiment of the invention relates 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 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., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformyl, N-ethylformyl or N,N-dimethylamino.

[0395] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0396]

[0397] in

[0398] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0399] One or more of R B Substituents can be covalently attached to A in place of hydrogen 2 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0400] w is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9.

[0401] A particular embodiment of the invention relates to compounds of formula (I), wherein w is 0.

[0402] A particular embodiment of the invention relates to compounds of formula (I), wherein w is 1 or 2.

[0403] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0404]

[0405] A particular embodiment of the invention relates to compounds of formula (I),

[0406] Among them A 2 yes

[0407]

[0408] in

[0409] Each X is independently C, N, O or S;

[0410] R 56 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 and R 74 are independently hydrogen, deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0411] Provided that if the maximum valency of a particular X is satisfied by covalent bonds to other ring atoms, no substituents (i.e., R 56 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 or R 74 ) is attached to the X.

[0412] A particular embodiment of the invention relates to compounds of formula (I) wherein R 65 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0413] A particular embodiment of the invention relates to compounds of formula (I) wherein R 66 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0414] A particular embodiment of the invention relates to compounds of formula (I) wherein R 67 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0415] A particular embodiment of the invention relates to compounds of formula (I) wherein R 68 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0416] A particular embodiment of the invention relates to compounds of formula (I) wherein R 69 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0417] A particular embodiment of the invention relates to compounds of formula (I) wherein R 70 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0418] A particular embodiment of the invention relates to compounds of formula (I) wherein R 71 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0419] A particular embodiment of the invention relates to compounds of formula (I) wherein R 72 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0420] A particular embodiment of the invention relates to compounds of formula (I) wherein R 73 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0421] A particular embodiment of the invention relates to compounds of formula (I) wherein R 74 is hydrogen or C 1-7 - alkyl, in particular hydrogen or methyl.

[0422] A particular embodiment of the invention relates to compounds of formula (I) wherein R 56 , R 65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 or R 74 One of the atoms is different from hydrogen.

[0423] A particular embodiment of the invention relates to compounds of formula (I) wherein R 56 , R65 , R 66 , R 67 , R 68 , R 69 , R 70 , R 71 , R 72 , R 73 or R 74 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., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formyl, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformyl, N-ethylformyl or N,N-dimethylamino.

[0424] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0425]

[0426] in

[0427] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0428] One or more of R B Substituents can be covalently attached to A in place of hydrogen 2 Any ring atom of B the maximized valence of the ring atom to which it is attached;

[0429] y is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0430] A particular embodiment of the invention relates to compounds of formula (I), wherein y is 0.

[0431] A particular embodiment of the invention relates to compounds of formula (I), wherein y is 1 or 2.

[0432] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 Selected from the following groups:

[0433]

[0434] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 It's hydrogen.

[0435] A particular embodiment of the invention relates to compounds of formula (I), wherein A 2 It is tert-butyl.

[0436] Specific compounds of formula (I) of the present invention are those selected from the group consisting of: 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) 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]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)pyridazine -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- 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-(2-methylpyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl]methyl]piperidin-1-yl]pyrimidine-4-carbonitrile; 4-((3-(2,4-dimethylthiazol-5-yl)-6-oxopyridazin-1(6H)-yl)methyl)piperidin-1-yl)pyrazine-2-carbonitrile; 4-[[4-[[3-(2,4-dimethylthiazol-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-[(2,4-difluorophenyl)methyl]piperidin-4-yl]methyl]-6-(2,4-dimethyl-1,3-thiazol-5-yl)pyridazin-3-one; [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-yl)-2-(1-pyrido[3,4-d]pyrimidin-4-ylpiperidin-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 pyridin-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] 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-methyl pyridazin-3-one; 2-[4-[3-(3,5-dimethylpyrazol-1-yl)-6-oxopyridazin-1-yl]piperidin-1-yl]pyridin-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- 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; 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-benzo[1,2,4-thiadiazol-5-yl)piperidin-4-yl]-6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-one; 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)-2-[1-(1,3,4-thiadiazol-2-yl)piperidin-4-yl]pyridazin-3-one )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)propionyl]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)methoxy]pyridazin-1-one 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)pyridazin-3-one; pyrazol-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-trifluorobutyryl)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- 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-(5-fluoropyrimidin-2-yl)piperidin-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; [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-(1 H-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- 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-cyclopentano[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-1-one pyridazin-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-fluoroquinazolin-4-yl)piperidin-4-yl)methyl)-6-(1H-1,2,4-triazol-1-yl)pyridazin-3(2H)-one; 2-((1-(1,6-dimethylthiazol-5-yl)piperidin-4-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)pyridazin-3(2H)-one methyl-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-triazacyclo[8.4.0.03,8]tetradec-3(8),4,9,11,13-pentaen-5-yl)-4-phenyl-1,3-thiazol-5-yl]-4-methoxybenzamide; 2-[[1-(1,3-benzo[ oxazol-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)sulfonylacetamide; 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-benzodihydro Indole-6-sulfonamide; N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3,5-dimethyl-1,2- oxadiazole-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]acrylamide; 2-(1,2-benzo 2-(1,3-Benzothiazol-2-ylsulfonyl)-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]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-yl Formamide; 3-(phenylsulfonyl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acrylamide; 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; and pharmaceutically acceptable salts thereof.

[0437] Specific compounds of formula (I) of the present invention are those selected from the group consisting of: 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; [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-(2-propan-2-ylpyrimidin-4-yl)piperidin-4-yl]methyl]pyridazin-3-one; oxazol-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; (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-dimethylthiazol-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 pyridazin-3-one; 2-[[1-(4,6-dimethylpyrimidin-2-yl)piperidin-4-yl]methyl]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-dimethyl-1,3-thiazol-5-yl)-2-[[1-[(5-methyl-1,2-; 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 )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- 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-triazacyclo[8.4.0.03,8]tetradecane-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)pyrazine-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 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-(4-chlorobenzyl)piperidin-4-yl)methyl)-6-(2,4 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] 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-benzo[1-(1,3-benzo[1-(1,3-benzo[1-(1,3-benzo[1-(1,3-benzo[1-(1,3-benzo[1-(1,3-benzo[1-(1,3-benzo[1-(1,3-benzo[1-(1,3-benzo[1-( 2-(3-cyclopropyl-6-oxopyridazin-1-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide; tert-butyl 4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidine-1-carboxylate; 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)sulfonylacetamide; 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-benzodihydro Indole-6-sulfonamide; N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3,5-dimethyl-1,2- oxadiazole-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-benzo 2-(1,3-Benzothiazol-2-ylsulfonyl)-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]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-yl formamide; 3-(phenylsulfonyl)-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; and pharmaceutically acceptable salts thereof.

[0438] Specific compounds of formula (I) of the present invention are those selected from the group consisting of: 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)methyl)-6-(pyridin-4-yl)pyridazin-3(2H)-one; [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 -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; and pharmaceutically acceptable salts thereof.

[0439] A specific embodiment of the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof represented by formula (II), wherein j is 2 and k is 2:

[0440]

[0441] in

[0442] A 1 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0443] A 2 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0444] R 1 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0445] R 2 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group;

[0446] or A 2 and R 2 Together they form C 1-7 -alkylene or C 2-7 -alkenylene;

[0447] Z is for 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-;

[0448] h is 1, 2, or 3;

[0449] i is 0, 1, or 2;

[0450] m is 0 or 1;

[0451] R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino;

[0452] Wherein R B Substituents, if any, are covalently attached to any ring atom in place of hydrogen, provided that no more than R B the maximized valence of the ring atom to which it is attached;

[0453] d is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

[0454] Among them 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.

[0455] A particular embodiment of the invention relates to compounds of formula (II), wherein Selected from the following groups:

[0456]

[0457] Specific compounds of formula (I) of the present invention are those selected from the group consisting of:

[0458] 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;

[0459] 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;

[0460] 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;

[0461] 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;

[0462] 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;

[0463] 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;

[0464] 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;

[0465] 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;

[0466] 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;

[0467] 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;

[0468] and pharmaceutically acceptable salts thereof.

[0469] The formulas of the compounds disclosed herein should be interpreted as encompassing all possible stereoisomers, enantiomers or epimers of the compounds, unless the formula indicates a specific stereoisomer, enantiomer or epimer. The formulas of the compounds disclosed herein should be interpreted as encompassing salts, esters, amides or solvates thereof of the compounds.

[0470] In certain embodiments, provided herein are compounds similar to compounds of formula (I) disclosed herein. The similarity between small molecule compounds can be determined using methods known in the art, such as, for example, deriving 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 incorporated herein in its entirety together with the references cited therein. In some embodiments, provided herein are compounds having 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 Tanimoto index compared to compounds of formula (I) disclosed herein.

[0471] The compounds of formula (I) disclosed herein can be developed and produced by many methods known to those skilled in the art (see below for specific methods).

[0472] Target, target region, target segment and nucleic acid base sequence

[0473] In certain embodiments, the compounds of formula (I) disclosed herein can target nucleic acids, wherein the target nucleic acid is an RNA encoding MYC or a portion thereof. Small molecules targeting RNA are useful because they combine the advantages of small molecule drugs (see Background Art) and the advantages of targeting RNA, for example, allowing the target range to be expanded beyond protein-coding genes to include non-coding regulatory RNAs, and allowing targeting of "undruggable" proteins that lack deep binding pockets. In certain embodiments, the target nucleic acid may include a nucleobase sequence encoding MYC, including but not limited to RefSeq Accession No. NC_000008.11 truncated from nucleotides 127735434 to 127742951 (incorporated herein as SEQ ID NO: 1), RefSeq Accession No. NM_002467.6 (incorporated herein as SEQ ID NO: 2) and RefSeq Accession No. NM_001354870.1 (incorporated herein as SEQ ID NO: 3) or a portion thereof, wherein an adenine base (A) can be interchanged with a uracil base (U). In some embodiments, the compounds of Formula (I) disclosed herein may also target certain other RNA transcript variants encoding MYC or portions thereof.

[0474] In certain embodiments, the compounds of formula (I) disclosed herein can target at least one target region in the target nucleic acid. The target region is a region defined by the structure or function of the target nucleic acid. Examples of target regions include, but are not limited to, exons, introns, exon-intron junctions, intron-exon junctions, exon-exon junctions, 3' untranslated regions (3'UTR), 5' untranslated regions (5'UTR), translation initiation regions, translation termination regions, 5' donor splice sites, 3' acceptor splice sites, start codons, upstream open reading frames (ORFs), repeat regions, hexanucleotide repeat amplifications, splicing enhancer regions, exon splicing enhancers (ESEs), splicing inhibition regions, exon splicing silencers (ESSs), intron splicing enhancers (ISEs), intron splicing silencers (ISSs), RNA destabilization motifs, RNA stabilization motifs, miRNA binding sites, RNA binding protein (RBP) sites or other defined nucleic acid regions. Information on such structurally or functionally defined target regions in RNAs such as MYC RNA is available in part through accession numbers in databases such as NCBI, GENBANK and ENSEMBL and references therein, and such information is incorporated herein in its entirety.

[0475] The target region may include one or more overlapping or non-overlapping target segments. In certain embodiments, the target segment length within the target region is less than 10000, 5000, 2500, 1000, 500, 250, 100 or 50 nucleotides. In some embodiments, the compound of formula (I) disclosed herein may target a target segment within the target region. In some embodiments, the compound 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 compound of formula (I) disclosed herein may target two or more target segments derived from different target regions.

[0476] Suitable target segments can specifically include a certain structural or functionally defined target region, such as, for example, a start codon or a stop codon. The determination of suitable target segments can include comparing the core base sequence of the target segment with other sequences in the entire transcriptome. For example, the BLAST algorithm can be used to identify the similarity regions between different sequences. This comparison can enable the selection of unique target segments, so as to develop specific targeted target nucleic acids and compounds with minimal non-specific targeting of other nucleic acids (i.e., off-target).

[0477] In some embodiments, targeting includes determining at least one target segment within a target nucleic acid, and the compound can interact with the target segment to produce a desired effect. The desired effect may be a reduction in the stability of the target nucleic acid, resulting in a reduction in RNA levels and a corresponding reduction in the protein levels encoded therein. The desired effect may be an increase in the stability of the target nucleic acid, resulting in an increase in RNA levels and a corresponding increase in the protein levels encoded therein. The desired effect may also be a change in the translation efficiency of the target nucleic acid, resulting in an unchanged RNA level, but an increase or decrease in the protein level encoded therein. The desired effect may also be a phenotypic change associated with a change in the RNA level of the target nucleic acid or a change in the protein level encoded by the target nucleic acid. In certain embodiments, the desired effect of targeting at least one target segment within a target nucleic acid encoding MYC using a compound of formula (I) disclosed herein is a reduction in MYC RNA levels. In other embodiments, the desired effect of targeting at least one target segment within a target nucleic acid encoding MYC using a compound of formula (I) disclosed herein is a reduction in MYC protein levels. In yet other embodiments, the desired effect of targeting at least one target segment within a target nucleic acid encoding MYC using a compound of Formula (I) disclosed herein is a phenotypic change associated with a decrease in MYC RNA levels or protein levels.

[0478] Therefore, some embodiments provide compounds of formula (I) disclosed herein, which can inhibit or reduce the expression or activity of MYC. In one embodiment, the compounds of formula (I) disclosed herein can target nucleic acids encoding MYC and inhibit its transcription. In one embodiment, the compounds can target nucleic acids encoding MYC and degrade or destabilize them. In one embodiment, the compounds can target nucleic acids encoding MYC and inhibit its translation. In another embodiment, the compounds can target nucleic acids encoding MYC and regulate its splicing, thereby reducing the expression or activity of MYC.

[0479] In certain embodiments, the inhibition or reduction of MYC RNA or MYC protein can be achieved by targeting MYC-related genes or pathways. Therefore, in certain embodiments, provided herein are compounds of formula (I) that can reduce or inhibit the expression, activity or signaling of MYC by targeting and inhibiting at least one gene or pathway that positively regulates or increases the expression, activity or signaling of MYC. In other embodiments, provided herein are compounds of formula (I) that can reduce or inhibit the expression, activity or signaling of MYC by targeting and increasing the expression or activity of at least one gene or pathway that negatively regulates or inhibits the expression of MYC.

[0480] Conjugates and complexes

[0481] In certain embodiments, the compound of formula (I) disclosed herein is conjugated or bonded or complexed with at least one other molecule, such as a peptide or polypeptide, an antibody, a lipid, a sugar, a nucleotide or an oligonucleotide, other polymers, a cleavage agent, a transporter, an intercalator, a molecular beacon, a cross-linking agent triggered by hybridization, a lipophilic agent, or a hydrophilic agent. These conjugates or complexes can provide many benefits for the compound, 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 pharmacodynamics or pharmacokinetic properties, and / or improved selectivity for a specific target. Certain embodiments may include a combination of one or more of the conjugates or complexes described herein.

[0482] In some embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with proteins or other polyamides, amines or similar molecules. In other embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with lipids, phospholipids, cholesterol or thiocholesterol, bile acid, fatty chains, hexylaminocarbonyloxycholesterol or another similar molecule. In other embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with another organic molecule, such as ether or thioether, steroid, biotin, phenazine, folic acid, phenanthridine, anthraquinone, acridine, adamantaneacetic acid, palmitoyl, fluorescein, rhodamine, coumarin, dye or other marker molecule, or other polymer, such as polyethylene glycol. In other embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with another compound having special electromagnetic properties or optical properties, such as a photolabile protective group.

[0483] In some embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with another drug or agent described herein for treating, preventing or ameliorating cancer. In other embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with another drug, such as, for example, another drug that relieves pain or other symptoms or improves uptake or delivery, such as blood thinners (e.g., aspirin, warfarin), anti-inflammatory and analgesic drugs (e.g., COX inhibitors, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, pranoprofen, carprofen, indomethacin, folic acid, tiaprofenic acid, diclofenac, niflumic acid, diazepines or benzodiazepines, barbiturates). Or antifungal agents, antiviral agents, antibiotics, or other drugs that promote at least one benefit in a treatment environment, the at least one benefit includes therapeutic efficacy, symptom relief, drug tolerance or side effect regulation, etc.

[0484] In some embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with an antibody or a monoclonal antibody that recognizes a specific cell type (e.g., cancer cell) or a specific antigen that is unique to a tissue, thereby enabling the compound of formula (I) to be delivered to a specific cell type or tissue. In some embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with a nanobody or a nanocarrier, which enables targeted delivery of the compound of formula (I) to a specific cell type or tissue. In other embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with another drug that promotes transcellular membrane transport or another drug that promotes trans-blood-brain barrier transport. In some embodiments, the compound of formula (I) disclosed herein is conjugated or complexed with one or more GalNAc residues that are recognized by asialoglycoprotein receptors, resulting in effective uptake of cells.

[0485] In some embodiments, the conjugates described herein are prodrugs, wherein they are converted (e.g., by enzymes in the body) into pharmacologically active drugs after administration, such as compounds of formula (I) disclosed herein. Prodrugs can be used, for example, to improve stability, improve solubility, increase permeability, increase drug absorption, prolong duration of action, or achieve selective transport of pharmacologically active drugs, etc. Currently, about 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)), 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 incorporated herein in their entirety along with the references cited therein.

[0486] In some embodiments, the compound of formula (I) disclosed herein can be conjugated with ribonucleases such as RNase L to induce degradation of target RNA. Such bivalent compounds are referred to as ribonucleases targeting chimeras (RIBOTACs), and are described by Dey et al. (Dey et al., Cell Chemical Biology, 26 (8): 1047-1049 (2019)), which are incorporated herein in their entirety together with the references cited therein. In other embodiments, the compound of formula (I) disclosed herein can be conjugated with a ligand of an E3 ubiquitin ligase to induce ubiquitination of a target protein and its subsequent degradation by the proteasome. Such bivalent compounds are referred to as proteolytic targeting chimeras (PROTACS), and are described by Toure et al. (Toure et al., Angew. Chem. Int. Ed., 55: 1966-1973 (2016)), which are incorporated herein in their entirety together with the references cited therein.

[0487] Pharmaceutical compositions and delivery methods

[0488] Some embodiments of the present invention provide pharmaceutical compositions or medicines comprising compounds of formula (I) disclosed herein and pharmaceutically acceptable carriers, diluents and / or other substances. Another embodiment relates to methods of preparing such pharmaceutical compositions or medicines using compounds of formula (I) disclosed herein. The carrier, diluent and / or other substances of the pharmaceutical composition must be "acceptable", i.e., compatible with the other ingredients of the composition and harmless to its recipient. In one embodiment, the carrier, diluent and / or other substance is therapeutically inert. The terms "pharmaceutical composition" and "medicine" are used interchangeably herein.

[0489] Pharmaceutical compositions or drugs are prepared, dosed, and administered according to good medical practice. Wu & Chen (US2018 / 0112272 A1) describes a list of common practices, which list is incorporated herein in its entirety along with the references cited therein. In some embodiments, a pharmaceutical composition or drug may comprise a formulation prepared by mixing at least one compound of formula (I) disclosed herein with a carrier or excipient. Suitable carriers and excipients are described in more detail in 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, along with the references cited therein.

[0490] In some embodiments, the pharmaceutical composition or medicine may include at least one compound of formula (I) disclosed herein and one or more substances commonly found in pharmaceutical preparations, such as, for example, adjuvants, anesthetics, antioxidants, buffers, carriers, colorants, diluents, emulsifiers, flavoring agents, glidants, lubricants, masking agents, opacifiers, fragrances, pH regulators, preservatives, processing aids, salts for changing osmotic pressure, solubilizers, stabilizers, surfactants, suspending agents, sweeteners and wetting agents, etc. The pharmaceutical composition or medicine may also include one or more substances to improve presentation, and / or to aid in the manufacture of the drug product. The pharmaceutical composition or medicine may also include additional therapeutically valuable substances. For example, a pharmaceutical composition or medicine may include a mixture of two or more compounds each of which is therapeutically beneficial, wherein at least one of these is a compound of formula (I) disclosed herein.

[0491] In some embodiments, for ease of administration and uniform dosage, the above-mentioned pharmaceutical composition or drug is prepared into a unit dosage form. As used herein, a unit dosage form refers to a physically discrete unit suitable as a single dose, each unit containing a predetermined amount of active ingredient (i.e., a compound of formula (I) disclosed in the present invention), which is associated with a carrier and / or other substances in the pharmaceutical composition and is calculated to produce a desired therapeutic effect. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder bags, wafers, suppositories, injection solutions or suspensions, etc., and their isolation multiples.

[0492] The dosage of the compounds of formula (I) disclosed herein can vary within wide limits and needs to be adjusted according to the individual requirements of each case. For example, in some embodiments, in the case of orally administered compounds, the daily dosage can be in the range of about 0.01 mg to about 1000 mg per person, although the upper and lower limits may be exceeded if necessary.

[0493] In certain embodiments, the pharmaceutical composition or medicament can be administered by any suitable means, including enteral, epidural, inhalation, intra-arterial, intracerebral, intracerebroventricular, intradermal, intralesional (if local treatment is desired), intramuscular, intranasal, intraocular, intraperitoneal, intrapulmonary, intrathecal, intravenous, intravitreal, oral, parenteral, transdermal, rectal, subcutaneous, topical (including buccal and sublingual), transdermal, transmucosal, and vaginal administration, etc.

[0494] In some embodiments, the pharmaceutical composition or medicament can be in any convenient form 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, etc.

[0495] The following are examples of pharmaceutical compositions and methods for preparing the same suitable for different routes of administration. In certain embodiments, pharmaceutical compositions for oral administration in liquid form, such as suspensions, syrups, elixirs, emulsions and solutions, may include liquid carriers or diluents, such as, for example, water, ethylene glycol, oils, alcohols, etc. In other embodiments, pharmaceutical compositions in solid form for oral administration, such as powders, pills, capsules and tablets, may include solid carriers, such as sugars (e.g., mannitol, lactose, sucrose, glucose, saccharin, etc.), magnesium, carbonates, kaolin, diluents, lubricants (e.g., silicon dioxide, stearic acid, magnesium stearate, talc, etc.), binders, disintegrants that promote solid dissolution (e.g., starch, clay, cellulose, row materials, gums and polymers, etc.), etc. Tablets and capsules represent the most advantageous oral dosage unit forms due to ease of administration, in which case solid pharmaceutical carriers are obviously employed.

[0496] In some embodiments, the pharmaceutical composition for parenteral administration, for example, in the form of an injectable solution or suspension, may include a carrier, such as sterile water, although other ingredients may be included, for example, to help dissolve. Injectable solutions may be prepared, wherein the carrier includes a mixture of saline solution, glucose solution or saline and glucose solution. Injectable solutions may be formulated in oil for extended action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerides of long-chain fatty acids and mixtures of these oils and other oils. Injectable suspensions may be prepared using suitable liquid carriers, suspending agents, etc. In certain embodiments, the pharmaceutical composition for parenteral administration may be a sterile solution, emulsion or suspension prepared by solid or lyophilized form before administration. In other embodiments, the pharmaceutical composition may include some adjuvants, anesthetics, buffers or wetting agents, which promote more effective distribution of the composition, facilitate the administration of the composition, or improve patient response or health.

[0497] Certain embodiments provide pharmaceutical compositions for transdermal administration (e.g., transdermal or topical), wherein the carrier optionally comprises a penetration enhancer and / or a suitable wetting agent, optionally in combination with a suitable additive of any nature in a smaller proportion, which additive does not produce a significant deleterious effect on the skin. The additive may facilitate transdermal administration and / or facilitate preparation of the desired composition. The pharmaceutical composition may be administered in various ways, for example, as a transdermal patch, as a spot, cream, gel or ointment, etc.

[0498] Some embodiments provide pharmaceutical compositions that can be administered through mucosa, such as in the form of sprays or suppositories. Other embodiments provide pharmaceutical compositions that can be administered intranasally (e.g., inhalants) and / or can be administered via aerosol delivery devices, such as nebulizers, sprayers, or vaporizers. Aerosol delivery devices and other aerosol delivery devices mentioned herein are well known to those of ordinary skill in the art and are included in various embodiments herein.

[0499] Certain embodiments of the present invention provide a method for delivering a compound of formula (I) disclosed herein or its pharmaceutical composition to a cell, tissue, animal or human subject. In some embodiments, a compound of formula (I) disclosed herein or its pharmaceutical composition uses one of the above-mentioned routes of administration or other routes of administration known to those of ordinary skill in the art to deliver. In some embodiments, a compound of formula (I) disclosed herein or its pharmaceutical composition is delivered via a targeted method, which directly introduces or guides a compound or pharmaceutical composition to a specific cell or tissue involved in a disease, such as, for example, a cancer cell or a 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 incorporated herein by reference in their entirety together with the references cited therein.

[0500] In some embodiments, the delivery method of the compound of formula (I) disclosed herein or its pharmaceutical composition includes naked delivery to cells, animals or human subjects. 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 involves the use of membrane fusion. In another embodiment, the delivery method includes the use of colloids containing polymer particles or nanoparticle solutions. Nanoparticles may include certain properties that help target certain areas for delivery or otherwise promote delivery, such as electromagnetic properties. In another embodiment, the delivery method includes the use of chemically 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 cells. These delivery methods may be used with or without the aforementioned complexes or conjugates of the compound of formula (I) disclosed herein. Certain complexes or conjugates can increase the delivery rate or stability of the compound and are included in these embodiments. Other methods of delivery involve standard practice known to those skilled in the art and are incorporated in certain embodiments herein.

[0501] Activity analysis of compounds and pharmaceutical compositions

[0502] The compounds of formula (I) disclosed herein, or pharmaceutical compositions thereof, may have variable activity, for example, as defined by a percentage reduction in target RNA levels, a percentage reduction in target protein levels, or a percentage reduction in target protein activity. In some embodiments, the target is MYC. In certain embodiments, a reduction in MYC RNA levels, including but not limited to RNA transcribed from the MYC gene and RNA translated into MYC protein, indicates a reduction or inhibition of MYC expression. In specific embodiments, a reduction in the level of one or more MYC transcripts disclosed by SEQ ID NOs: 1–3 indicates a reduction or inhibition of MYC expression. In some embodiments, a reduction in the level of MYC protein indicates a reduction or inhibition of MYC expression. In specific embodiments, a reduction in the level of one or more MYC proteins indicates a reduction or inhibition of MYC expression, and the one or more MYC proteins are the translation products of one or more MYC transcripts disclosed by SEQ ID NOs: 1–3 herein.

[0503] In other embodiments, a reduction in the activity of a MYC protein that is a translation product of one or more MYC transcripts disclosed herein as SEQ ID NOs: 1-3 indicates a reduction or inhibition of MYC activity. The activity of MYC refers to one or more activities typically performed by the MYC transcripts or proteins described herein, such as, for example, regulation of cell proliferation, cell cycle, cell growth, differentiation, angiogenesis, apoptosis, immunity, stress response, or tumorigenesis. In certain embodiments, a compound of formula (I) disclosed herein, or a pharmaceutical composition thereof, can selectively target and reduce the level or activity of one or more specific MYC transcript variants and proteins encoded therein, and such a reduction in the level or activity of one or more MYC transcript variants or proteins indicates a reduction in MYC expression or activity.

[0504] In yet other embodiments, certain phenotypic changes resulting from administration of a compound of Formula (I) disclosed herein, or a pharmaceutical composition thereof, 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, reduced cancer cell growth or proliferation, reduced cancer cell viability, reduced cancer cell migration, reduced cancer cell invasion, reduced cancer cell metastasis, reduced angiogenesis, reduced or increased apoptosis, and the like.

[0505] In certain embodiments, changes in other genes, mRNAs, proteins, or pathways in the cell that result from reduced or inhibited expression or activity of MYC, as well as changes known to those of skill in the art, are incorporated herein as an indication of reduced or inhibited expression or activity of MYC.

[0506] Analysis of RNA levels

[0507] In certain embodiments, the reduction or inhibition of MYC expression by the compound of formula (I) disclosed herein or its pharmaceutical composition can be evaluated by measuring the reduction of MYC RNA transcript levels. RNA analysis can be performed on poly (A) + mRNA or total cell RNA. Methods for RNA isolation are well known in the art, and include, for example, the use of TRIZOL reagent (Invitrogen, Carlsbad, CA) according to the manufacturer's recommended protocol, or using an RNA extraction kit (Qiagen), etc. 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 reverse transcription, followed by quantitative real-time PCR using ABI PRISM 7600, 7700 or 7900 sequence detection systems (PE-Applied Biosystems, Foster City, CA), etc., according to the manufacturer's instructions.

[0508] Before quantitative real-time PCR, the separated RNA first undergoes reverse transcription reaction to produce complementary DNA (cDNA), which is then used as a substrate for real-time PCR amplification reaction. Reagents for reverse transcription and real-time PCR are commercially available (e.g., Invitrogen, Carlsbad, CA). Reverse transcription reaction and real-time PCR reaction can be performed sequentially in the same sample well or different sample wells. The level of the target gene or RNA obtained by real-time PCR can be normalized using the total RNA level quantitatively measured by, for example, RIBOGREEN (Invitrogen, Carlsbad, CA), or using the expression level of genes (such as cyclophilin A or beta actin) whose expression in cells is more or less stable. The RNA quantitative method using RIBOGREEN is described in Jones et al. (Jones et al., Analytical Biochemistry, 265:368-374 (1998)), which is incorporated herein in its entirety together with the references cited therein. CYTOFLUOR 4000 instrument (PE Applied Biosystems) can be used to measure RIBOGREEN fluorescence. The expression level of cyclophilin A or beta actin can be quantified by real-time PCR in the same well used for quantifying the target RNA level (i.e., by performing multiple reactions), or by performing in separate wells. Probes and primers that hybridize to target nucleic acids encoding MYC can be designed using methods known in the art, and may include the use of software such as PRIMER EXPRESS software (Applied Biosystems, Foster City, CA). Other methods for measuring reduced MYC RNA levels are described in Embodiment 2, which are included in the embodiments herein.

[0509] Protein level analysis

[0510] In certain embodiments, the reduction or inhibition of MYC expression by the compound of formula (I) disclosed herein or its pharmaceutical composition can be evaluated by measuring the reduction of MYC protein level. Several methods for quantitatively or measuring the protein level of MYC are well known in the art, such as Western blot analysis, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, immunocytochemistry, fluorescence activated cell sorting (FACS), immunohistochemistry, protein activity assay, quantitative protein assay, bicinchoninic acid assay (BCA assay) also known as Smith assay, etc. Conventional monoclonal or polyclonal antibody generation methods known in the art can be used to generate antibodies specific to target proteins (such as MYC), or antibodies can be identified and commercially obtained from various sources (such as MSRS antibody catalog (Aerie Corporation, Birmingham, MI)). Antibodies for detecting mouse, rat, monkey and human MYC are commercially available. Other methods for measuring the reduction of MYC protein levels are described in Embodiment 1, which are included in some embodiments herein.

[0511] In vitro testing of compounds

[0512] The compounds of formula (I) disclosed herein or their pharmaceutical compositions can be applied to cells cultured in vitro to assess their effects on the expression or activity of a target gene (e.g., MYC), or 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 a compound of formula (I) disclosed herein or its pharmaceutical composition to cultured cells results in a reduction or inhibition of MYC protein expression (e.g., see Example 1). In other embodiments, administration of a compound of formula (I) disclosed herein or its pharmaceutical composition to cultured cells results in a reduction or inhibition of MYC RNA expression (e.g., see Example 2). In some embodiments, administration of a compound of formula (I) disclosed herein or its pharmaceutical composition to cultured cells results in one or more phenotypes, such as, for example, reduced cancer cell growth or proliferation, reduced cancer cell viability, and reduced apoptosis. (e.g., see Examples 3-5).

[0513] In certain embodiments, the cultured cells used to test compounds in vitro are animal or human cancer-derived cells, such as, for example, breast cancer cells (e.g., MCF7, MDA-MB-231, MDA-MB-468, HS 578T, BT-549, and T-47D, etc.), Burkitt's 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., LOXIMVI, 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.), etc. In certain embodiments, the cultured cells are derived from a MYC-driven cancer. Examples of cancer-derived cells, including MYC-driven cancer cells, are described in the catalogs of commercial suppliers, such as, for example, 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 using commercially available reagents (e.g., Invitrogen Life Technologies, Carlsbad, CA) according to the supplier's instructions.Cells can be cultured and tested in multi-well plates, such as 6-well plates, 24-well plates, 48-well plates, 96-well plates, 384-well plates, etc.

[0514] Any method known to those skilled in the art can be used to assess the compound of formula (I) disclosed herein or its pharmaceutical composition applied to cultured cells resulting in one or more phenotypes, such as, for example, a reduction in cell growth and proliferation, a reduction in cell viability, or a reduction or increase in apoptosis. Examples of assays assessing cell growth and proliferation or cell viability include colorimetric assays using dyes such as MTT, XTT, MTS, and CCK-8, fluorescence-based assays such as ApoTox-Glo, and luminescence-based assays such as CellTiter-Glo, etc. Examples of assays assessing apoptosis include ApoTox-Glo, caspase-Glo (3 / 7, 8, and 9), annexin V, etc. In certain embodiments, the disclosed compounds have 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 the selected assay. In other embodiments, the disclosed compounds reduce the growth or viability of cancer cells (such as MYC-driven cancer cells) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% at a concentration of less than 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 compounds reduce the growth or viability of healthy (non-cancer) cells by no more than 50%, 40%, 30%, 20%, 10%, 5%, or less at a concentration of less than about 100 μM, 50 μM, 20 μM, 10 μM, 1 μM, 0.1 μM, 0.05 μM, 0.01 μM, or less.

[0515] In vivo testing of compounds

[0516] The compounds of formula (I) disclosed herein or their pharmaceutical compositions can be administered in vivo to animals or human subjects to evaluate their properties, such as, for example, pharmacokinetic characteristics, safety, maximum tolerated dose (MTD), absorption, distribution, metabolism and excretion (ADME), 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 rate, cancer cell growth, cancer metastasis, behavior, body weight, metabolism, etc. In some embodiments, the compounds of formula (I) disclosed herein or their pharmaceutical compositions are administered to animals or human subjects, resulting in reduced or inhibited expression and / or activity of MYC protein and / or RNA. In some embodiments, the compounds of formula (I) disclosed herein or their pharmaceutical compositions are administered to animals or human subjects, resulting in one or more phenotypes, such as, for example, reduced tumor volume (i.e., tumor regression), reduced cancer cell growth or proliferation, reduced cancer metastasis, increased survival of animals or human subjects, or other desired results with respect to specific phenotypes (e.g., body weight, metabolism, etc.). In some embodiments, testing can be performed in healthy animals or human subjects. In other embodiments, testing can be performed in an animal model of the disease (e.g., a cell line-derived xenograft (CDX) model, a patient-derived xenograft (PDX) model, a syngeneic model, an orthotopic model, a humanized model, a spontaneous or induced cancer model, etc.), or a human subject diagnosed with cancer.

[0517] In certain embodiments, the compound of formula (I) disclosed herein is formulated in a pharmaceutically acceptable diluent, such as phosphate buffered saline, for administration to animals. Administration includes any route of administration described herein, such as, for example, oral, intrathecal, intraperitoneal, intravenous, and subcutaneous. The method for calculating the appropriate dose and dosing frequency of the compound disclosed herein is well known in the art, and depends on factors such as animal weight and route of administration. After the compound disclosed herein or its pharmaceutical composition is applied to the animal, the expression level of the target gene (such as MYC) of the animal is monitored at a specified time point, as well as the effects on other phenotypes (such as, for example, survival rate, cancer cell growth, cancer metastasis, behavior, body weight, metabolism, etc.). The level of MYC RNA or MYC protein can be measured in different tissues of the animal using methods known in the art and described herein, such as, for example, CSF, plasma, brain, spinal cord, lung, liver, kidney, etc. Other modifications are known to those skilled in the art and are considered to be included in the embodiments herein.

[0518] In certain embodiments, administration of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof results in a reduction of MYC RNA by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or a range defined by any two of these values. In certain embodiments, administration of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof results in a reduction of MYC protein by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or a range defined by any two of these values. In certain embodiments, administration of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof results in a reduction of tumor size by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or 90%, or a range defined by any two of these values. In certain embodiments, administration of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof results in a reduction of tumor metastasis. In certain embodiments, administration of a compound of Formula (I) disclosed herein, or a pharmaceutical composition thereof, results in an increase in the survival rate of an animal or human subject by at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, or 99%, or a range defined by any two of these values.

[0519] How to use and treatment methods

[0520] Some embodiments provide methods for reducing MYC expression in cells or tissues, including applying a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to cells, animals or humans, thereby reducing MYC expression. Other embodiments provide methods for reducing MYC activity in cells or tissues, including applying a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to cells, animals or humans, thereby reducing MYC activity. Other embodiments provide methods for achieving one or more phenotypic results, such as, for example, reduced cancer cell growth or proliferation, reduced cancer cell viability, reduced apoptosis, reduced tumor volume (i.e., tumor regression), reduced cancer metastasis, increased survival rate of animals or human subjects, or other desired results for a particular phenotype (e.g., body weight, metabolism, etc.), including applying a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to cells, animals or humans. Yet other embodiments provide methods for treating diseases, such as cancer, including applying an effective amount of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to an animal or human. In a specific embodiment, cancer is a MYC-driven cancer.

[0521] In certain embodiments, provided herein are methods for treating a human subject diagnosed with cancer (such as a MYC-driven cancer), comprising administering a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to a human individual. In certain embodiments, provided herein are methods for prophylactically reducing MYC expression or activity in a human subject to prevent a disease, such as cancer, wherein the human subject is at risk of developing a cancer, such as a MYC-driven cancer. In other embodiments, a compound of formula (I) disclosed herein or a pharmaceutical composition thereof is administered to a human subject to treat or improve cancer symptoms.

[0522] In a specific embodiment, a MYC-driven cancer refers to a C-MYC-driven cancer, such as, for example, breast cancer, Burkitt's 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, squamous cell carcinoma of the lung), non-Burkitt's lymphoma, medullary thyroid carcinoma, 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, etc. In certain embodiments, MYC-driven cancers refer to N-MYC-driven cancers, such as, for example, astrocytomas, lower grade gliomas of the brain, breast cancer, glioblastomas, lung cancer (e.g., small cell lung cancer), medullary thyroid cancer, medulloblastomas, neuroblastomas, ovarian cancer, pancreatic cancer, pheochromocytomas and paragangliomas, prostate cancer, retinoblastomas, rhabdomyosarcomas (e.g., alveolar rhabdomyosarcomas), and testicular cancer, among others.

[0523] Other embodiments provide the use of a compound of formula (I) disclosed herein or its pharmaceutical composition for reducing the expression or activity of MYC. Still other embodiments provide the use of a compound of formula (I) disclosed herein or its pharmaceutical composition for achieving one or more phenotypic results, such as, for example, reduced cancer cell growth or proliferation, reduced cancer cell viability, reduced apoptosis, reduced tumor volume (i.e., tumor regression), reduced cancer metastasis, increased survival rate of animals or human subjects, or other desired results with respect to a particular phenotype (e.g., body weight, metabolism, etc.). Still other embodiments provide the use of a compound of formula (I) disclosed herein or its pharmaceutical composition for treating, preventing or ameliorating cancer, such as MYC-driven cancer.

[0524] Certain embodiments provide a compound of formula (I) disclosed herein or a pharmaceutical composition thereof, for reducing the expression or activity of MYC. Certain other embodiments provide a compound of formula (I) disclosed herein or a pharmaceutical composition thereof, for achieving one or more phenotypic results, such as, for example, reduced cancer cell growth or proliferation, reduced cancer cell viability, reduced apoptosis, reduced tumor volume (i.e., tumor regression), reduced cancer metastasis, increased survival of animals or human subjects, or other desired results with respect 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 treating, preventing or ameliorating cancer, such as MYC-driven cancer.

[0525] Some embodiments provide the use of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof in the manufacture of a drug for reducing MYC expression or activity. In certain embodiments, a compound of formula (I) disclosed herein or a pharmaceutical composition thereof is used to manufacture a drug for achieving one or more phenotypic results, such as, for example, reduced cancer cell growth or proliferation, reduced cancer cell viability, reduced apoptosis, reduced tumor volume (i.e., tumor regression), reduced cancer metastasis, increased survival of animals or human subjects, or other desired results with respect 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 to manufacture a drug to treat, prevent, or improve cancer in a patient diagnosed with or susceptible to cancer (such as MYC-driven cancer).

[0526] In other embodiments, provided herein is a method for preventing, treating or improving other non-cancer diseases, including applying a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to a cell, tissue, animal or human subject. In a specific embodiment, such diseases are associated with MYC expression or activity, wherein targeting MYC to reduce or inhibit its expression or activity can provide therapeutic benefits. Examples of such diseases include inflammatory diseases, autoimmune diseases, metabolic diseases, age-related diseases, etc. Specific examples include asthma, renal cystic diseases (e.g., polycystic kidney disease), Crohn's disease, lipid metabolism diseases, autoimmune encephalomyelitis, etc. Madden et al. describe examples of such diseases (Madden et al., Mol. Cancer, 20, Article 3 (2021)), and the disclosure of the application is incorporated herein by reference in its entirety together with its references.

[0527] In certain embodiments, provided herein is a method for treating a human subject in need thereof by administering a therapeutically effective amount of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof to a human subject, wherein the compound of formula (I) or a pharmaceutical composition thereof may target one or more MYC nucleic acids disclosed herein or a portion thereof. In some embodiments, a therapeutically effective amount of a compound of formula (I) disclosed herein or a pharmaceutical composition thereof is administered, accompanied by monitoring MYC RNA levels, protein levels or activity in an individual to determine the individual's response to the administration of the compound or pharmaceutical composition. A physician may use the response of a human subject to the administration of the compound to determine the dose, regimen and duration of the therapeutic intervention.

[0528] Therapeutic methods including applying a compound of formula (I) disclosed herein or its pharmaceutical composition or drug to cells, tissues, animals or human subjects can vary in composition, dosage and dosage scheduling. A unit dose is a predetermined therapeutically effective amount of a compound of formula (I) disclosed herein or its pharmaceutical composition and drug administered. A unit dose may vary according to various factors, including but not limited to body weight, age, sex, severity of symptoms, medical history and the enthusiasm of treatment. A schedule is the frequency of unit dose administration. One of ordinary skill in the art can determine the size of a unit dose and the administration schedule of a compound or its pharmaceutical composition and drug, and incorporate it into certain embodiments herein.

[0529] In certain embodiments, the compounds of formula (I) disclosed herein or their pharmaceutical compositions or drugs are co-administered with one or more other agents. The compounds, pharmaceutical compositions or drugs described herein may be prepared in a single formulation together with one or more other agents, or prepared separately. In some embodiments, one or more other agents are designed to treat diseases, conditions, symptoms or disorders different from the compounds, pharmaceutical compositions or drugs described herein. In other embodiments, one or more other agents are designed to treat diseases, conditions, symptoms or disorders identical to the compounds, pharmaceutical compositions or drugs described herein. In some embodiments, one or more other agents are co-administered with the compounds, pharmaceutical compositions or drugs described herein to produce an additive effect. In certain embodiments, one or more other agents are co-administered with the compounds, pharmaceutical compositions or drugs described herein to produce a synergistic or super-additive effect, wherein the effect produced by the co-administration of the two is greater than the sum of the effects of each being administered separately. In other embodiments, one or more other agents are co-administered with the compounds, pharmaceutical compositions or drugs described herein to treat the undesirable side effects of the compounds, pharmaceutical compositions or drugs described herein. In certain embodiments, the compounds, pharmaceutical compositions or drugs described herein are co-administered with one or more other agents to prevent or delay the onset of symptoms, slow disease progression, reduce side effects, improve therapeutic efficacy or otherwise improve patient outcomes. Co-administration as used herein may refer to situations where one or more other agents are administered simultaneously with the compounds, pharmaceutical compositions or drugs described herein, as well as situations where one or more other agents are administered before or after the administration of the compounds, pharmaceutical compositions or drugs described herein (e.g., hours, days or weeks, etc.).

[0530] In certain embodiments, one or more other agents co-administered with a compound, pharmaceutical composition, or medicament described herein may include agents comprising, for example, antisense oligonucleotides, other oligonucleotides (e.g., siRNA, ribozymes, deoxyribozymes, or aptamers), antibodies, peptides, small molecule compounds, nucleic acid vectors, cell therapy (e.g., CAR-T) or gene therapy agents, and the like. In certain embodiments, one or more agents co-administered with the compounds, pharmaceutical compositions, or medicaments described herein include drugs that are typically administered to treat or improve cancer symptoms, such as, for example, alkylating agents (e.g., altretamine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, melphalan, temozolomide, and trabectidine, etc.), antimetabolites (e.g., azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, 6-mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and dipivoxil, etc.), antitumor antibiotics (e.g., bole, The invention relates to biologic response modifiers (e.g., Avastin, Erbitux, Herceptin, and Rituximab), which enhance the body's immune system to fight cancer growth or disrupt processes required for cancer growth or spread (e.g., dexamethasone and prednisone), nitrosoureas (e.g., carmustine, lomustine), plant alkaloids and natural products (e.g., docetaxel, etoposide, irinotecan, paclitaxel, teniposide, topotecan, vinblastine, vincristine, and vinorelbine), and sex hormones (e.g., leuprolide, tamoxifen, etc.). In certain embodiments, one or more pharmaceutical 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, folinic acid, thiaprofen, diclofenac, niflumic acid, diazepines or benzodiazepines (e.g., diazepam) and barbiturates, etc.), drugs that improve uptake or delivery, such as blood thinners (e.g., aspirin and warfarin, etc.), antifungal agents, antiviral agents, antibiotics, or other drugs that provide at least one benefit in the treatment setting, the at least one benefit including therapeutic efficacy, symptom relief, drug tolerability, or side effect modulation.

[0531] In certain embodiments, one or more agents that may be co-administered with a compound, pharmaceutical composition, or medicament described herein include an additional modulator that can reduce MYC expression or activity. In certain embodiments, the dose of the co-administered agent is lower than the dose that would be administered if the co-administered agent were administered alone.

[0532] Development Methodology

[0533] In certain embodiments, the present invention provides methods for developing small molecule compounds, which can target MYC or its related genes or pathways, thereby reducing the expression or activity of MYC. In certain embodiments, the method for developing compounds is completely computational. In some embodiments, the method for developing compounds involves biochemical or cell-based methods, such as screening and selection. In some embodiments, the method for developing compounds involves a combination of computational methods and biochemical or cell-based methods. Such development methods include standard practices known to those skilled in the art, and are combined in certain embodiments herein.

[0534] In some embodiments, the computational methods may involve artificial intelligence or machine learning software, rely on macromolecular databases, utilize high-throughput analysis, or any combination thereof. 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. (eds.) 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 the computational methods described by Merk et al. (Merk et al., Molecular Informatics, 37: 1700153 (2018)) represent some available computational methods, and these documents are incorporated herein in their entirety together with the references cited therein. In some embodiments, the structure of a target RNA (such as MYC or a portion thereof) is predicted by calculation. Thereafter, a computational library of small molecule compounds is docked with the target individually by calculation, and a computational method is used to determine the binding energy of each small molecule compound to the target. Small molecule compounds predicted to have favorable binding energy to the target RNA are preferentially used for further analysis and development. In some embodiments, new small molecule compounds are generated from fusions of existing molecules or atoms from one or more databases for computational screening. Other computational methods are well known to those of ordinary skill in the art and are included in various embodiments herein.

[0535] In certain embodiments, the method for developing small molecule compounds includes high-throughput biochemistry or cell-based screening methods, which are known to those of ordinary skill in the art. The physical library of small molecules is constructed or obtained from commercially available sources. By introducing small molecules into the selected target molecule, washing or separation methods are then implemented to determine binding affinity and / or specificity, for the selected target molecule, such as MYC screening these libraries. The example of such methods 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 together with the references cited therein. In some embodiments, the combination of small molecule compounds and 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, etc. In other embodiments, cell-based methods involve treating cells with a library of small molecule compounds, followed by detection of target RNA levels (e.g., using RT-qPCR or RNA-seq, etc.) and / or protein (e.g., using Western blot, ELISA, alpha screening, or homogeneous time-resolved fluorescence (HTRF), etc.) for identifying compounds that can modulate the expression or activity of a target such as MYC. 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 small molecules or molecular complexes formed between small molecules and selected target molecules. Control or negative selection steps can be used to screen out small molecules that have off-target binding activity with other molecules that are not the selected target molecules. In addition, small molecule screening against selected target molecules at different concentrations is used to determine other properties, such as IC 50 , EC50, efficacy, etc. Further descriptions of methods and procedures for developing small molecule 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 by reference in their entirety along with the references cited therein. Other biochemical or cell-based screening methods are well known to those of ordinary skill in the art and are included in various embodiments herein.

[0536] In certain embodiments, the method for developing small molecule modulators includes discovery techniques based on fragments known to those of ordinary skill in the art. These methods relate to screening a small molecule fragment library containing one or more binding epitopes for use in binding affinity and / or specificity to a target molecule, such as MYC. Typically, small molecule fragments have a molecular weight of about 120 daltons-250 daltons. In some cases, these discovery methods based on fragments are combined with computational methods, some of which will be described below. Examples of discovery techniques based on fragments include leader identifications by fragment evolution, leader identifications by fragment connections, leader identifications by fragment self-assembly, and leader progress by fragment optimization, which are described in this article. Typically, the assessment of target molecule binding sites, the formation of fragment complexes, and the subsequent determination of binding efficacy or specificity are carried out by structural, morphological, and chemical data obtained from evaluation tools, such as nuclear magnetic resonance spectroscopy, mass spectrometry, or X-ray crystallography.

[0537] In lead identification by fragment evolution, a library of fragments is applied to a selected target molecule and the strength and specificity of binding is determined. Fragments with higher binding specificity are then reacted or evolved with various other fragments to form fragment complexes, and fragment complexes with higher binding specificity are screened.

[0538] In lead identification by fragment ligation, a library of fragments is screened by binding specificity to multiple binding sites of a selected target molecule. Two or more fragments with high binding specificity to two or more adjacent binding sites on the selected target molecule are chemically ligated together.

[0539] In lead identification by fragment self-assembly (also known as combinatorial chemistry), a library of fragments capable of self-assembly is introduced to a selected target molecule. The fragments are allowed to 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 are able to assemble together and simultaneously bind to the selected target molecule via complementary reactive groups. Once assembled, these fragment complexes can be isolated to evaluate their chemical and structural properties.

[0540] In lead development by fragment optimization, fragment libraries are used to modify the properties of existing modulators or fragment complexes. Typically, this approach is used to address the optimization of certain properties, such as selectivity, solubility, stability, or efficacy.

[0541] Examples and further discussion of methods and procedures for developing small molecule modulators via fragment-based discovery 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 incorporated by reference in their entirety, along with the references cited therein. Other methods are well known to those skilled in the art and are included in the various embodiments herein.

[0542] Diagnostics and Test Kits

[0543] 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 susceptibility to cancer (such as a MYC-driven cancer 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 reduced risk or reduced susceptibility to cancer (such as a MYC-driven cancer disclosed herein). In some embodiments, a method for determining a subject's susceptibility to cancer (such as a MYC-driven cancer disclosed herein) includes obtaining a sample, including a tissue, body fluid, or other biological sample from a subject, detecting the expression level of at least one MYC RNA transcript associated with a sequence described by SEQ ID NO: 1-3, wherein different expression levels of the transcript are associated with different susceptibility to the disease, and determining 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 using a compound of formula (I) disclosed herein or a conjugate thereof.

[0544] In certain embodiments, methods for determining risk or susceptibility to a disease, or methods for diagnosing the above-mentioned diseases, can be applied to predict the prognosis of human individuals diagnosed with cancer (such as MYC-driven cancer) or experiencing symptoms associated with cancer. In other embodiments, the above-mentioned methods for determining disease risk or susceptibility or disease diagnosis methods can be used to assess the probability of response of human individuals to treatment methods and / or modulators for treating, preventing or ameliorating symptoms associated with cancer (such as MYC-driven cancer). In one embodiment, these methods can be used to select treatment methods or modulators for treating subjects diagnosed with the disease.

[0545] 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 predicting the prognosis of a human individual diagnosed with or experiencing symptoms associated with a disease; or assessing the probability of a human individual responding to a treatment method and / or modulator for treating, preventing, or ameliorating symptoms associated with a disease. In some embodiments, the disease is cancer, such as a MYC-driven cancer as described herein.

[0546] Kits useful for any of the methods described herein may include any components useful for any of the methods described herein, including but not limited to probes (e.g., hybridization probes, allele-specific oligonucleotides), enzymes (e.g., for RFLP analysis, activity assays), reagents for nucleic acid amplification, reagents for directly analyzing at least one allele of at least one polymorphic marker within or associated with MYC, reagents for indirectly analyzing at least one allele of at least one polymorphic marker within or associated with MYC, reagents for detecting the expression or activity of MYC, reagents for detecting signal transduction through pathways associated with MYC, etc. In one embodiment, the kit may include necessary buffers. In another embodiment, the kit may alternatively provide reagents for other disease-specific diagnostic methods known in the art to be implemented in conjunction with the methods described herein.

[0547] In certain embodiments, the reagents in the kit include at least one compound of formula (I) disclosed herein or a complex or conjugate thereof, which is capable of interacting with MYC, or otherwise detecting the expression of MYC, the activity of MYC, or signal transduction through pathways associated with MYC. In another embodiment, the kit comprises at least one or more labeled compounds of formula (I) disclosed herein, and reagents for detecting the label. Suitable labels may include, but are not limited to, radioisotopes, fluorescent labels, enzyme labels, enzyme cofactor labels, magnetic labels, spin labels, or epitope labels, etc.

[0548] In certain embodiments, the kit and the device include a lookup table containing correlation data between the expression level of at least one transcript associated with the sequence described by SEQ ID NO: 1-3 and disease susceptibility or disease prognosis or response to at least one disease treatment selectively evaluated by the kit. Another group of embodiments relates to a method for manufacturing an agent using a compound of formula (I) disclosed herein, which is used to diagnose or assess a human individual's susceptibility to a disease, or the prognosis of a disease, or the response to a disease treatment. In one embodiment, the kit also includes a set of instructions for using the reagents comprising the kit. In another embodiment, the kit includes a set of instructions or guidelines for interpreting the test results using the reagents comprising the kit.

[0549] Another set of embodiments provides a kit (also referred to as a pharmaceutical package and used interchangeably) comprising a compound of formula (I) disclosed herein, or a pharmaceutical composition thereof and a drug, and a set of instructions for administering the compound or its pharmaceutical composition and drug to humans. In some embodiments, an individual identified as a carrier of at least one allele of at least one polymorphic marker associated with MYC-driven cancer is instructed to take a prescription dose of a compound of formula (I) disclosed herein, or a pharmaceutical composition thereof and a drug. In other embodiments, an individual with an increased risk of cancer (such as MYC-driven cancer) or an increased susceptibility to cancer is instructed to take a prescription dose of a compound of formula (I) disclosed herein, or a pharmaceutical composition thereof and a drug. In other embodiments, an individual diagnosed with cancer (such as MYC-driven cancer) is instructed to take a prescription dose of a compound of formula (I) disclosed herein, or a pharmaceutical composition thereof and a drug.

[0550] Computer readable media and devices

[0551] Compositions, methods and test kits as described herein can be implemented in whole or in part as computer executable instructions on computer-readable media. As understood by those skilled in the art, the various steps of compositions, methods and test kits as described herein can be implemented as various blocks, operations, routines, tools, modules and technologies, which can then be implemented in any combination of hardware, firmware, software or hardware, firmware and / or software. In certain embodiments, hardware specific 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), etc. In other embodiments, when implemented as software, software can be stored in any computer-readable medium known in the art, including but not limited to solid state hard disks, disks, optical disks or other storage media, in the RAM or ROM or flash memory of a computer, processors, hard disk drives, thumb drives, optical disk drives, tape drives, etc. In one embodiment, software can be delivered to a user or computing system via any delivery method known in the art, including but not limited to by communication channels, such as the Internet, wireless connections, satellite connections, telephone lines, computer-readable disks or other removable computer storage mechanisms.

[0552] One group of embodiments provides a suitable computing system environment known in the art to implement the combinations, methods and kits described herein, including but not limited to mobile phones, laptops, personal computers, server computers, multiprocessor systems, microprocessor-based systems, set-top boxes, programmable consumer electronics, network PCs, minicomputers, mainframe computers, cloud computing environments, and distributed computing environments including any of the above systems or devices, etc. In some embodiments, the steps of the compositions, methods or kits described herein are implemented via computer executable instructions, such as program modules, including but not limited to routines, programs, objects, components, data structures, etc., which perform specific tasks or implement specific abstract data types. In one embodiment, the methods and apparatus are practiced in a distributed computing environment, where tasks are performed by remote processing devices connected via a communication network. In one embodiment, these methods and apparatus are practiced in an integrated computing environment. In integrated and distributed computing environments, program modules may be located in both local and / or remote computer storage media, including memory storage devices.

[0553] Therefore, one group of embodiments provides a computer-readable medium with computer-executable instructions for determining the effect of applying a compound of formula (I) disclosed herein or its pharmaceutical composition and drug to a cell of an animal or human subject, the computer-readable medium including data indicating the level of at least one protein, RNA, biomarker or other phenotype, and a routine stored on the computer-readable medium and suitable for being executed by a processor to determine the effect of applying a compound or its composition from the data. In certain embodiments, the determined effect is a change in MYC RNA levels, or a change in MYC protein levels, or a change in one or more phenotypes, such as cell growth or proliferation, cell viability, cell morphology, cell cycle arrest, cell migration, cell invasion, apoptosis, survival rate, cancer cell growth, cancer metastasis, behavior, body weight, metabolism, etc. In one embodiment, the computer-readable medium is used to determine the progression of a disease, such as cancer, and its response to applying a compound of formula (I) disclosed herein or its pharmaceutical composition and drug to a human subject.

[0554] Another group of embodiments provides a computer-readable medium with computer-executable instructions for developing compounds of formula (I) disclosed herein using at least one computational method described herein or other computational methods known to those skilled in the art, which methods are also included in the embodiments herein. The computer-readable medium may contain data associated with a specific nucleotide sequence disclosed herein, SEQ ID NO, or a portion thereof, and any polypeptide sequence generated by transcription and translation of the nucleotide sequence. The computer-readable medium may also be suitable for execution by a processor to develop compounds of formula (I) disclosed herein from the data.

[0555] 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. Therefore, it should be understood that the compositions, methods and kits described herein are only illustrative and do not limit the scope of the present invention.

[0556] Example

[0557] The following examples are presented to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are neither intended to limit the scope of what the inventors consider to be their invention, nor are they intended to represent or imply that the following experiments are all or only experiments performed. It should be understood by those skilled in the art that various changes and / or modifications may be made to the present invention shown in the specific embodiments without departing from the spirit or scope of the present invention as broadly described. It should also be understood that these examples provide feasible guidance on using the combined features of the present disclosure to apply such compositions, methods and systems to other uses. Therefore, the current embodiments are considered to be illustrative and non-restrictive in all respects.

[0558] In certain embodiments, these examples may be implemented by a computer or other processing device in conjunction with and / or running software, wherein these methods and features, software and processors utilize specialized methods to analyze data.

[0559] While efforts have been made to ensure accuracy with respect to numbers used (eg, amounts, strengths, temperatures, etc.), some experimental errors and deviations should be accounted for.

[0560] Example 1: Regulation of MYC protein expression by test compounds

[0561] The MYC Homogeneous Time-Resolved Fluorescence (HTRF) Assay Kit) (CisBio / PerkinElmer 63adek 053peg) was used to quantify the level of MYC protein in human cell lines (e.g., A549, HepG2) after treatment with test compounds according to the following protocol. Human cells cultured in DMEM-10% FBS medium were seeded at 20,000 cells per well in a 96-well plate. After 1 day, the cells were treated with the test compound 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, #4 lysis buffer was added to produce a cell lysate. 10 μL of the cell lysate was added to 10 μL of a premixed 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 incubation for 3 hours, HTRF compatible plate reader is used to read fluorescence readings under the emission wavelength (respectively 620nm and 665nm) of donor fluorophore and acceptor fluorophore.The ratio of acceptor and donor fluorescence emission signal of each sample is calculated by dividing the fluorescence signal at 665nm by the signal at 620nm, and further normalized by dividing by the concentration of total protein in the sample determined by BCA determination.The value obtained in this way is expressed as the percentage of the sample without compound, only treated with solvent (DMSO).Relative to the sample treated with DMSO, the MYC protein of lower percentage in the sample indicates that the percentage of MYC protein level reduction is larger due to the test compound, and vice versa.

[0562] Table 1 provides the percentage reduction in MYC protein levels due to specific test compounds when tested using the above HTRF assay protocol. Specific compounds of formula (I) disclosed herein reduce MYC protein levels by more than 10%, 20%, 30%, 40%, 50%, 60% or 70% compared to samples treated with solvent (DMSO) alone.

[0563] The reduction level of MYC protein after treatment with test compound is also assessed by western blotting according to the following scheme.Human cancer cell line (for example, A549 or HepG2) is seeded in 96 well plates with 20,000 cells per well.After 1 day, the test compound treatment cell is about 10 μM with final concentration.After 2 days of incubation period, supernatant is removed from wells, and RIPA buffer is added to produce cell lysate.By western blotting analysis lysate, and connect GAPDH-specific antibody (for example, Proteintech 10828-1-AP) with MYC-specific antibody (for example, Proteintech 10494-1-AP) to detect lysate together, as loading control.The intensity of western blotting band is quantitatively (image J) by FIJI.After treatment with test compound, the relative expression value of MYC is calculated by the intensity of the MYC band of sample divided by the intensity of its own GAPDH band.The value so obtained is expressed as the percentage of the sample without compound, only with solvent (DMSO) treatment. A lower percentage of MYC protein in a sample relative to the DMSO treated sample indicates a greater percentage reduction in MYC protein levels due to the test compound, and vice versa.

[0564] Table 2 provides the percentage of reduction in MYC protein levels due to specific test compounds when tested using the above-described Western blot assay. Specific compounds of Formula (I) disclosed herein reduce MYC protein levels by more than 10%, 20%, 30%, 40%, 50% or 60% compared to samples treated with solvent (DMSO) alone.

[0565] Example 2: Regulation of MYC RNA expression by test compounds

[0566] According to the following scheme, RT-qPCR is used to evaluate the reduction level of MYC RNA after treatment with the test compound. Human cancer cell lines (e.g., A549, HepG2) are seeded in 96-well plates with 20,000 cells per well. After 1 day, the cells are treated with a test compound at a final concentration of about 10 μM. After 1 day of incubation, the supernatant is removed from the wells, and according to the protocol of the kit manufacturer, the lysate from the cell-CT 1-Step Power SYBR Green kit (Invitrogen A25599) is added to produce cell lysates. Then follow the protocol of the kit manufacturer, use a pair of MYC specific primers (e.g., SEQ ID NO: 4 and SEQ ID NO: 5) to detect MYC RNA, and a pair of β-actin specific primers (e.g., SEQ ID NO: 6 and SEQ ID NO: 7) to detect β-actin RNA, and perform RT-qPCR for each sample, as a loading control. The relative expression levels of MYC RNA and β-actin RNA are calculated by using a standard curve generated by a series of dilutions 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 the percentage of the sample without compound and treated with solvent (DMSO) only. Relative to the sample treated with DMSO, the lower percentage of MYC RNA in the sample indicates that the percentage of MYC RNA level reduction is larger due to the test compound, and vice versa.

[0567] Table 3 provides the percentage of reduction in MYC RNA levels due to specific test compounds when tested using the above RT-qPCR assay. Specific compounds of Formula (I) disclosed herein reduce MYC RNA levels by more than 10%, 20%, 30% or 40% compared to samples treated with solvent (DMSO) alone.

[0568] Example 3: Effects of test compounds on cell viability measured using CCK-8 assay

[0569] According to the following scheme, the effect of the test compound on cell viability was determined 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.) were seeded in 96-well plates at 20,000 cells per well. After 1 day, cells were 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- or 3-day incubation period, 10 μL of a CCK-8 solution containing WST-8 dye was added to each well according to the kit manufacturer's protocol. After incubation for 1 hour to 4 hours, the absorbance at 450 nm was measured using an ELISA reader. The absorbance at 450 nm measures the amount of WST-8 reduced to WST-8 alpha by cellular dehydrogenases, which is proportional to the number of viable cells. The cytotoxic effects of the test compounds at different concentrations were calculated by subtracting the ratio of the absorbance at 450 nm of the sample treated with the compound to the absorbance of the sample treated with the solvent (DMSO) alone without the compound from 1. The higher the value, the greater the cytotoxic effect of the test compound on the cell (corresponding to the greater reduction in the activity of the cell dehydrogenases), and vice versa. The IC values ​​of the cytotoxic effects of each test compound in A549, HepG2, JeKo-1 and / or MDA-MB-231 cells 50 The IC value was determined by plotting a dose-response curve to calculate the concentration of the test compound that produces half of the maximal cytotoxic effect. 50 It is also measured in non-cancerous human cell lines (e.g., HEK-293 and / or HaCaT) as a surrogate for healthy cells to determine the therapeutic window of the test compound (i.e., the concentration range in which the test compound selectively kills cancer cells but not healthy cells). The therapeutic index of a test compound is defined herein as its IC in HEK-293 cells. 50 Divided by its IC in HepG2 cells 50 The higher the therapeutic index, the safer and more useful the test compound is as a cancer drug because it exhibits greater selectivity in killing cancer cells over healthy cells.

[0570] Table 4 provides the IC values ​​of specific test compounds when tested using the CCK-8 assay described above. 50 When tested using the above CCK-8 assay, certain compounds of Formula (I) exhibit an IC of less than 10 μM, less than 1 μM, or less than 0.5 μM. 50When tested using the above CCK-8 assay, certain compounds of Formula (I) exhibit therapeutic indices greater than 1, greater than 10, or greater than 100. As a benchmark, one of the most well-known MYC inhibitors, sAJM589, which acts by inhibiting the MYC-MAX protein-protein interaction, exhibited IC values ​​of 28.4 μM, 20.5 μM, and 34.2 μM when tested in A549, HepG2, and HEK-293 cells, respectively. 50 (The therapeutic index is 1.67). Therefore, the CCK-8 assay results show that one or more compounds of formula (I) disclosed herein are more effective in killing cancer cells than sAJM589. In addition, one or more compounds of formula (I) disclosed herein have a higher therapeutic index (and therefore will be a safer drug) than sAJM589.

[0571] Example 4: Effects of Test Compounds on Cell Viability Determined Using the CellTiter-Glo 2.0 Assay

[0572] According to the following scheme, the effect of test compounds on cell viability is also determined using CellTiter-Glo 2.0 assay kit (Promega G9241). Human cancer cell lines (e.g., HepG2) and non-cancerous cell lines (e.g., HEK-293) are seeded in 96-well plates with 20,000 cells per well. After 1 day, cells are treated with test compounds at various concentrations (e.g., 10nM, 31.6nM, 100nM, 316nM, 1 μM, 3.16 μM, 10 μM, 20 μM, etc.). After 2 days of incubation, CellTiter-Glo 2.0 is performed according to the kit manufacturer's protocol to determine. In short, 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 culture medium containing cells). The contents were mixed on an orbital shaker for 2 minutes to induce cell lysis, and incubated at room temperature for 10 minutes, and then the luminescent signal was measured using a microplate reader. The intensity of the luminescent signal is directly proportional to the amount of ATP present, and the amount of ATP is then directly proportional to the number of metabolically active cells. The cytotoxic effects of the test compounds of different concentrations were calculated by subtracting the luminescent signal of the sample treated with the compound from 1 with the ratio of the luminescent signal of the sample treated with no compound, only with solvent (DMSO). Higher values ​​indicate that the cytotoxic effects of the test compounds on cells are larger (corresponding to a larger reduction in metabolically active cells), and vice versa. The IC values ​​of the cytotoxic effects of each test compound in HepG2 cells 50 The IC value was determined by plotting a dose-response curve to calculate the concentration of the test compound that produces half of the maximal cytotoxic effect. 50It is also measured in non-cancerous human cell lines (e.g., HEK-293) as a surrogate for healthy cells to determine the therapeutic window of the test compound (i.e., the concentration range in which the test compound selectively kills cancer cells but not healthy cells). The therapeutic index of a test compound is defined herein as its IC in HEK-293 cells. 50 Divided by its IC in HepG2 cells 50 The higher the therapeutic index, the safer and more useful the test compound is as a cancer drug in selectively killing cancer cells while minimizing side effects on healthy cells.

[0573] Table 5 provides the IC values ​​of specific test compounds when tested using the CellTiter-Glo 2.0 assay described above. 50 When tested using the CellTiter-Glo 2.0 assay described above, certain compounds of Formula (I) exhibit an IC of less than 10 μM, less than 1 μM, or less than 0.2 μM. 50 When tested using the CellTiter-Glo 2.0 assay described above, certain compounds of Formula (I) exhibit therapeutic indices greater than 1, greater than 10, or greater than 100. In contrast, one of the most well-known MYC inhibitors, sAJM589, which acts by inhibiting the MYC-MAX protein-protein interaction, exhibited IC values ​​of 13 μM and 12.2 μM when tested in HepG2 cells and HEK-293 cells, respectively. 50 (The therapeutic index is 0.94). In addition, one of the most well-known cancer drugs that kills dividing cells by interfering with the normal function of microtubule growth, paclitaxel (taxol), showed an IC of 7.5 μM and 27 μM when tested in HepG2 and HEK-293 cells, respectively. 50 (Therapeutic index is 3.6). Thus, the CellTiter-Glo 2.0 assay shows that one or more compounds of Formula (I) disclosed herein are more effective in killing cancer cells than sAJM589. In addition, one or more compounds of Formula (I) disclosed herein have a higher therapeutic index (and therefore will be a safer drug) than both sAJM589 and paclitaxel.

[0574] Example 5: Determination of the Effects of Test Compounds on Cell Viability and Apoptosis Using the ApoTox-Glo Triplex Assay

[0575] According to the following scheme, the effect of test compound on cell viability and apoptosis is determined using ApoTox-Glo triple assay kit (Promega G6320). Human cancer cell lines (e.g., HepG2) and non-cancerous cell lines (e.g., HEK-293) are seeded in 96-well plates with 20,000 cells per well. After 1 day, cells are treated with test compounds at various final concentrations (e.g., 10nM, 31.6nM, 100nM, 316nM, 1 μM, 3.16 μM, 10 μM, 20 μM, etc.). After 2 days of incubation, ApoTox-Glo triple assay is performed according to the protocol of the kit manufacturer. Briefly, 20 μL of viability / cytotoxicity reagent containing GF-AFC substrate (cell permeable substrate for measuring protease activity of live cells) and bis-AAF-R110 substrate (cell impermeable substrate for measuring protease activity of dead cells) was added to each sample and mixed briefly by orbital shaking (300 rpm-500 rpm, approximately 30 seconds). After incubation at 37°C for 30 minutes, the samples were shaken at two wavelengths (400 Ex / 505 Em ) and (485 Ex / 520 Em ) to evaluate the protease activity of live cells and dead cells, respectively. After measuring the protease activity of live cells and dead cells, 25 μl of luminescent DEVD-peptide substrate containing caspase-3 / 7 and caspase-Glo 3 / 7 reagent containing thermostable luciferase were added to each sample and briefly mixed by orbital shaking (1300rpm–1500rpm, about 30 seconds). After incubation at room temperature for 30 minutes, the luminescent signal was measured using a microplate reader. The luminescent signal is directly related to caspase-3 / 7 activity, which is a key indicator of apoptosis.

[0576] According to ApoTox-Glo triple assay, the cytotoxic effect of the test compound is calculated as follows. The live-dead ratio is calculated by dividing the fluorescent signal of the live cell protease activity by the fluorescent signal of the dead cell protease activity. The cytotoxic effect of the test compound under different concentrations is calculated by dividing the live-dead ratio of the sample treated with the compound by the live-dead ratio of the sample treated with no compound, only with the solvent (DMSO), and then subtracting the result from 1. Higher values ​​indicate that the cytotoxic effect of the test compound on the cell is larger (corresponding to the lower live-dead ratio assessed by the live cell protease activity and the dead cell protease activity), and vice versa. The IC value of the cytotoxic effect of each test compound in the HepG2 cell 50 The IC value was determined by plotting a dose-response curve to calculate the concentration of the test compound that produces half of the maximal cytotoxic effect. 50It is also measured in non-cancerous human cell lines (e.g., HEK-293) as a surrogate for healthy cells to determine the therapeutic window of the test compound (i.e., the concentration range in which the test compound selectively kills cancer cells but not healthy cells). The therapeutic index of a test compound is defined herein as its IC in HEK-293 cells. 50 Divided by its IC in HepG2 cells 50 The higher the therapeutic index, the safer and more useful the test compound is as a cancer drug in selectively killing cancer cells while minimizing side effects on healthy cells.

[0577] Table 6 provides the IC values ​​of specific test compounds when tested using the ApoTox-Glo Triplex Assay described above. 50 When tested using the ApoTox-Glo Triplex Assay described above, certain compounds of Formula (I) exhibit an IC of less than 10 μM, less than 1 μM, or less than 0.2 μM. 50 When tested using the ApoTox-Glo Triplex Assay described above, certain compounds of Formula (I) exhibited therapeutic indices greater than 1, greater than 10, or greater than 100. In contrast, one of the best-known MYC inhibitors, sAJM589, which acts by inhibiting the MYC-MAX protein-protein interaction, exhibited IC values ​​of 3 μM and 13.6 μM when tested in HepG2 and HEK-293 cells, respectively. 50 (Therapeutic index is 4.53). In addition, one of the most well-known cancer drugs that kills dividing cells by interfering with the normal function of microtubule growth, paclitaxel (taxol), showed IC values ​​of 2.6 μM and 6.9 μM when tested in HepG2 and HEK-293 cells, respectively. 50 (Therapeutic index is 2.65). Thus, the ApoTox-Glo triple assay shows that one or more compounds of Formula (I) disclosed herein are more effective in killing cancer cells than sAJM589. In addition, one or more compounds of Formula (I) disclosed herein have a higher therapeutic index (and therefore will be a safer drug) than both sAJM589 and paclitaxel.

[0578] The results of the ApoTox-Glo triple assay show that with the increase of sAJM589 and paclitaxel concentrations, the fold change of caspase 3 / 7 activation in HepG2 cells increases, indicating that the cytotoxic effects of sAJM589 and paclitaxel are mediated via apoptotic pathways. On the contrary, increasing the concentration of the compound of formula (I) disclosed herein leads to 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 non-apoptotic pathways. These results are consistent with the effect of the compound of formula (I) disclosed herein in reducing MYC protein levels (see Example 1), because it is known that MYC upregulates caspase activity, and MYC inhibition has been shown to cause non-apoptotic cancer cell death and growth stagnation (Fornari et al., Biochem.Pharmacol., 51 (7): 931-940 (1996)). The fold change of caspase 3 / 7 activation was calculated by dividing the luminescence signal of compound treated samples by the luminescence signal of samples without compound and treated with solvent only (DMSO). The fold change of caspase 3 / 7 activation after treatment of HepG2 cells with different concentrations of test compounds is reported in Table 7.

[0579] Example 6: Determination of in vivo efficacy of test compounds against cancer cells using a mouse hollow fiber model

[0580] The in vivo efficacy of test compounds (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 was determined using a 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 were added to the hollow fibers ( Implant membrane, green: batch number: 20051617, blue: batch number: 20008858, white: batch number: 20051615) and sealed at both ends. Three hollow fibers, each containing a different cancer cell line, were surgically implanted subcutaneously into both the left and right wings of the mouse (a total of six hollow fibers per mouse). Drug treatment began on day 0, i.e., day 3, after fiber implantation. Each treatment group had 2 mice (4 hollow fibers per cancer type) Group 1; vehicle control; Group 2: gemcitabine control administered intraperitoneally (ip) once every three days at 50 mg / kg; Group 3: test compound administered orally at 50 mg / kg once a day for 5 days. All animals were euthanized at the end of the 5th day of overdose CO2 treatment. Fibers were removed from mice and the cytotoxicity of the compounds to cells in the hollow fibers was determined using a modified MTT assay. Mean % net cell growth was calculated using the formula [(mean OD (day 5) - mean OD (day 0)) / (mean OD (day 0)) x 100%]. Mean % inhibition of cell growth by treatment was calculated relative to the mean % net cell growth of the day 5 vehicle control for the specific cancer cell line.

[0581] The results show that once a day, 50mg / kg of the test compound is orally administered for 5 days, effectively inhibiting the growth of MYC-driven cancers in vivo, such as TNBC, pancreatic cancer and liver cancer. The test compound shows the highest efficacy (88.2%) for TNBC growth inhibition, followed by pancreatic cancer (63.0%) and liver cancer (28.1%). The study shows that the test compound is effective for metastatic TNBC in vivo for which standard therapeutic drugs are ineffective (MDA-MB-231 is from metastatic TNBC patients and is generally used for modeling of advanced breast cancer). In a subsequent study inspired by the huge difference in HepG2 efficacy in vitro and in vivo, it was found that the efficacy of the test compound against 3 cancers in the hollow fiber model was underestimated because the test compound interacted with the MTT assay for evaluating 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 compounds against MDA-MB-231, Mia PaCa-2, and HepG2 by 2-fold, 3-fold, and 21-fold, respectively. Therefore, the true efficacy of the test compounds for growth inhibition of TNBC, pancreatic cancer, and liver cancer using the mouse hollow fiber model is expected to be >90% for all 3 cancers.

[0582] Based on gastrointestinal signs (e.g., abdominal distension, diarrhea, soft stools, bloody stools, constipation) and general clinical signs (e.g., lethargy, weight loss, salivation, hunched back, restlessness, dehydration, head tilt, lying down), once daily oral administration of 50 mg / kg of the test compound did not produce significant changes in body weight relative to the vehicle-treated group, nor did it cause any signs of toxicity in the treated mice. This provides early data confirming the safety of the test compound administered once daily for 5 days at a therapeutically effective dose.

[0583] Example 7: Determination of the in vivo efficacy of test compounds against cancer cells using a mouse xenograft model of TNBC

[0584] The in vivo efficacy of the 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 was determined using a mouse xenograft model of TNBC (MDA-MB-231). 5×10 6 MDA-MB-231 cells (in 0.2 ml of FBS-free medium containing 50% Matrigel) were injected into the subcutaneous tissue of each mouse. When the average tumor volume reached 100 mm 3 Treatment was started at 1:00 pm (day 0). Tumor-bearing mice were treated orally with vehicle and different doses of test compound (15 mg / kg, 35 mg / kg, 50 mg / kg and 100 mg / kg) once daily for 3 weeks. Tumor volume (mm) after cell implantation was measured every 2-3 days throughout the study. 3 ). At the end of the treatment period, a portion of the tumor tissue was resected and homogenized to analyze the level of the MYC biomarker using ELISA. Blood samples were collected from mice treated with the test compound 8 hours after the final dose.

[0585] The results show that treatment with the test compound resulted in a dose-dependent reduction in mean tumor volume compared to the vehicle control on day 21 (Table 8). This was associated with a dose-dependent increase in the test compound concentration in plasma and a dose-dependent decrease in the MYC biomarker level in the tumor after treatment with the test compound (Table 9). The histopathology of the tumor showed that treatment with the test compound resulted in a dose-dependent reduction in tumor cells, increased necrosis, and reduced angiogenesis compared to the vehicle. The reduction in tumor cell bodies and blood vessels in the treatment group compared to the vehicle control indicated tumor regression. Throughout the study, the weight and clinical signs of the animals were apparently normal, which confirmed that the test compound was safe when administered once a day at a therapeutically effective dose for 3 weeks.

[0586] surface

[0587] Table 1: Percent reduction of MYC protein by test compounds using HTRF assay

[0588]

[0589] Table 2: Percent reduction of MYC protein by test compounds using Western blot

[0590]

[0591] Table 3: Percent reduction of MYC RNA by test compounds using RT-qPCR

[0592]

[0593]

[0594] Table 4: IC values ​​of test compounds determined using CCK-8 assay 50 and therapeutic index

[0595]

[0596]

[0597] Table 5: Using CellTiter-Glo 2.0 Determination of IC of test compounds 50 and therapeutic index

[0598]

[0599] Table 6: IC of test compounds using ApoTox-Glo triplex assay 50 and therapeutic index

[0600]

[0601] Table 7: Fold changes in caspase 3 / 7 activation in HepG2 using the ApoTox-Glo triplex assay

[0602]

[0603] Table 8: Tumor volume over time after treatment with vehicle and different doses of test compound

[0604]

[0605] Table 9: Concentrations of test compounds in plasma and in tumors after treatment with different doses of test compounds MYC biomarker levels

[0606]

Claims

1. A compound of formula (I) and its pharmaceutically acceptable salts, tautomers, N-oxides and solvates: in A 1 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; A 2 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; R 1 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; R 2 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; or A 2 and R 2 Together they form C 1-7 -alkylene or C 2-7 -alkenylene; Z is for 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, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino; Wherein R B Substituents, if any, are covalently attached to any ring atom in place of hydrogen, provided that no more than R B the maximized valence of the ring atom to which it is attached; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13; Among them 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; The prerequisite is that j and k are not both 0 in the same compound.

2. The compound according to claim 1 and its pharmaceutically acceptable salt, tautomer, N-oxide and solvate, wherein j is 2 and k is 2, which is represented by formula (II): in A 1 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; A 2 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; R 1 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; R 2 is hydrogen, halogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; or A 2 and R 2 Together they form C 1-7 -alkylene or C 2-7 -alkenylene; Z is for 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; m is 0 or 1; R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino; Wherein R B Substituents, if any, are covalently attached to any ring atom in place of hydrogen, provided that no more than R B the maximized valence of the ring atom to which it is attached; d is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; Among them 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.

3. The compound according to claim 1 or claim 2 and its pharmaceutically acceptable salt, tautomer, N-oxide and solvate, wherein A 1 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; A 2 It is hydrogen, C 1-7 -alkyl, C 2-7 -Alkenyl, C 3-8 - cycloalkyl, aryl or heterocyclic group; R 1 is hydrogen or C 1-7 -alkyl; R 2 is hydrogen or C 1-7 -alkyl; h is 1; i is 1; m is 0, and the bridging A in formula (I) or (II) 1 and the Z part of N is A 1 Direct single covalent bond substitution between and N; R B is bromine, chlorine, fluorine or iodine; Wherein R B Substituents, if any, are covalently attached to any ring atom in place of hydrogen, provided that no more than R B the maximized valence of the ring atom to which it is attached; d is 0, 1, 2, 3, or 4; Among them 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.

4. The compound according to any one of claims 2 to 3, wherein Select from the group consisting of:

5. A compound according to any one of claims 1 to 4, wherein A 1 Select from the group consisting of: in R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino; One or more of R B Substituents can be covalently attached to A in place of hydrogen 1 any ring atom of R, including any one or two 6-membered rings, provided that no more than R B the maximized valence of the ring atom to which it is attached; q is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

6. A compound according to any one of claims 1 to 5, wherein A 1 Select from the group consisting of:

7. A compound according to any one of claims 1 to 6, wherein A 2 Select from the group consisting of: in R B represents a non-hydrogen substituent, where each R B Independently for deuterium, C 1-7 -alkyl (e.g., methyl, ethyl, propyl, isopropyl, etc.), C 3-8 - cycloalkyl (e.g., cyclopropyl, cyclobutyl, etc.), halo (e.g., bromine, chloride, fluorine or iodine), haloalkyl (e.g., monofluoromethyl, difluoromethyl, trifluoromethyl, etc.), cyano, methoxy, hydroxy, formyl, acetyl, 2-hydroxyacetyl, 2-hydroxypropionaldehyde, formamido, sulfonyl, methylsulfonyl, ethylsulfonyl, 1-methylformamido, N-ethylformamido or N,N-dimethylamino; One or more of R B Substituents can be covalently attached to A in place of hydrogen 2 Any ring atom of B the maximized valence of the ring atom to which it is attached; u is 0, 1, 2, 3, or 4.

8. A compound according to any one of claims 1 to 7, wherein A 2 Select from the group consisting of:

9. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 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-(3,5-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-(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; 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]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; 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- [(4-( ... 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-triazacyclo[8.4.0.03,8]tetradec-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)pyrazine-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-Benzo[ oxazol-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; tert-Butyl 4-[[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]methyl]piperidine-1-carboxylate; 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)sulfonylacetamide; 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-benzodihydro In-6-sulfonamide; N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]-3,5-dimethyl-1,2- Azole-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-Benzo oxazol-3-yl)-N-[2-[3-(2,4-dimethyl-1,3-thiazol-5-yl)-6-oxopyridazin-1-yl]ethyl]acetamide; 2-(1,3-Benzothiazol-2-ylsulfonyl)-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]propionamide; 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.

10. The compound according to any one of claims 1 to 9, wherein one or more hydrogens are replaced by deuterium.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 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 or tissues, the method comprising administering the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 to cells, animals or humans, so that the expression or activity of MYC is reduced.

13. A method for treating, preventing or ameliorating cancer in a subject, the method comprising administering to the subject a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11.

14. The method of claim 13, wherein the cancer is a MYC driven cancer.

15. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for reducing the expression or activity of MYC in a cell or tissue.

16. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 for treating, preventing or ameliorating cancer in a subject, particularly MYC-driven cancer.

17. A compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 for use in reducing the expression or activity of MYC in a cell or tissue.

18. The compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11, for use in treating, preventing or ameliorating cancer in a subject, particularly MYC-driven cancer.

19. Use of a compound according to any one of claims 1 to 10 or a pharmaceutical composition according to claim 11 in the manufacture of a medicament for reducing the expression or activity of MYC in a cell or tissue.

20. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 in the manufacture of a medicament for treating, preventing or ameliorating cancer, particularly MYC-driven cancer.

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