Compounds and methods for inhibiting poly(ADP-ribose) polymerases

Abstract

Described herein are compounds that inhibit poly(ADP-ribose) polymerase (PARP) and pharmaceutical compositions comprising the same. In certain embodiments, the compounds are suitable for treating, ameliorating, and / or preventing cancer. In certain embodiments, the compounds are suitable for treating, ameliorating and / or preventing neurodegenerative diseases and / or disorders, including but not limited to Parkinson's disease, Alzheimer's disease, Lewy body dementia, Alzheimer's disease related dementia or amyotrophic lateral sclerosis.

Description

[0001] TITLE Compounds and Methods for Inhibiting Poly(ADP-Ribose) Polymerases CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No.63 / 520,516, filed August 18, 2023, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This disclosure was made with government support under GM130302 and CA259037 awarded by the National Institutes of Health. The government has certain rights in the invention. SEQUENCE LISTING The XML file named “046483-7368WO1 - Sequence Listing.xml” created on July 17, 2024, comprising 5.5 KB, is hereby incorporated by reference in its entirety. BACKGROUND Poly (ADP-ribose) polymerases (PARPs) are a large family of enzymes that post- translationally catalyze poly (ADP-ribosyl)ation (PARylation) of acceptor proteins such as histones, transcription factors, and PARP itself. PARylation activity of these PARPs is essential for DNA damage repair. Several PARP inhibitors (PARPis) have been approved for treating certain cancers, and others are being evaluated for treating cancers. There are also indications from in vitro tests that PARPis may have beneficial effects in treating neurodegenerative diseases such as Alzheimer’s disease and related dementias (ADRDs), amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD), and Lewy body dementia / Parkinson’s disease (LBD / PD). Currently available PARPis, however; are not ideal for treating all types of cancers (especially brain cancers) or neurodegenerative diseases. Many of the PARPis have been shown to have off-target toxicities and suffer from, e.g., short serum half-life, cost, and resistance. In the case of treating neurodegenerative diseases with PARPis, the concentrations of the inhibitors required to achieve effective anti-neurodegenerative treatments as estimated from the cell-based experiments are likely too high to be considered safe. Therefore, there is a need to develop novel PARPis that are more effective in treating cancers and / or neurodegenerative diseases and do not have the adverse effects of the currently available PARPis or have milder adverse effects comparing to the currently available PARP inhibitors. The present invention addresses this need. BRIEF SUMMARY In one aspect, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R1a, R1b, R1c, R2a, R2b, R2c, and R3are defined elsewhere herein: In certain embodiments, the compound of Formula (I) has a structure of Formula (II), wherein R1a, R1b, R1c, R2a, R2b, R2c, and R4are defined elsewhere herein: In certain embodiments, the compound of Formula (I) has a structure of Formula (III), wherein R1a, R1b, R1c, R2a, R2b, R2c, R4, m, na, and nb are defined elsewhere herein: .In certain embodiments, the compound of Formula (I) has a structure of Formula (IVA), wherein R1a, R1b, R1c, R2a, R2b, R2c, and R4are defined elsewhere herein: . In certain embodiments, the compound of Formula (I) has a structure of Formula (IVB), wherein R1a, R1b, R1c, R8are defined elsewhere herein: . In certain embodiments, the compound of Formula (I) has a structure of Formula (V), wherein R1a, R1b, R1c, and R7, and p are defined elsewhere herein: In certain embodiments, the compound of Formula (I) has a structure of Formula (VI), wherein R1a, R1b, R1c, R2a, R2b, R2c, R7, m, na, nb, and p are defined elsewhere herein: . In certain embodiments, the compound of Formula (I) has a structure of Formula (VII), wherein R1a, R1b, R1c, and R7are defined elsewhere herein:

[0002] In certain embodiments, the compound of Formula (I) has a structure of Formula (VIII), wherein R1a, R1b, R1c, R7, R8, L1, and p are defined elsewhere herein: In another aspect, the disclosure provides a pharmaceutical composition comprising at least one compound of the disclosure, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, and at least one pharmaceutically acceptable carrier. In another aspect, the disclosure provides a method of inhibiting at least one PARP, the method comprising contacting the PARP with the compound of the disclosure, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of the disclosure. In another aspect, the disclosure provides a method of treating, ameliorating, and / or preventing a PARP-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the disclosure, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of the disclosure. BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. FIGs.1A-1B: Veliparib core scaffold modifications modulate PARP1 allostery. FIG. 1A: representative FP DNA competition assay showing that UKTT15 (15) increases PARP1 retention on DNA damage similar to EB-47. Compounds 75, 77, and 82 have a milder effect while compound 65 does not appear to promote PARP1 retention and might even disfavor retention (bottom); average percentage of PARP1 bound at 200 s (top). FIG.1B: representative FP DNA binding assay showing that UKTT15 (15) increases PARP1 DNA binding affinity. Again, compounds 75 and 77 mildly increase PARP1 affinity while compounds 65 and 82 show little to no difference. Average KD values derived from the FP DNA binding assay. FIGs.2A-2G: Crystal structures of target compounds bound to CATΔHD. FIG.2A: crystal structure of PARP1 apo CAT domain (beige, PDB: 7AAA) with the nicotinamide binding pocket (N) and adenosine binding pocket (A) of PARP1 active site highlighted in green. FIG.2B: crystal structure of EB-47 bound to PARP1 CAT domain (PDB: 6VKQ). EB- 47 contacts both the nicotinamide binding pocket and the ADP-ribose binding pocket. FIG. 2C: crystal structure of UKTT15 (15) bound to PARP1 CAT domain (PDB: 6VKO). UKTT15 (15) does not contact the ADP-ribose binding pocket, but rather occupies a pocket in between helix αF and αD in the HD and the active site loop (ASL) in the ART fold. FIGs. 2D-2F: crystal structures of compounds 75 (FIG.2D), 82 (FIG.2E) and 65 (FIG.2F) bound to their respective PARP1 CATΔHD domain. The HD of PARP1 is represented after having overlayed the structure of PARP1 apo CAT domain (PDB: 7AAA). (G) Compounds 75, 82, and 65 with a 2FO-FC weighted electron density overlaid. FIGs.3A-3F: Compound 75 contacts helices αD and αF of the HD. FIG.3A: the ΔVE / compound 75 structure was determined at 3.9 Å (one of the two complexes in the asymmetric unit is shown). FIG.3B: the CATΔHD / compound 75 structure is superposed to the CAT domain of the ΔVE structure highlighting that the compound contacts helices αD and αF of the HD following a rearrangement of its benzimidazole group (FIG.3C). FIG.3D: compound 75 with a 2FO-FC weighted electron density overlaid. FIG.3E: surface representation of the CAT domain structure of compound 75 bound to ΔVE highlighting that the compound substituent is buried at the interface of helices αD and αF and the ASL. FIG. 3F: surface representation of the CAT domain structure of UKTT15 (15) bound to the CAT domain (PDB 6VKO) highlighting that the compound contributes to a groove in between helices αD and αF and the ASL and remains accessible to the solvent. FIGs.4A-4G: Hydrogen / deuterium exchange-mass spectrometry (HXMS). FIG.4A: HXMS difference plots between PARP1 / DNA complex and PARP1 / DNA / 75 complex at 100 s. The consensus HX difference plot for the binding of the 75 and UKTT15 (15) is shown on the top for comparison. FIG.4B: HXMS difference plots between PARP1 / DNA complex and PARP1 / DNA / 65 complex at 100 s. The consensus HX difference plot for the binding of the 65 is shown on the top. FIG.4C: HXMS difference plots between PARP1 / DNA complex and PARP1 / DNA / 82 complex at 100 s. The consensus HX difference plot for the binding of the 82 is shown on the top. For panels FIGs.4A-4C, each thin horizontal bar represents a PARP1 peptide. FIG.4D: panels (i-iv) represents the HX of the representative peptides of Zn3, WGR, αB, and αF for PARP1+DNA, and PARP1+DNA+PARPi. An average from three replicates with SD represented by error bars and asterisks indicating P <0.05 from two-sided t-test between PARP1+DNA and PARP1+DNA+PARPi is shown. Purple dotted line indicates maxD i.e., number of residues minus first two residues (back-exchange within experimental timescale) and minus number of prolines due to no backbone amide hydrogen. FIG.4E: consensus HXMS percentage differences with compounds 75 mapped to the crystal structure of PARP1 on DNA damage (PDB 4DQY). FIG.4F: consensus HXMS percentage differences with compound 65 mapped to the crystal structure of PARP1 on DNA damage (PDB 4DQY). FIG.4G: consensus HXMS percentage differences with compound 82 mapped to the crystal structure of PARP1 on DNA damage (PDB 4DQY). FIGs.5A-5K: PARP1 dose-response curves for certain exemplary compounds of the present disclosure and veliparib. FIG.6A: SDS-PAGE activity assay showing PARP1 inexistant or greatly reduced catalytic activity in the presence of veliparib, EB-47, and certain exemplary compounds of the present disclosure. FIG.6B: additional representative curves for FP DNA competition assay comparing PARP1 release from DNA damage in the presence of veliparib, EB-47, and certain exemplary compounds of the present disclosure. FIG.6C: additional representative curves for FP DNA binding assay to monitor PARP1 DNA damage binding affinity in the presence of veliparib, EB-47, and certain exemplary compounds of the present disclosure. DETAILED DESCRIPTION Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of “about 0.1% to about 5%” or “about 0.1% to 5%” should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement “about X to Y” has the same meaning as “about X to about Y,” unless indicated otherwise. Likewise, the statement “about X, Y, or about Z” has the same meaning as “about X, about Y, or about Z,” unless indicated otherwise. In this document, the terms “a,” “an,” or “the” are used to include one or more than one unless the context clearly dictates otherwise. The term “or” is used to refer to a nonexclusive “or” unless otherwise indicated. The statement “at least one of A and B” or “at least one of A or B” has the same meaning as “A, B, or A and B.” In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are described. As used herein, each of the following terms has the meaning associated with it in this section. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, pharmacology, and organic chemistry are those well-known and commonly employed in the art. Description PARP-mediated cancer Poly (ADP-ribose) polymerases (PARPs) are a large family of enzymes that post- translationally catalyze poly (ADP-ribosyl)ation (PARylation) of acceptor proteins such as histones, transcription factors, and PARP itself. PARylation activity of these PARPs is essential for DNA damage repair. Among the seventeen known PARP-isoforms, nuclear DNA damage repair enzyme PARP-1, the founding member of this family, is clinically validated as an anticancer drug target. PARP inhibitors (PARPis) are useful for the treatment of cancers through at least two mechanisms: (1) by increasing tumor sensitivity to cytotoxic drugs that damage DNA, and (2) by inducing “synthetic lethality” in cancer cells that are highly dependent on PARP function, due to deficiency in homologous recombination (HR) DNA double-strand-break (DSB) repair pathway such as in BRCA1 / BRCA2 mutations. Four PARPis (olaparib or 4-[(3-[(4-cyclopropylcarbonyl)piperazin-1-yl]carbonyl)-4- fluorophenyl]methyl(2H)phthalazin-1-one; niraparib or 2-[4-[(3S)-3-piperidyl]phenyl]indazole- 7-carboxamide; rucaparib or 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro- 6H-azepino[5,4,3-cd]indol-6-one); and talazoparib ((8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1- methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one) were recently approved by the US FDA as single agents to treat HR-defective cancers and in combination therapy with other cytotoxic drugs. Veliparib (2-((R)-2-methylpyrrolidin-2-yl)-1H- benzimidazole-4-carboxamide) is currently undergoing advanced clinical trials as a combination therapy in cancer patients. Although PARPis have been useful in treating triple negative breast cancer or TNBC (which to some extent also mimics BRCA1 mutant phenotype), overexpression of PARP-1 in these cancers produces less than desirable synthetic lethality. Furthermore, some of these clinical PARP inhibitors are substrates of ABC transporters and suffer from short serum half-life, cost, resistance, and off-target toxicities such as hematologic toxicity. Moreover, veliparib has relatively low selectivity among the PARP family, particularly to TNKS-1 and TNKS-2, which may raise clinical safety concerns. Further, veliparib is a catalytic inhibitor of PARP-1 and has been shown to possess very poor PARP-trapping efficiency, which has been known to produce potent cytotoxicity in vitro and in vivo. Unfortunately, a substantial proportion of cancers develop resistance to veliparib treatment subsequent to initial response. PARP-mediated neurodegenerative disease(s) and / or disorder(s) The human PARP family of proteins includes >17 members with distinctive multi- domain structures and diverse roles in a wide variety of cellular processes. Of which, PARP-1, PARP-2, TNKS1 / PARP5a, and TNKS2 / PARP5b catalyze the addition of poly(ADP-ribose) (PAR) chains. The most studied PARP enzyme is PARP-1, whose catalytic activity is acutely stimulated upon binding to DNA breaks in the cellular response to DNA damage. PARPs activate DNA repair in response to oxidative DNA damage by mediating the attachment of PAR polymers on itself (auto-modification) and other proteins (hetero-modification). PARP-1 is responsible for the 90% of the NAD+-dependent synthesis of PAR polymers. DNA single-strand break (SSB) repair and protein post-translational modifying PARPs plays an important role in the cellular defense against oxidative stress. Overactivation of PARPs in response to oxidative DNA SSBs causes depletion of NAD+and ATP leading to necrotic dopamine (DA) neuronal cell death. One of the prominent mechanisms underlying PD is the toxic drain of cellular energy pools through NAD+consumption. This leads to disruption of mitochondrial bioenergetics and alteration in the redox state of the complex I substrate NAD+. Several reports indicated beneficial effects of PARP inhibitor (PARPi) use in in vitro models of Alzheimer’s Disease and related dementias (ADRDs), including Alzheimer’s Disease (AD), amyotrophic lateral sclerosis / frontotemporal dementia (ALS / FTD), and Lewy body dementia / Parkinson’s Disease (LBD / PD). Transactive response DNA binding protein 43 kDa (TDP-43) is an abundant nuclear protein that is mislocalized to the cytoplasm of degenerating neurons in ALS / FTD patients, where it undergoes a liquid-to-solid state transition from liquid- liquid phase separation (LLPS) and forms insoluble protein aggregates. TDP-43 inclusions are found in approximately 97% of ALS patients and >40% of FTD patients, thus serving as a key pathological hallmark for both diseases. Further, hippocampal atrophy in AD is associated with the abundance of TDP-43. Further evidence suggested that Tau and TDP-43 misfolded proteins were co-localized in neuronal cells. TDP-43 noncovalently binds to PAR polymers via PAR-binding motifs embedded in the nuclear localization signal of TDP- 43. TDP-43-PAR interaction promotes LLPS of TDP-43 and is required for pathologic accumulation of TDP-43 in stress granules in mammalian neurons. Inhibition of PARPs has been shown to reduce TDP-43 recruitment in stress granules and combined inhibition of PARP1 / 2 and TNKS resulted in decreased formation of cytoplasmic inclusions of TDP-43. Based on this concept, PARPi veliparib and olaparib were able to reduce PAR levels and partially rescue TDP-43-induced cell death in neuronal cells. TNKS2 inhibitor, XAV939, also partially rescued the accumulation of TDP-43 in cytoplasmic foci. The use of 5 µM concentration of these inhibitors to achieve partial rescue in cell-based experiments significantly exceeded the biochemical IC50 values reported for PARP inhibition. As a result, high (potentially toxic) oral doses would be required for existing PARPi to serve as effective anti-neurodegenerative treatments. Moreover, existing PARPi strongly trap PARP-1 on DNA breaks, a cause for cellular toxicity. Thus, there exists a need for the development of more effective and safer PARPi. As described above, NAD+also serves as a co-enzyme for PARP enzymatic activity, and PARP1 is a major NAD+-consuming nuclear enzyme involved in repairing cellular DNA SSBs. Prolonged activation of PARP leads to reduced cellular NAD+pools, which in turn results in ATP depletion and bioenergetics collapse. High PARP activity causes loss of DA neurons and mitochondrial dysfunction. The pathological hallmark of PD is the presence of Lewy bodies that are accumulations of the protein α-synuclein. α-Synuclein noncovalently binds to PAR through its basic N-terminus and this interaction leads to the formation of more toxic α-synuclein fibrils (more potent fibril strain) that is also readily transmitted to nearby cells. Pathologic α-synuclein via feed-forward mechanism activates PARP1 and increases PAR levels leading to acceleration of the formation of pathologic α-synuclein and PARP1-mediated cell death. Increased PAR levels in the cerebrospinal fluid and brains of patients suggests that PARP activation is involved in the pathogenesis of PD. PARP activation and dopaminergic neuron loss has been shown in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, a selective complex I inhibitor) and other neurotoxins-induced Parkinsonism in mouse models. Overactivation of PARP-1 also contributes to the PAR-mediated translocation of mitochondrial protein apoptosis-inducing factor (AIF) into the nucleus to induce caspase- independent programmed cell death (Parthanatos) that occurs in PD. PARP-1 gene knockout mice were rescued from MPTP-induced neurotoxicity. Potent PARPi demonstrated amelioration of MPP+(active form of MPTP)- and α-synuclein-induced cytotoxicity in in vitro and in vivo PD models. PARPi attenuated toxin-induced neurotoxicity in animal models of PD. These preclinical findings clearly demonstrated the therapeutic potential of novel anti-trapping brain- penetrable least cytotoxic PARPi in PD. Consequently, inhibiting PARP activity or supplying NAD+-containing dietary supplements leads to improved mitochondrial function and PD-related phenotypes and also prevent degeneration of DA neurons in the substantia nigra pars compacta. Repurposing of novel PARPi for non-oncological indications such as neurodegenerative diseases will require conceptual changes in how PARPi targeted to these diseases are designed. Unlike PARPi used in the cancer clinic, (i) newly developed PARPi must efficiently cross the blood-brain-barrier (BBB), (ii) unlike PARP-trapping (PARP poisoning) that leads to cell death as a desirable property to treat cancers, new PARPi targeted to the brain for treating ADRDs should be pure catalytic PARPi that do not accelerate PARP-trapping potential in order to ensure acceptable therapeutic index, (iii) unlike existing PARPi, new PARPi should be PARP- 1 / 2 / TNKS-isoform selective, and (iv) new PARPi should not be substrates of ABC transporters located in the BBB to ensure delivery of therapeutically effective amounts of PARPi into the brain. This disclosure thus expands the disease-modifying potential of PARPi to treat neurodegenerative diseases for which no cure is currently available. In a non-limiting aspect, the present study relates to the discovery that PARPis can be specifically designed such that the inhibitors are able to “trap” the PARP protein allosterically at a DNA break, or does not do so. Without wishing to be limited by any theory, PARPis that allosterically trap PARP proteins at DNA breaks causes robust cytotoxicity and is sometimes more desirable for being used as anti-cancer agents, as treating cancers requires cancer cells to be killed. Without wishing to be limited by any theory, PARPis that do not allosterically trap PARP proteins at DNA breaks causes significantly less cytotoxicity and is sometimes more desirable for being used to treat neurodegenerative diseases, as neurons and other types of cells are not supposed to be damaged when treating neurodegenerative diseases. In another non-limiting aspect, the present study further realized that PARPis able to cross the blood-brain barrier simplifies the delivery of compounds when treating, ameliorating, and / or preventing neurodegenerative diseases. Based on such realizations, the present invention developed a series of PARPis useful in treating, ameliorating, and / or preventing cancer and / or have disease-modifying modalities for neurodegenerative diseases. Accordingly, in aspects, the present invention is directed to PARPis useful for treating, ameliorating, and / or preventing a cancer, as well as compositions / kits including the same and methods thereof. In some aspects, the present invention is directed to PARPis useful for treating, ameliorating and / or preventing a neurodegenerative disease, as well as compositions / kits including the same and methods thereof. Definitions The term “about” as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. A disease or disorder is “alleviated” if the severity or frequency of at least one sign or symptom of the disease or disorder experienced by a patient is reduced. As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group comprising at least one carbon atom connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. In certain embodiments, alkoxy includes (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy. Unless stated otherwise, the alkoxy may be optionally substituted. As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbon atoms). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Certain specific examples include (C1-C6)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n- hexyl and cyclopropylmethyl. Unless stated otherwise, alkyl may be optionally substituted. The term “alkylene” or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia). In certain embodiments, the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g., -CH2-) different (e.g., -CH2CH2-) carbon atoms. As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized ∏ (pi) electrons, where n is an integer. As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings, wherein at least one ring is aromatic) wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. In certain embodiments, aryl includes phenyl and naphthyl. Unless stated otherwise, aryl may be optionally substituted. As used herein, the term “binding” refers to the adherence of molecules to one another, such as, but not limited to, enzymes to substrates, antibodies to antigens, DNA strands to their complementary strands. Binding occurs because the shape and chemical nature of parts of the molecule surfaces are complementary. A common metaphor is the “lock-and-key” used to describe how enzymes fit around their substrate. The term “cancer” as used herein refers to an abnormal growth of cells that tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). The types of cancer contemplated herein include, but are not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma), ovary) or other endocrine organ (thyroid, pancreas), prostate, skin (melanoma), hematological tumors (such as leukemia) or multiple myeloma. As used herein, the term “cycloalkyl,” by itself or as part of another substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e., C3-C6 means a cyclic group comprising a ring group consisting of three to six carbon atoms). Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Certain specific examples include (C3-C6)cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless stated otherwise, cycloalkyl may be optionally substituted. The term “cycloalkylene” or “cycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical (e.g., , inter alia). In certain embodiments, the term may be regarded as a product of removal of two hydrogen atoms from the corresponding cycloalkane (e.g., cyclobutyl) by removal of two hydrogen atoms from the same (e.g., different (e.g., carbon atoms. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. Except where this distinction is important, disease and disorder are used interchangeably herein. An “effective amount” or “therapeutically effective amount” of a compound is that amount of compound sufficient to provide a beneficial effect to the subject to which the compound is administered. As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. In some embodiments, halogen is fluorine, chlorine, or bromine. In some embodiments, halogen is fluorine or chlorine. As used herein, the term “haloalkyl” as used by itself or as part of another group refers to an alkyl substituted with one or more independently selected fluorine, chlorine, bromine and / or iodine atoms. In some embodiments, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In some embodiments, the haloalkyl group is a C1-10haloalkyl group. In some embodiments, the haloalkyl group is a C1-6 haloalkyl group. In some embodiments, the haloalkyl group is a C1-4 haloalkyl group. As used herein, the term “heteroalkyl” by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group comprising carbon atoms and one or more heteroatoms selected from the group consisting of O, N, and S, and wherein the N and S atoms may be optionally oxidized, and the N heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and - CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2- NH-OCH3, or -CH2-CH2-S-S-CH3. Unless stated otherwise, heteroalkyl may be optionally substituted. The term “heteroarylene” or “heteroarylenyl” as used herein refers to a bivalent heteroaryl radical (e.g., 2,4-pyridylene). In certain embodiments, the term may be regarded as a divalent radical formed by the removal of two hydrogen atoms from one or more rings of a heteroaryl moiety, wherein the hydrogen atoms may be removed from the same or different rings, preferably the same ring. The term “heterocycloalkyl” as used herein refers to a unsubstituted or substituted, stable, mono- or multi-cyclic ring system that contains at least one carbon atom and one to six heteroatoms selected from the group consisting of N, O, and S, and wherein the N and S heteroatoms may be optionally oxidized, and the N atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure. Unless stated otherwise, heterocyclyl may be optionally substituted. The term heterocycloalkyl group can also be a C2 heterocycloalkyl, C2-C3 heterocycloalkyl, C2-C4heterocycloalkyl, C2-C5heterocycloalkyl, C2-C6heterocycloalkyl, C2-C7heterocycloalkyl, C2-C8heterocycloalkyl, C2-C9heterocycloalkyl, C2-C10heterocycloalkyl, C2- C11 heterocycloalkyl, and the like, up to and including a C2-145 heterocycloalkyl. For example, a C2 heterocycloalkyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocycloalkyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, and the like. It is understood that a heterocycloalkyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocycloalkyl ring. The heterocycloalkyl group can be substituted or unsubstituted. The term “heterocycloalkylene” or “heterocycloalkylenyl” as used herein refers to a bivalent saturated cycloalkyl radical (e.g., , inter alia). In certain embodiments, the term may be regarded as a product of removal of two hydrogen atoms from the corresponding heterocycloalkane (e.g., piperidine) by removal of two hydrogen atoms from the same (e.g., ) different (e.g., ) carbon atom(s) and / or heteroatom(s). Non-limiting examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin and hexamethyleneoxide. As used herein, the term “heteroaryl” or “heteroaromatic” refers to a 5- to 20-membered heterocycle having aromatic character. The ring one to thirteen carbon atoms, one to six heteroatoms independently selected from nitrogen, oxygen, and sulfur. A heteroaryl may include one or more rings, provided that at least one ring is aromatic. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Non-limiting examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl. Non-limiting examples of polycyclic heteroaryls include indolyl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8- naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2- benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5- benzothiazolyl), purinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl. As used herein, the IC50refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of PARP, in an assay that measures such response. The phrase “inhibit,” as used herein, means to reduce a molecule, a reaction, an interaction, a gene, an mRNA, and / or a protein’s expression, stability, function, or activity by a measurable amount or to prevent entirely. Inhibitors are compounds that, e.g., bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate a protein, a gene, and an mRNA stability, expression, function, and activity, e.g., antagonists. As used herein, the terms “poly (ADP-ribose) polymerase” or “PARP” refers to the family of the enzyme poly (ADP-ribose) polymerase that includes approximately 18 proteins, particularly poly (ADP-ribose) polymerase-1 (PARP-1) and / or poly (ADP-ribose) polymerase-2 (PARP-2). The phrase “PARP inhibitor” as used herein refers to a composition or compound that reduces at least in part, as compared to a control system that lacks the inhibitor, PARP activity, PARP expression or both, either directly or indirectly, using any method known to the skilled artisan. In certain embodiments, the presence of an inhibitor results in complete inhibition of PARP. As used herein, a “PARP-modulated disease” refers to a disease associated with excess PARP activity (cancer and inflammatory disorders) or a pathological lack of PARP activity (genotoxicity). The terms “patient,” “subject,” “individual,” and the like are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In certain non-limiting embodiments, the patient, subject or individual is a human. As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the disclosure within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the disclosure, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the disclosure, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the disclosure. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the disclosure are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. As used herein, the language “pharmaceutically acceptable salt” or “therapeutically acceptable salt” refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. Unless specified otherwise, all groups disclosed herein may be optionally substituted. For example, reference to heterocyclyl, such as piperidin-3-yl herein is understood to include both unsubstituted and substituted piperidin-3-yl. The term “substituted” as applied to the groups described herein refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In certain embodiments, the substituents vary in number between one and four. In other embodiments, the substituents vary in number between one and three. In yet another embodiments, the substituents vary in number between one and two. In certain embodiments, the substituents are independently selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)-C1-C6 alkyl, C1- C6haloalkyl, C1-C6haloalkoxy, halo, cyano (-CN), -ORa, optionally substituted aryl (e.g., phenyl-(C1-C3 alkyl)-, such as, but not limited to, benzyl or substituted benzyl), optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(=O)ORa, -OC(=O)Ra, -SRa, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -N(Ra)S(=O)2Ra, -NO2, -N(Ra)C(=O)Ra, -C(=O)NRaRa, and -N(Ra)(Ra), wherein each occurrence of Rais independently H, optionally substituted C1-C6alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Ragroups combine with the N to which they are bound to form a heterocycle In certain embodiments, each occurrence of alkyl, cycloalkyl, heterocycloalkyl, alkynyl, alkenyl, and heterocycloalkenyl is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, halo, cyano (- CN), -ORa, optionally substituted phenyl (thus yielding, in non-limiting examples, optionally substituted phenyl-(C1-C3 alkyl), such as, but not limited to, benzyl or substituted benzyl), optionally substituted heteroaryl, optionally substituted heterocyclyl, -C(=O)ORa, -OC(=O)Ra, - SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRa, -N(Ra)S(=O)2Ra, -N(Ra)C(=O)Ra, -C(=O)NRaRa, and -N(Ra)(Ra), wherein each occurrence of Rais independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Ragroups combine with the N to which they are bound to form a heterocycle. In certain embodiments, “substituted alkyl” or “substituted cycloalkyl” means alkyl or cycloalkyl, as defined above, substituted by one, two or three substituents, including but not limited to halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -N(CH3)2, (1-methyl-imidazol-2- yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C1- C4)alkyl, -C(=O)NH2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SO2NH2, - C(=NH)NH2, and -NO2. In some embodiments, the alkyl or cycloalkyl contains one or two halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, In some embodiments, the alkyl or cycloalkyl contains halogen, alkoxy and -OH. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl. In certain embodiments, each occurrence of aryl, heteroaryl, heteroarylenyl, and heterocyclyl, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 hydroxyalkyl, (C1-C6 alkoxy)-C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, halogen, -CN, -ORa, -N(Ra)(Ra), -NO2, - C(=O)N(Ra)(Ra), -C(=O)ORa, -OC(=O)Ra, -SRa, -S(=O)Ra, -S(=O)2Ra, -N(Ra)S(=O)2Ra, - S(=O)2N(Ra)(Ra), acyl, and C1-C6 alkoxycarbonyl, wherein each occurrence of Rais independently H, C1-C6 alkyl, or C3-C8 cycloalkyl, wherein in Rathe alkyl or cycloalkyl is optionally substituted with at least one selected from the group consisting of halogen, -OH, C1- C6alkoxy, and heteroaryl; or substituents on two adjacent carbon atoms combine to form - O(CH2)1-3O-. In certain embodiments, the alkyl, cycloalkyl, heteroaryl, heterocyclyl, aryl, or benzyl group is optionally independently substituted with at least one group selected from the group consisting of C1-C6 alkyl; C1-C6 alkoxy; C1-C6 haloalkyl; C1-C6 haloalkoxy; -NH2, -NH(C1-C6 alkyl), -N(C1-C6alkyl)(C1-C6alkyl), halogen, -OH; -CN; phenoxy, -NHC(=O)H, -NHC(=O)C1- C6alkyl, -C(=O)NH2, -C(=O)NHC1-C6alkyl, -C(=O)N(C1-C6alkyl)(C1-C6alkyl), tetrahydropyranyl, morpholinyl, -C(=O)CH3, -C(=O)CH2OH, -C(=O)NHCH3, -C(=O)CH2OMe, or an N-oxide thereof. As used herein, “treating”, “treatment”, “treating a disease or disorder” or the like means reducing the frequency with which a symptom of the disease or disorder is experienced by a patient. It further encompasses therapy. Accordingly, the compositions and methods of the present disclosure can be used in applications. Therefore “treating” or “treatment” of a state, disorder or condition includes: (i) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (ii) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms. Ranges: throughout this disclosure, various aspects may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Compounds In one aspect, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof: . In certain embodiments, the compound of Formula (I) is a compound of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: . In certain embodiments, the compound of Formula (I) is a compound of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: .In certain embodiments, the compound of Formula (I) is a compound of Formula (IVA), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: . In certain embodiments, the compound of Formula (I) is a compound of Formula (IVB), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: . In certain embodiments, the compound of Formula (I) is a compound of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: , In certain embodiments, the compound of Formula (I) is a compound of Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof:

[0003] , In certain embodiments, the compound of Formula (I) is a compound of Formula (VII), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: In certain embodiments, the compound of Formula (I) is a compound of Formula (VIII), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof: . In certain embodiments, The compound of Formula (I), (II), or (V) is not methyl 2-(4-(4- (4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5-carboxylate. R1a, R1b, and R1cIn certain embodiments, R1a, R1b, and R1cin the compound of Formula (I), (II), (III), (IVA), (IVB), (V), (VI), (VII), and (VIII) are each independently selected from the group consisting of H, C1-C6 alkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB). In certain embodiments, at least one of R1a, R1b, and R1cis H. In certain embodiments, at least two of R1a, R1b, and R1care H. In certain embodiments, each of R1a, R1b, and R1care H. In certain embodiments, R1aand R1bare H and R1cis F. In certain embodiments, R1a, R1b, and R1care each H. In certain embodiments, R1ais H. In certain embodiments, R1ais F. In certain embodiments, R1bis H. In certain embodiments, R1bis F. In certain embodiments, R1cis H. In certain embodiments, R1cis F. R2a, R2b, and R2cIn certain embodiments, R2a, R2b, and R2cin the compound of Formula (I), (II), (III), and (IVA), are each independently selected from the group consisting of H and C1-C6alkyl. In certain embodiments, R2ais H. In certain embodiments, R2bis H. In certain embodiments, R2cis H. R3In certain embodiments, R3in the compound of Formula (I) is . In certain embodiments, A is selected from the group consisting . In certain embodiments, L1is selected from the group consisting of a bond, -C(=O)-, - C(=O)N(R6)-, and -C(=O)N(R6)-C1-C3alkylenyl-. In certain embodiments, L2is selected from the group consisting of a bond, -C2-C8 heterocycloalkylenyl-, and -C2-C8heteroarylenyl-. In certain embodiments, R4is selected from the group consisting of H, C1-C6alkoxy, -C2- C8 heterocycloalkyl, -C6-C10 aryl, and heteroaryl, wherein the -C2-C8 heterocycloalkyl is independently substituted with 0, 1, 2, or 3 of R8or R9, and each of -C6-C10 aryl and heteroaryl is independently substituted with 0, 1, 2, or 3 of R7or R9. In certain embodiments, when both L1and L2are a bond, R4is not H. In certain embodiments, L2and R4can combine with the atoms to which they are bound to form a monocyclic or bicyclic C2-C12heterocyclyl substituted with 0, 1, 2, or 3 R7. A In certain embodiments of Formula (I), A is selected from the group consisting of . , . In certain embodiments, . L1In certain embodiments of Formula (I) or (VIII), L1in the compound of Formula (I) and (VIII) is selected from the group consisting of a bond, -C(=O)-, -C(=O)N(R6)-, and - C(=O)N(R6)-C1-C3 alkylenyl-. In certain embodiments, L1is . In certain embodiments, L1 is . In certain embodiments, L1is . In certain embodiments, L1is . L2In certain embodiments of Formula (I), L2in the compound of Formula (I) is selected from the group consisting of a bond, -C2-C8 heterocycloalkylenyl-, and -C2-C8 heteroarylenyl-. In certain embodiments, L2is . In certain embodiments, L2is . In certain embodiments, L2is . In certain embodiments, L2is . In certain embodiments, L2is . In certain embodiments, L2is . In certain embodiments, L2is . In certain embodiments, L2is . In certain embodiments, . R5a, R5b, R5c, and R5dIn certain embodiments of Formula (I), R5a, R5b, R5c, and R5din the compound of Formula (I) are each independently selected from the group consisting of H, C1-C6 alkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB). In certain embodiments, R5ais H. In certain embodiments, R5bis H. In certain embodiments, R5cis H. In certain embodiments, R5dis H. R6In certain embodiments, R6in the compound of Formula (I) and (VIII) is selected from the group consisting of H and C1-C6alkyl. In certain embodiments, R6is H. RAand RBIn certain embodiments, each occurrence of RAand RBis independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10aryl, and heteroaryl. In certain embodiments, each occurrence of RAand RBis independently H or C1-C6 alkyl. occurrence of RAand RBis independently H. R4In certain embodiments, R4in the compound of Formula (I), (II), (III), and (IVA) is selected from the group consisting of H, C1-C6 alkoxy, -C2-C8 heterocycloalkyl, -C6-C10 aryl, and heteroaryl, wherein the -C2-C8heterocycloalkyl is independently substituted with 0, 1, 2, or 3 of R8or R9, and each of -C6-C10aryl and heteroaryl is independently substituted with 0, 1, 2, or 3 of R7or R9. In certain embodiments, R4is selected from the group consisting of H, C1-C6 alkoxy, s . In certain embodiments, R4is . In certain embodiments, R4 . R4-R7In certain embodiments, R4comprises R7substitution. In such embodiments, R4refers to the combination of R4and R7. In certain embodiments, R4is H. In certain embodiments, R4is OCH3. In certain embodiments, R4is . In certain embodiments, R4is . In certain embodiments, . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, R4is . In certain embodiments, embodiments, R4is certain embodiments, R4is . In certain embodiments, . In certain embodiments, R4is . In certain embodiments, R4is . In certain * embodiments, R4is . In certain embodiments, R4is . In certain embodiments, R4is . In certain embodiments, . certain embodiments, R4is . In certain embodiments, R4is . In certain embodiments, certain embodiments, embodiments, certain embodiments, certain embodiments, certain embodiments, R4is embodiments, certain embodiments, . In certain embodiments, certain embodiments, R4is In certain embodiments, R4 embodiments, . certain embodiments, . n certain embodiments, certain embodiments, n certain embodiments, certain embodiments, R4is , L2and R4In certain embodiments, L2and R4in the compound of Formula (I) combine to form . R7In certain embodiments of Formula (I), (II), (III), (IVA), (V), (VI), (VII), or (VIII), R7is independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C2-C6 alkynyl, C2-C8 heterocycloalkyl, C2-C8 hydroxyheterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD). In certain embodiments, R7is CH3. In certain embodiments, R7is CH2OH. In certain embodiments, R7is CH(OH)CH3. In certain embodiments, R7is CH(CH3)2. In certain embodiments, R7is CH2CH2OMe. In certain embodiments, R7is CF3. In certain embodiments, R7is CH2CH2CH3. In certain embodiments, R7is cyclopentyl. In certain embodiments, R7is OCH3. In certain embodiments, R7is OCH2CH3. In certain embodiments, R7is NH2. In certain embodiments, R7is C(=O)OH. In certain embodiments, R7is C(=O)OCH3. In certain embodiments, R7is C(=O)OCH2CH3. In certain embodiments, R7is C(=O)CH3. In certain embodiments, R7is SCH3. In certain embodiments, R7is S(=O)2CH3. In certain embodiments, R7is S(=O)2NH2. In certain embodiments, R7is NHS(=O)2CH3. In certain embodiments, R7is Cl. In certain embodiments, R7is Br. In certain embodiments, R7is CN. In certain embodiments, R7is C≡CH. In certain embodiments, R7is C(=O)NH2. In certain embodiments, R7is C(=O)NHCH3. In certain embodiments, R7is C(=O)NHCH2CF3. In certain embodiments, R7is . In certain 7 , , In certain embodiments, R7is . In certain embodiments, R7is . . In certain embodiments, R7is . In certain embodiments, R7is . In certain embodiments, . R8In certain embodiments of Formula (I), (II), (III), (IVA), (IVB), or (VIII), each occurrence of R8is independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C(=O)ORC, C(=O)RC, and C(=O)N(RC)(RD). In certain embodiments, R8is H. In certain embodiments, R8is CH3. In certain embodiments, R8is C(=O)O(C1-C6 alkyl). In certain embodiments, R8is C(=O)O(C3-C8cycloalkyl). In certain embodiments, R8is C(=O)NH(C1-C6alkyl). In certain embodiments, R8is C(=O)NH(C3-C8cycloalkyl). In certain embodiments, R8is C(=O)OC(CH3)3. L2-R4-R7In certain embodiments of Formula (I), L2and R4combine to form certain embodiments, L2and R4combine to form certain embodiments, L2and R4combine to form certain embodiments, L2and R4combine to form . In certain embodiments, L2and R4combine to form certain embodiments, L2and R4combine to form2 and R4combine to form . In certain embodiments, B is . In certain embodiments, B is certain embodiments, B is . In certain embodiments, embodiments, embodiments, certain embodiments, B is embodiments, certain embodiments, B is , certain embodiments, certain embodiments, B is embodiments, certain embodiments, B is

[0004] . In certain embodiments, certain embodiments, B is . In certain embodiments, certain embodiments, B is certain embodiments, certain embodiments, B is

[0005] embodiments, certain embodiments, certain embodiments, certain embodiments, . In certain embodiments, certain embodiments, B is , certain embodiments, embodiments, . In certain embodiments, B is . In certain embodiments, B is . In certain embodiments, B is . In certain embodiments, embodiments, B is . In certain embodiments, B is . In certain embodiments, certain embodiments, B is . In certain embodiments, certain embodiments, B is embodiments, . In certain embodiments, . n embodiments, , n embodiments, . naand nbIn certain embodiments, nais 0, 1, 2, or 3. In certain embodiments, nais 0. In certain embodiments, nais 1. In certain embodiments, nais 2. In certain embodiments, nais 3. In certain embodiments, nbis 0, 1, 2, or 3. In certain embodiments, nbis 0. In certain embodiments, nbis 1. In certain embodiments, nbis 2. In certain embodiments, nbis 3. In certain embodiments, the sum of na+ nbis 2, 3, or 4. In certain embodiments, the sum of na+ nbis 2. In certain embodiments, the sum of na+ nbis 3. In certain embodiments, the sum of na+ nbis 4. m In certain embodiments, m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. p In certain embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments of Formula (I), (II), (III), (IVA), (IVB), (V), (VI), or (VII), or (VII), the C1-C6alkyl or C3-C8cycloalkyl, either of which is optionally substituted with at least one of halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C3-C8 cycloalkoxy, and -OH. In some embodiments, the substituted alkyl is -CH2OH, CH(CH3)OH, -CH2F, -CHF2, -CF3, or - CH2CF3. In some embodiments, the alkyl is -CH3. In some embodiments, the alkyl is -CH2CH3. In some embodiments, the alkyl is -CH2CH2OCH3. In some embodiments, the alkyl is - CH(CH3)2. In some embodiments, the alkyl is -(CH2)2CH3. In some embodiments, the alkyl is - (CH2)3CH3. In some embodiments, the alkyl is - C(CH3)3. In some embodiments, the alkyl is - CH2CH(CH3)2. In some embodiments, the alkyl is -CH(CH3)CH2CH3. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. In some embodiments, the halogen is Br. In some embodiments, the halogen is I. In some embodiments, the heterocyclyl is piperidinyl. In some embodiments, the piperidinyl is piperidin-4-yl. In some embodiments, the piperidinyl is piperidin-3-yl. In some embodiments, the piperidinyl is piperidin-2-yl. In some embodiments, the piperidinyl is piperidin-1-yl. In some embodiments, the piperidinyl is 4-hydroxy-piperidin-1-yl. In some embodiments, the heterocyclyl is pyrrolidinyl. In some embodiments, the pyrrolidinyl is pyrrolidin-2-yl. In some embodiments, the pyrrolidinyl is pyrrolidin-3-yl. In some embodiments, the heterocyclyl is azetidinyl. In some embodiments, the azetidinyl is azetidin-3-yl. In some embodiments, the heterocyclyl is oxetanyl. In some embodiments, the oxetanyl is oxetan-3-yl. In some embodiments, the heterocyclyl is morpholinyl. In some embodiments, the morpholinyl is morpholin-2-yl. In some embodiments, the morpholinyl is morpholin-3-yl. In some embodiments, the morpholinyl is morpholin-4-yl. In some embodiments, the heterocyclyl is tetrahydropyranyl. In some embodiments, the heterocyclyl is tetrahydro-2H-pyran-4-yl. In some embodiments, the heteroaryl is pyridinyl. In some embodiments, the pyridinyl is pyridin-2-yl. In some embodiments, the pyridinyl is pyridin-3-yl. In some embodiments, the pyridinyl is pyridin-4-yl. In some embodiments, the heteroaryl is pyrimidinyl. In some embodiments, the pyrimidinyl is pyrimidin-2-yl. In some embodiments, the pyrimidinyl is pyrimidin-4-yl. In some embodiments, the pyrimidinyl is pyrimidin-5-yl. In some embodiments, the heteroaryl is pyrazolyl. In some embodiments, the heteroaryl is 1H-pyrazol-4-yl, which is optionally substituted. In some embodiments, the heteroaryl is 1- methyl-1H-pyrazol-4-yl. In some embodiments, the cycloalkyl is cyclopropyl. In some embodiments, the cycloalkyl is cyclobutyl. In some embodiments, the cycloalkyl is cyclohexyl. In some embodiments, the cycloalkyl is bicyclo[1.1.1]pentyl. In some embodiments, the heteroaryl is pyridinyl. In some embodiments, the pyridinyl is pyridin-2-yl. In some embodiments, the pyridinyl is pyridin-3-yl. In some embodiments, the pyridinyl is pyridin-4-yl. In some embodiments, the heteroaryl is pyrimidinyl. In some embodiments, the pyrimidinyl is pyrimidin-2-yl. In some embodiments, the pyrimidinyl is pyrimidin-4-yl. In some embodiments, the pyrimidinyl is pyrimidin-5-yl. In certain embodiments, the compound is selected from the group consisting of: 2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 6-fluoro-2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((azetidin-3-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(azetidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((piperidin-4-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (R)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (S)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (R)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; (S)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; ethyl 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5- carboxylate; 2-(4-(4-(5-acetylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-(methylthio)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(5-(methylsulfonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(methylsulfonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-sulfamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-(methylsulfonamido)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-cyanopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-ethynylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-cyano-4-methoxypyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-ethoxypyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-(cyclopropylmethoxy)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(hydroxymethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(1-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-isopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(5-bromo-4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-fluoro-4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(4-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(5-(3-cyanoazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(3-hydroxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(methylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-((3,3-difluorocyclobutyl)carbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-6-fluoro- 1H-benzo[d]imidazole-4-carboxamide; 6-fluoro-2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; ethyl 2-(4-((4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)methyl)piperidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(3-((4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)methyl)azetidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(3-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)azetidin-1-yl)pyrimidine- 5-carboxylate; ethyl 2-(6-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-2,6-diazaspiro[3.3]heptan-2- yl)pyrimidine-5-carboxylate; 2-(4-(((1-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(((1-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)azetidin-3-yl)methyl)carbamoyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(((1-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; ethyl 7-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate; 2-(4-(3-cyclopentyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(3-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(3-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(1H-benzo[d]imidazole-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(3-(4-(1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-((1-(1H-benzo[d]imidazol-2-yl)-2-methylpropan-2-yl)carbamoyl)phenyl)-1H- Attorney Docket No.046483-7368WO1 benzo[d]imidazole-4-carboxamide; methyl 2-(2-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)ethyl)-1H- benzo[d]imidazole-5-carboxylate; 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5- carboxylic acid; 2-(3-((2-amino-4,5-dimethylphenyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-((2-(5-methyl-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-((2-(5-chloro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; tert-butyl 4-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H-1,2,3-triazol-1- yl)piperidine-1-carboxylate; 2-(4-(4-methoxypiperidine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4,7-diazaspiro[2.5]octane-4-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(2,2-dimethylpiperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-chloro-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromo-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; and 2-(4-((2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide.

[0006] Table 1. In another aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound of the present disclosure and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition further comprises at least one additional therapeutically effective agent. The compounds described herein can possess one or more stereocenters, and each stereocenter can exist independently in either the (R) or (S) configuration. In certain embodiments, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein. Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In certain embodiments, a mixture of one or more isomer is utilized as the therapeutic compound described herein. In other embodiments, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis and / or separation of a mixture of enantiomers and / or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography. The methods and formulations described herein include the use of N-oxides (if appropriate), crystalline forms (also known as polymorphs), solvates, amorphous phases, and / or pharmaceutically acceptable salts of compounds having the structure of any compound(s) described herein, as well as metabolites and active metabolites of these compounds having the same type of activity. Solvates include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like. In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol. In other embodiments, the compounds described herein exist in unsolvated form. In certain embodiments, the compound(s) described herein can exist as tautomers. All tautomers are included within the scope of the compounds presented herein. In certain embodiments, compounds described herein are prepared as prodrugs. A “prodrug” refers to an agent that is converted into the parent drug in vivo. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In other embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, sites on, for example, the aromatic ring portion of compound(s) described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In certain embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group. Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to2H,3H,11C,13C,14C,36Cl,18F,123I,125I,13N,15N,15O,17O,18O,32P, and35S. In certain embodiments, isotopically-labeled compounds are useful in drug and / or substrate tissue distribution studies. In other embodiments, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements). In yet other embodiments, substitution with positron emitting isotopes, such as11C,18F,15O, and13N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non- labeled reagent otherwise employed. In certain embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser & Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4thEd., (Wiley 1992); Carey & Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000,2001), and Green & Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein. Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein. In certain embodiments, reactive functional groups, such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted participation in reactions. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In other embodiments, each protective group is removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal. In certain embodiments, protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t- butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable. In certain embodiments, carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively- removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups are blocked with fluoride labile silyl carbamates. Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react. Typically blocking / protecting groups may be selected from allyl, benzyl (Bn), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), methyl, ethyl, t-butyl, t-butyldimethylsilyl (TBDMS), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), t-butyloxycarbonyl (Boc), para- methoxybenzyl (PMB), triphenylmethyl (trityl), acetyl, and fluorenylmethoxycarbonyl (FMOC). Other protecting groups, plus a detailed description of techniques applicable to the creation of protecting groups and their removal are described in Greene & Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosure. Methods In one aspect, the present disclosure provides a method of treating, ameliorating, and / or preventing a PARP-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of the present disclosure or the pharmaceutical composition of the present disclosure. In certain embodiments, the disease or disorder is cancer. In certain embodiments, the cancer is selected from the group consisting of breast cancer, ovarian cancer, liver cancer, melanoma, lung cancer, malignant pancreatic cancer, stomach cancer, colon cancer, neuroblastoma, glioblastoma, multiple myeloma, Kaposi’s sarcoma, skin cancer, and prostate cancer. In certain embodiments, the disease or disorder is a neurodegenerative disease or disorder. In certain embodiments, the neurodegenerative disease or disorder is selected from the group consisting of Parkinson’s disease (PD), Alzheimer’s disease (AD), Lewy body dementia, Alzheimer’s disease related dementia, and Amyotrophic lateral sclerosis (ALS). In certain embodiments, the at least one compound or pharmaceutical composition is administered to the subject by at least one route selected from the group consisting of oral, topical, nasal, inhalational, vaginal, buccal, rectal, peritoneal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous. In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. The present disclosure relates in part to the identification of novel PARP inhibitors, which find use in treating, ameliorating, and / or preventing PARP-related neurodegenerative diseases and disorders. The present disclosure provides novel inhibitors of PARPs, as well as compositions comprising the same, and their use in treating, ameliorating, and / or preventing PARP-mediated disease(s) and / or disorder(s). In one aspect, the compounds of the disclosure bind to and inhibit at least one PARP. Accordingly, in various embodiments, the disclosure provides a method of inhibiting at least one PARP in a subject (e.g., at least one of PARP-1, PARP-2, TNKS-1, TNKS-2, PARP-6, PARP-7, PARP-8, PARP-10, or PARP-14). In yet other embodiments, more than one PARP are inhibited. In other embodiments, the method comprises administering to the subject a compound and / or composition of the disclosure. In some embodiments, the compounds of the disclosure may be administered in combination with at least one additional therapeutic agent that treats, ameliorates, and / or prevents cancer. These additional therapeutic agents include temozolomide, irinotecan, cisplatin, carboplatin, paclitaxel, avelumab, decitabine, bevacizumab, gemcitabine, binimetinib, ganitumab, cediranib, durvalumab, vorinostat, radiation, sapacitabine, prexasertib, cetuximab, abiraterone, prednisone, metronomic cyclophosphamide, adavosertib, tremelimumab, gefitinib, tamoxiphen, palbociclib, fulvestrant, topotecan, doxorubicin, ribociclib, palbociclib, abemaciclib, and the like. Administration / Dosage / Formulations The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the subject either prior to or after the onset of the disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions described herein to a patient, preferably a mammal, more preferably a human, may be carried out using known procedures, at dosages and for periods of time effective to treat the disease or disorder in the patient. An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat the disease or disorder in the patient. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic compound described herein is from about 1 and 5,000 mg / kg of body weight / per day. One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation. Actual dosage levels of the active ingredients in the pharmaceutical compositions described herein may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. In particular, the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds described herein employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the compound(s) described herein are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic compound. In certain embodiments, the compositions described herein are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions described herein comprise a therapeutically effective amount of a compound described herein and a pharmaceutically acceptable carrier. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. In certain embodiments, the compositions described herein are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions described herein are administered to the patient in range of dosages that include, but are not limited to, once every day, every two, days, every three days to once a week, and once every two weeks. It is readily apparent to one skilled in the art that the frequency of administration of the various combination compositions described herein varies from individual to individual depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, administration of the compounds and compositions described herein should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient is determined by the attending physician taking all other factors about the patient into account. In certain embodiments, a composition as described herein is a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound described herein, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, or reduce one or more symptoms of a disease or disorder in a patient. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and / or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents. Routes of administration of any of the compositions described herein include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the compositions described herein can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions described herein are not limited to the particular formulations and compositions that are described herein. Oral Administration For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent. For oral administration, the compound(s) described herein can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents; fillers; lubricants; or wetting agents. Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions. The liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents; emulsifying agent; non-aqueous vehicles; and preservatives. Parenteral Administration For parenteral administration, the compounds as described herein may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and / or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and / or dispersing agents may be used. Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph. Helv or similar alcohol. Dosing The therapeutically effective amount or dose of a compound described herein depends on the age, sex and weight of the patient, the current medical condition of the patient and the progression of the disease or disorder in the patient being treated. The skilled artisan is able to determine appropriate dosages depending on these and other factors. A suitable dose of a compound described herein can be in the range of from about 0.01 mg to about 5,000 mg per day, such as from about 0.1 mg to about 1,000 mg, for example, from about 1 mg to about 500 mg, such as about 5 mg to about 250 mg per day. The dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage may be the same or different. For example, a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses. It is understood that the amount of compound dosed per day may be administered, in non- limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. In the case wherein the patient’s status does improve, upon the doctor’s discretion the administration of the compound(s) described herein is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a “drug holiday”). The length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday includes from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is reduced to a level at which the improved disease is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms and / or infection. The compounds described herein can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50with minimal toxicity. The dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size / volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application. It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present disclosure. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. EXAMPLES Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Materials and Methods Reagents, Solvents, and Instrumentation Chemicals used for the synthesis of intermediates and target compounds were purchased from several commercial sources such as Enamine LLC (Monmouth Jct., NJ), Ark Pharm (Arlington Heights, IL), Combi-Blocks (San Diego, CA), Alfa Aesar (Ward Hill, MA), Accela Chembio (San Diego, CA), Aldrich Chemical Co. (Milwaukee, WI), Chem-Impex Int. Inc. (Wood Dale, IL), Oakwood Products (West Columbia, SC), Oxchem Corporation (Wood Dale, IL), and Synthonix (Wake Forest, NC) and were used as received without further purification. Reactions were monitored using thin layer chromatographic (TLC) analysis with silica gel onaluminum backed plates (250-micron particle size, purchased fromAgela Technologies) byvisually inspecting changes in the Rf values using UV light at 254 nm. Intermediates and target compounds were subjected to1H NMR experiments using Bruker 400 UltrashieldTM spectrometer (1H at 400 MHz) equipped with a z-axis gradient probe.1H NMR chemical shifts were reported with reference to tetramethylsilane peak (TMS as an internal standard) in parts per million (o ppm). The1H NMR data were represented as: chemical shift (multiplicity s (singlet), bs (broad singlet), d (doublet), t (triplet), dd (doublet of doublets), dt (doublet of triplets), tt (triplet of triplets), h (hextate), m (multiplet), number of protons and coupling constant). Column chromatography Column chromatography purifications were performed using silica gel (40-63 µm) and flash chromatography was conducted using REVELERIS® X2 flash chromatography system. Preparative TLC was performed using Silica Gel GF 1000 µm 20 x 20 cm glass backed plates. Purity and mass analysis for target compounds was performed on an Agilent 1260 infinity series liquid chromatography (LC) system (using Agilent Eclipse plus C18, 3.5 μm, 4.6 mm × 100 mm column) connected with Agilent 6120 quadrupole mass spectrometer (MS). Acetonitrile (ACN) and water (0.1% formic acid) mixtures were used as mobile phase for the analysis. A 12 min gradient run was performed with 30-70% ACN in water. High-resolution mass spectroscopy (HRMS) analysis for compounds in the disclosure were assayed on a Waters Xevo G2-XS Q-Tof mass spectrometer equipped with H-Class UPLC inlet and LockSpray electrospray ionization (ESI).PARP1 enzyme inhibition assayThe IC50 values for target compounds against PARP1 enzyme were calculated from a 10-point concentration-response curve using the BPS PARP1 Chemiluminescence Activity Assay Kit (Catalog #80551) (BPS Bioscience). Expression constructs and mutagenesis The following PARP1 constructs were expressed from a pET28 expression vector (Novagen) with an N-terminal hexahistidine tag: PARP1 WT (residues 1-1014), CATΔHD (residues 678-787) and Zn1-Zn3 Δ Zn2 domains (residues 1-366 Δ97-206). The WGR-CAT domain (518-1014) with the ΔVE mutation was expressed from a pET24 expression vector (Novagen) with a C-terminal hexahistidine tag. All mutations and deletions were performed using the QuickChange protocol (Stratagene) and verified by automated Sanger DNA sequencing. Protein expression and purification PARP1 WT and mutant proteins were expressed and purified as described previously using three chromatography steps: Ni2+-affinity, heparin, and gel filtration. Crystallization and data collection PARP1 CATΔHD was mixed with either compound 82, compound 65 or compound 75 in the following buffer: 25 mM HEPES pH 8.0, 150 mM NaCl, 1 mM EDTA, and 0,1 mM TCEP at the following concentrations: CATΔHD (30 mg / mL) and compound 82 (1.1 mM in DMSO, 10% final), CATΔHD (20 mg / mL) and compound 65 (0.73 mM in DMSO, 10% final), CATΔHD (10 mg / mL) and compound 75 (0.365 mM in DMSO, 7% final). All crystals were grown by sitting drop vapor diffusion at 20 °C by mixing the PARP1 CATΔHD / compound complex with an equal amount of 20% PEG3000, 0.1 M sodium citrate pH 5.5 (pH adjusted with citric acid). Crystals were cryo-protected in 20% PEG3000, 0.1 M sodium citrate pH 5.5, 20% sucrose and 1.1 mM of target compound prior to flash cooling in liquid nitrogen. The PARP1 ΔVE / DNA complex was formed by mixing Zn1-Zn3 Δ Zn2 and WGR- CATΔVE at 300 µM each with a 5-bp DNA duplex at 165 µM (5’-CGACG-3’) in the following buffer: 25 mM HEPES pH 8.0, 150 mM NaCl, 1mM EDTA, and 0.1 mM TCEP. Crystals were grown by sitting drop vapor diffusion at 20 °C by mixing the PARP1ΔVE / DNA complex with an equal amount of 12% PEG 6000 and 100 mM MES pH 6.5. To obtain compound 75 bound to a PARP1ΔVE / DNA complex, compound 75 (in DMSO, final concentration of 625 mM) was spiked into wells containing PARP1ΔVE / DNA crystals (5% DMSO final). The compound heavily precipitated upon addition to the wells. Nevertheless, the crystals were kept in the presence of the compound for three days and then were rapidly transferred to a solution of 10% PEG 6000, 100 mM MES pH 6.5, 25% glycerol, 0.1 mM TCEP, 75 mM NaCl and 700 µM compound 75 (6% DMSO final) prior to flash cooling in liquid nitrogen. X-ray diffraction data for all PARP1 / compound complexes was collected at beamline 8.3.1 of the Advanced Light Source. The data was processed using XDS. Structure determination of PARP1 / compound complexes All PARP1 / compound complex structures were determined by molecular replacement (MR) using the program PHASER as implemented in the CCP4 suite. The structure of PARP1 CAT domain bound to A968427 (PDB 3GJW) was used as search model for CATΔHD after deleting the HD and ligand A968427 from the PDB file. The structure of PARP1 apo ΔVE (PDB 7S6M) was used as search model for the PARP1ΔVE / compound 75 complex. All models were constructed using COOT and refined in REFMAC5 (CCP4 suite) and / or phenix.refine (Phenix suite) using TLS, geometric restraints, and NCS (when applicable). All of the atoms of compounds 65 and 82 were modeled in their respective crystal structures, despite a lack of clear electron density for their substituent groups, in contrast to the compound core electron density that was well defined. As such, it should be noted that the substituents are very mobile, as corroborated by high crystallographic B-factors relative to the compound core, and that they are likely to adopt a variety of conformations. Fluorescence polarization Both the DNA competition assay and the DNA binding assays were essentially performed as described previously and are described in greater details in this section. All fluorescence polarization experiments were performed at least three times. Figures associated with each experiment display representative curves. For the DNA competition assay, 40 nM PARP1 WT was incubated with 20 nM of dumbbell DNA with a central nick carrying an internal fluorescent FAM group (5’-GCT GAG C / FAMT / T CTG GTG AAG CTC AGC TCG CGG CAG CTG GTG CTG CCG CGA- 3’) (SEQ ID NO:1) for 30 min at room temperature in 12 mM HEPES pH 8.0, 60 mM KCl, 8mM MgCl2, 4% glycerol, 5.7 mM BME,0.075 mg / ml BSA, 5% DMSO with or withoutVeliparib, EB-47 or target compounds (100 µM). A competitor unlabeled DNA of the same sequence was added at 2 µM and FP was measured over time on a VictorV plate reader (Perkin Elmer). For the DNA binding assay, increasing concentrations of PARP1 WT was incubated for 30 min at RT with 5 nM of an 18- bp DNA duplex (5’-GGGTTGCGGCCGCTTGGG-3’) (SEQ ID NO:2) that carried a fluorescent FAM group on the complementary 5’ terminus in the following buffer: 12 mM HEPES pH 8.0, 300 mM NaCl, 4% glycerol, 5.7 mM BME, 0.075 mg / ml BSA, 5% DMSO with or without Veliparib, EB-47 or target compounds (150 µM). FP was measured over time on a VictorV plate reader (Perkin Elmer) and a 1:1 binding model was fit to the data using Matlab (MathWorks). SDS-PAGE PARP1 activity assay The SDS-PAGE PARP1 activity assay was performed essentially as described. PARP1 WT (300 nM) was preincubated with 300 nM of an 18-bp DNA duplex with or without Veliparib, EB-47 or target compounds (75 µM) for 10 min at RT in the presence of 5% DMSO.4 mM NAD+was added to the reaction and the mixture was incubated for 1 min or 5 min before quenching with addition of SDS loading buffer containing 0.1 M EDTA. The reactions were resolved on SDS-PAGE and stained with Imperial Protein Stain (Pierce). Hydrogen / deuterium exchange-mass spectrometry (HXMS) 5 µM of SSB DNA (5’ GCT GGC TTC GTA AGA AGC CAG CTC GCG GTC AGC TTG CTG ACC GCG) (SEQ ID NO:3) was added to 2.6 µM of PARP1. PARP1 and DNA were incubated for 30 min. To make the PARP1 / DNA / PARPi complex, 5.2 µM of respective PARPi was added to PARP1 / DNA complex and incubated for another 30 min. At roomtemperature, 15 µL of deuterium on-exchange buffer (10 mM HEPES,pD 7.0, 150 mMNaCl, in D2O, pD = pH + 0.4138) was added to the PARP1, the PARP1 / DNA complex, and the PARP1 / DNA / PARPi complex. This yielded a final D2O concentration of 75%. At 100 s, 20 µL was aliquoted into 30 µL of ice-cold quench buffer (1.66 M guanidine hydrochloride, 10 % glycerol, and 0.8 % formic acid to make a final pH of 2.4-2.5) and immediately frozen in liquid nitrogen. The non-deuterated (ND) samples of PARP1 were prepared in 10 mM HEPES, pH 7.0, 150 mM NaCl buffer and each 20 µL aliquot was quenched into 30 µL of quench buffer. To mimic the on-exchange experiment, the fully deuterated (FD) samples were prepared in 75 % deuterium in triplicate (n=3) and denatured under acidic conditions (0.5 % formic acid). For every amide proton along the entire polypeptide chain to undergo full exchange, the samples were incubated for 48 h. At 0 °C, 50 µL of samples were melted and rapidly injected into pepsin column and pumped with an initial flow rate of 50 µL min-1for 2 min followed by 150 µL min-1for another 2 min. Via coupling, pepsin (Sigma) was immobilized to POROS 20 AL support (Applied Biosystems) in a 64 µL column (2 mm x 2 cm, Upchurch). TARGA C85 µm Piccolo HPLC column (1.0 x 5.0 mm, Higgins Analytical) was used to trap the peptic peptides and later these peptides were analyzed through C18 HPLC column (0.3 x 75 mm, Agilent) with a 12- 100% buffer B gradient at 6 µL / min (Buffer A: 0.1% formic acid; Buffer B: 0.1% formic acid, 99.9% acetonitrile). The effluent was electrosprayed into the Exactive Plus EMR- Orbitrap (Thermo Fisher Scientific). MS data acquisition over the mass range 200-2000 m / z were acquired on the Exactive Plus EMR- Orbitrap (Thermo Fisher Scientific) at 60,000 resolution. The effluent was electrosprayed with ion spray voltage of 3.5 kV and capillary temperature operated at 250 °C. PARP1 peptide identification ND samples were injected into LTQ orbitrap XL, (Thermo Fisher Scientific) for tandem mass spectroscopy (MS / MS) to identify PARP1 peptides. At 200- 2000 m / z scan range at 15,000 resolution the ions were fragmented by CID with normalized collision energy. The SEQUEST from Bioworks was employed to identify the potential PARP1 peptides. A 4 ppm of peptide tolerance and 0.1 AMU of fragment tolerance was used against an extensive decoy sequence database (custom database) containing the sequence of PARP1, pepsin and other common contaminants identified in prior HXMS studies. Non-specific digestion was employed to search the PARP1 peptic peptides. To generate an exclusion listfrom the firstMS / MS of ND, a MATLAB based program called ExMS2 was used with Ppepscore of 0.1. Withthis exclusion list, MS / MS on second ND second was employed to collectthe MS2 scan of the less intense peptides that were not identified in the previous ND sample. To increase the number of unique peptides and sequence coverage of the protein, the above steps were repeated four times. All the output files generated through SEQUEST were pooled and a final list of PARP1 peptides containing sequence, RT, and charge were generated by EXMS2. HXMS analysis and plotting Peptide information generated through ExMS2 was added into the peptide source tab of HDExaminer (Sierra Analytics). This identifies the deuterated peptides for every protein state (PARP1, PARP1 / DNA, and PARP1 / DNA / PARPi). For each peptide, the extent of deuteration was compared as measured in the FD sample to the theoretical maximal deuteration (i.e., if no back exchange occurs - loss of deuterium after quench). FD revealed a back-exchange in experiments of 27-30%. To further assess the quality of each peptide the mass spectra was manually checked. An in-house script written in MATLAB was used to obtain the difference plot for the deuteration levels between any two protein states. Example 1: Compound synthesis General Methods Method A N,N-Diisopropylethylamine (3 equiv) and O-(benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium hexafluorophosphate (HBTU) (1.1 equiv) was added at 0 °C to a stirred solution of the appropriate carboxylic acid (1 equiv) in N,N-dimethylformamide (DMF), and the reaction was stirred for 30 min at the same temperature. Subsequently, the appropriate amine (1.1 equiv) was added as such or by dissolving in minimum volume of DMF to the reaction mixture, and the reaction was stirred at room temperature for overnight. The reaction mixture was then diluted with cold water and sat. aqueous NaHCO3, filtered off the precipitation, and solid was washed with water, hexanes, and dried under vacuo. The resulting crude coupled products were purified by flash chromatography using gradient DCM and methanol combinations as the mobile phase, wherein the concentration of methanol in dichloromethane was varied from 1 to 15% based on the nature of product to be purified. Method B To a stirred solution of Boc protected intermediate (1.51 mmol) in dichloromethane (20 mL) at 0oC, was added solution of 4N HCl / Dioxane (10 mL) dropwise. The reaction mixture was allowed to stir at room temperature for 6 h. After completion of the reaction, solvent was removed under reduced pressure and the resulting residue was triturated with methanol: diethyl ether (1:9) to affect precipitation of the product. Filtered off the solid and dried under vacuo to furnish free amine as hydrochloride salt. Method C Appropriate amine salt (1 equiv) was dissolved in mixture of dioxane / DMF (9:1) in a reaction vial (with 5-10 mL volume capacity), subsequently N,N- diisopropylethylamine (3 equiv) and appropriate 2-chloropyrimidine (1 equiv). The reaction mixture vial was irradiated under microwave condition (160 °C, Biotage Initiator+) for 45–60 min. After complete consumption of starting compounds, the dioxane was removed under reduced pressure and resulting residue was diluted by adding cold water to affect the precipitation of solid product. The resulting solid was filtered off, washed with cold water and hexanes, and dried in vacuo. Further, the crude product was purified by flash chromatography (silica gel column) using methanol / dichloromethane (0 / 100% to 15 / 85%) gradient to furnish pure products. Method D Acetylene derivative (0.38 mmol) was added to a reaction vial (with 0.5 - 2 mL volume capacity) and subsequently, azide (0.42 mmol), triethyl amine (0.76 mmol), Cu(I)I (catalytic amounts) and DMSO (2 mL) were added. The mixture was then subjected to microwave irradiation for 2 h at 150°C. The reaction was then diluted with ethyl acetate and the mixture was then extracted 3X with saturated NaHCO3 and 3X with brine solutions, each time discarding the aqueous portion after each extraction. The organic layer was then dried using MgSO4and filtered through a celite. The solution thus obtained was then dried under vacuum and washed with methanol to obtain substituted 1,2,3-triazole derivatives. Scheme 1. Reagents and conditions: (a) 4-formylbenzoic acid, NH4OAc, DMF, 100 °C, 7 h, 80-85%; (b) N- Boc piperazine, HBTU, DIPEA, DMF, 0 °C to rt, overnight, 75-79%; (c) 4 N HCl / dioxane, DCM, 0 °C to rt, 6 h, 72-81%. Scheme 2. Reagents and conditions: (a) NaN3 or N3R4, Cu(I)I, Et3N, DMSO, mw, 150 °C, 4-8 h. Scheme 3. Reagents and conditions: (a) appropriately substituted 2-chloropyrimidines, DIPEA, dioxane / DMF (9:1), microwave, 160 °C, 45-60 min, 32-66%. Ring het refers to a monocyclic or bicyclic heterocycloalkyl (e.g., piperidinyl, azetidinyl, and 2,6-diazaspiro[3.3]heptanyl, inter alia). Scheme 4. Reagents and conditions: (a) HBTU, DIPEA, substituted triazolopiperazine or substituted benzimidazole, DMF, 0 °C to rt, overnight, 55-72%. L refers to a bond or optionally substituted C1-C3 alkylenyl. (1) Synthesis of 2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide dihydrochloride 4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoic acid (1A) To a solution of 2,3-diamino benzamide (1000 mg, 6.62 mmol) in DMF (10.0 mL), 4- formyl benzoic acid (1090 mg, 7.28 mmol) was added, followed by the subsequent addition of ammonium acetate (770 mg, 9.92 mmol). The mixture was then heated at 60 °C for a period of 6 h after which the solvent was evaporated under vacuum. The resulting solid was washed with methanol and water to obtain 1A as light to dark yellow powder (1600 mg, 86% yield). NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 13.25 (br s, 1H), 9.32 (s, 1H), 8.37 (d, J = 8.2 Hz, 2H), 8.15 (d, J = 8.2 Hz, 2H), 7.94 – 7.74 (m, 3H), 7.40 (t, J = 7.8 Hz, 1H). LC-MS (ESI): m / z, 282.1 ([M+H]+calcd. for C15H11N3O3, 282.1). tert-butyl 4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazine-1-carboxylate (1B) The amide coupling reaction was performed according to the method A using 61 (500 mg, 1.78 mmol), HBTU (809 mg, 2.13 mmol), N,N-diisopropylethylamine (619 µL, 3.56 mmol), and N-boc piperazine (364 mg, 1.96 mmol) to obtain the boc-protected compound as a beige solid (685 mg, 85%) after flash chromatography purification. It was then directly taken in next synthetic step without characterization 2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide dihydrochloride (1C) To a stirred solution of Boc intermediate (680 mg, 1.51 mmol) in dichloromethane (20.0 mL) at 0 °C, was added solution of 4N HCl / Dioxane (10.0 mL) slowly dropwise. The reaction mixture was allowed to stir at room temperature for 6h. After completion of the reaction, solvent was removed under reduced pressure and the resulting residue was triturated with methanol: diethyl ether (1:9) to affect precipitation of the product. Filtered off the solid and dried under vacuo to furnish compound 1 (510 mg, 87%) as beige solid. Mp 256 – 258 °C;1H NMR (400 MHz, DMSO-d6) δ 9.68 (br s, 2H), 8.99 (s, 1H), 8.43 (d, J = 8.2 Hz, 2H), 7.95 (d, J = 7.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 6.02 (br s, 2H), 4.07 – 3.46 (m, 4H), 3.29 – 3.03 (m, 4H); HRMS (ESI): m / z, calcd. for C19H20N5O2+[M]+350.1612, found 350.1646; HPLC purity: 97.7% (tR= 0.85 min). (2) Synthesis of 4-(4-(4-carbamoyl-6-fluoro-1H-benzo[d]imidazol-2- yl)benzoyl)piperazinium dihydrochloride The desired compound was synthesized according to Scheme 1. 4-(4-carbamoyl-6-fluoro-1H-benzo[d]imidazol-2-yl)benzoic acid (2A) Compound 2A was synthesized from 2,3-diamino-5-fluorobenzamide (500 mg, 2.95 mmol), 4-formylbenzoic acid (443 mg, 2.95 mmol) and ammonium acetate (341 mg, 4.42 mmol) using a procedure similar to that described for the synthesis of compound 1A and was obtained as pale brown solid (710 mg, 80%).1H NMR (400 MHz, DMSO-d6) δ 13.78 (s, 1H), 13.26 (br s, 1H), 9.27 (s, 1H), 8.36 (d, J = 8.0 Hz, 2H), 8.14 (d, J = 8.2 Hz, 2H), 8.04 (s, 1H), 7.67 – 7.58 (m, 2H); LC-MS (ESI): m / z, 300.1 ([M+H]+calcd. for C15H10FN3O3, 300.1). 4-(4-(4-carbamoyl-6-fluoro-1H-benzo[d]imidazol-2-yl)benzoyl)piperazinium dihydrochloride (2B) Amide coupling and Boc deprotection were same as described for compound 1 using compound 2A (600 mg, 1.28 mmol) and was obtained as pale brown solid (458 mg, 81%). Mp 248 – 250 °C; NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 9.20 (s, 1H), 8.36 (d, J = 8.0 Hz, 2H), 8.02 (s, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.66 – 7.60 (m, 2H), 3.47 – 3.43 (m, 8H), 3.28 – 3.05 (m, 2H). HRMS (ESI): m / z, calcd. for C19H19FN5O2+[M]+368.1517, found 368.1555; HPLC purity: 95.2% (tR= 0.83 min). (3) Synthesis of 2-(4-((azetidin-3-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide dihydrochloride Compound 3 was synthesized from compound 1A (500 mg, 1.78 mmol) and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (365 mg, 357 µL, 1.96 mmol) following steps and using procedure similar to that described for the synthesis of compound 1, and was obtained as cream- colored solid (507 mg, 73%). Mp 149 – 151 °C;1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.94 (t, J = 5.4 Hz, 1H), 8.90 – 8.71 (br s, 2H), 8.38 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 4.03 – 3.92 (m, 2H), 3.88 – 3.77 (m, 4H), 3.53 (t, J = 5.8 Hz, 2H), 3.11 – 2.99 (m, 1H);13C NMR (101 MHz, DMSO-d6) δ 166.72, 166.56, 151.07, 150.90, 136.79, 135.38, 130.25, 128.54, 128.24, 128.12, 124.17, 124.08, 122.62, 116.56, 48.76, 41.43, 32.13; HRMS (ESI): m / z, calcd. for C19H21N5O2+[M]+350.1612, found 350.1629; HPLC purity: 98.2% (tR = 0.82 min). (4) Synthesis of 2-(4-(azetidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide dihydrochloride Compound 4 was synthesized from compound 1A (500 mg, 1.78 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (337 mg, 1.96 mmol) following steps and using procedure similar to that described for the synthesis of compound 1, and was obtained as cream-colored solid (413 mg, 88%). Mp >300 °C (decomposes at this temperature);1H NMR (400 MHz, DMSO-d6) δ 9.54 (d, J = 6.5 Hz, 1H), 9.28 – 9.06 (m, 2H), 8.42 (d, J = 8.4 Hz, 2H), 8.14 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 7.5 Hz, 1H), 7.88 – 7.79 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 4.94 – 4.81 (m, 2H), 4.24 – 4.09 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 166.80, 165.57, 150.58, 136.41, 135.46, 134.54, 128.85, 128.71, 128.53, 124.86, 124.69, 122.38, 116.93, 52.15, 42.11; HRMS (ESI): m / z, calcd. for C18H18N5O2+[M]+336.1455, found 336.1479; HPLC purity: 97.1% (tR= 0.92 min). (5) Synthesis of 2-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-1H- Compound 5 was prepared from compound 1A (250 mg, 0.89 mmol) and tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate (194 mg, 0.98 mmol) following steps and using procedure similar to that described for the synthesis of ccompound 1, and was obtained as beige solid (150 mg, 65%). Mp 260 – 260 °C;1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.41 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 4.90 – 4.60 (br s, 2H), 4.19 – 3.97 (m, 4H), 3.79 – 3.68 (m, 2H), 3.66 – 3.56 (m, 2H); LC-MS (ESI): m / z, 362.2 ([M]+calcd. for C20H21N5O22+, 362.2); HPLC purity: 95.4% (tR= 0.79 min). (6) Synthesis of 2-(4-((piperidin-4-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide dihydrochloride Compound 6 was synthesized from compound 1A (250 mg, 0.89 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (365 mg, 357 µL, 1.96 mmol) following steps and using procedure similar to that described for the synthesis of compound 1, and was obtained as cream solid (180 mg, 69%). Mp 260 – 262 °C1H NMR (400 MHz, DMSO-d6) δ 8.89 – 8.75 (m, 2H), 8.60 – 8.48 (br s, 1H), 8.37 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.83 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 3.33 – 3.18 (m, 4H), 2.93 – 2.77 (m, 2H), 1.92 – 1.78 (m, 3H), 1.48 – 1.31 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 166.74, 166.10, 151.12, 137.05, 135.42, 128.40, 128.09, 124.14, 124.01, 122.61, 116.54, 44.50, 43.23, 34.12, 26.71; HRMS (ESI): m / z, calcd. for C21H24N5O2+[M]+378.1925, found 378.1940; HPLC purity: 99.6% (tR = 0.81 min). (7) Synthesis of (R)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide dihydrochloride Compound 7 was synthesized from compound 1A (250 mg, 0.89 mmol) and (R)-tert- butyl 3-aminopyrrolidine-1-carboxylate hydrochloride (218 mg, 0.98 mmol) following steps and using procedure similar to that described for the synthesis of compound 1, and was obtained as cream solid (154 mg, 59%). Mp 227 – 229 °C;1H NMR (400 MHz, DMSO-d6) δ 9.37 – 9.25 (m, 1H), 9.24 – 9.08 (m, 2H), 8.94 (d, J = 6.5 Hz, 1H), 8.38 (d, J = 8.2 Hz, 2H), 8.12 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 4.63 – 4.52 (m, 1H), 3.49 – 3.34 (m, 2H), 3.32 – 3.19 (m, 2H), 2.28 – 2.15 (m, 1H), 2.12 – 1.96 (m, 1H); HRMS (ESI): m / z, calcd. for C19H20N5O2+[M]+350.1612, found 350.1628; HPLC purity: 97.5% (tR= 0.82 min). (8) Synthesis of (S)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide dihydrochloride Compound 8 was prepared from compound 1A (250 mg, 0.89 mmol) and (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate hydrochloride (218 mg, 0.98 mmol) following steps and using procedure similar to that described for the synthesis of compound 1, and was obtained as cream solid (143 mg, 53%). Mp 227 – 229 °C;1H NMR (400 MHz, DMSO-d6) δ 9.61 – 9.48 (m, 1H), 9.46 – 9.34 (m, 1H), 9.13 – 8.99 (m, 2H), 8.41 (d, J = 8.3 Hz, 2H), 8.17 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 7.4 Hz, 1H), 7.90 – 7.80 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 4.68 – 4.54 (m, 1H), 3.50 – 3.36 (m, 2H), 3.34 – 3.20 (m, 2H), 2.30 – 2.15 (m, 1H), 2.12 – 1.98 (m, 1H); HRMS (ESI): m / z, calcd. for C19H20N5O2+[M]+350.1612, found 350.1638; HPLC purity: 97.6% (tR = 0.82 min). (9) Synthesis of 2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 9 was prepared according to Scheme 2, as described herein. 2-(4-ethynylphenyl)-1H-benzo[d]imidazole-4-carboxamide (9A) Compound 9A was prepared in the same manner as compound 1A using 4- ethynylbenzaldehyde (474 mg, 3.64 mmol) and 2,3-diaminobenzamide (500 mg, 3.31 mmol) as pale to dark yellow powder (150 mg, 16% yield). NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 9.32 (s, 1H), 8.27 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.44 (s, 1H). ESI-MS: m / z 262.1.1 (C16H11N3O requires 262.1, [M + H]+). 2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (9B) Compound 9A (100 mg, 0.38 mmol) was added to a reaction vial (with 0.5-2 mL volume capacity) and subsequently, tert-butyl 3-azidopyrrolidine-1-carboxylate (89 mg, 0.42 mmol), triethyl amine (0.11 mL, 0.76 mmol), Cu(I)I (catalytic amounts) and DMSO (2 mL) were added. The mixture was then subjected to microwave irradiation for 2 h at 150°C. The reaction was then diluted with ethyl acetate and the mixture was then extracted 3X with saturated NaHCO3and 3X with brine solutions, each time discarding the aqueous portion after each extraction. The organic layer was then dried using MgSO4 and filtered through a celite. The solution thus obtained was then dried under vacuum and washed with methanol to obtain Boc- protected intermediate (110 mg, 61% yield). Without further characterization the N-boc intermediate was then treated with conc. HCl for overnight. The reaction was concentrated under vacuum and washed with methanol to obtain the title compound as cream colored solid in quantitative yield.1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.77 (s, 1H), 9.09 (s, 1H), 9.01 (s, 1H), 8.43 (d, J = 8.3 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.94 (dd, J = 7.5, 1.1 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 5.53 (tt, J = 7.2, 4.0 Hz, 1H), 3.78 (dq, J = 14.4, 6.1 Hz, 2H), 3.45 (t, J = 6.9 Hz, 2H), 2.59 (dq, J = 15.4, 8.0 Hz, 1H), 2.49-2.39 (m, 1H). Anal. Calcd for C20H21Cl2N7O.2.55H2O.0.5CH3OH: C, 53.82; H, 4.74; N, 21.97; O, 3.58. Found: C, 48.15; H, 5.27; N, 19.01. (10) Synthesis of (R)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H- benzo[d]imidazole-4-carboxamide dihydrochloride Compound 10 was prepared essentially according to steps and procedures used in the preparation of compound 9 using (R)-tert-butyl 3-azidopyrrolidine-1-carboxylate.1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.77 (s, 1H), 9.09 (s, 1H), 9.01 (s, 1H), 8.43 (d, J = 8.3 Hz, 2H), 8.11 (d, J = 8.4 Hz, 2H), 7.94 (dd, J = 7.5, 1.1 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H), 5.53 (tt, J = 7.2, 4.0 Hz, 1H), 3.78 (dq, J = 14.4, 6.1 Hz, 2H), 3.45 (t, J = 6.9 Hz, 2H), 2.59 (dq, J = 15.4, 8.0 Hz, 1H), 2.49-2.39 (m, 1H). ESI-MS: m / z 445.12 (C20H21Cl2N7O, requires 445.12, [M + H]+). (11) Synthesis of (S)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H- benzo[d]imidazole-4-carboxamide dihydrochloride Compound 11 was prepared essentially according to steps and procedures used for compound 9 using (S)-tert-butyl 3-azidopyrrolidine-1-carboxylate. ESI-MS: m / z 445.12 (C20H21Cl2N7O, requires 445.12, [M + H]+). (12) Synthesis of 2-(4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H- benzo[d]imidazole-4-carboxamide dihydrochloride Compound 12 was prepared from Boc protected compound 85 a cream colored solid essentially according to steps and procedures used for compound 9.1H NMR (400 MHz, DMSO- d6) δ 9.51-9.35 (m, 1H), 9.35-9.18 (m, 1H), 8.99 (s, 1H), 8.91 (s, 1H), 8.43 (d, J = 8.4 Hz, 2H), 8.20-8.09 (m, 2H), 7.98-7.76 (m, 3H), 7.49 (t, J = 7.8 Hz, 1H), 4.92 (dq, J = 10.6, 5.2, 4.1 Hz, 1H), 3.50-3.36 (m, 2H), 3.16 (q, J = 11.6 Hz, 2H), 2.46-2.15 (m, 4H). Anal. Calcd for C21H23Cl2N7O.1.35H2O: C, 53.82; H, 4.74; N, 21.97. Found: C, 48.15; H, 5.27; N, 19.01. (13) Synthesis of 2-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 13 was prepared according to Scheme 3 and Method C.1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.35 (s, 1H), 8.40 (d, J = 4.7 Hz, 2H), 8.34 (d, J = 8.0 Hz, 2H), 7.93-7.74 (m, 3H), 7.68 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 6.69 (t, J = 4.7 Hz, 1H), 3.96-3.65 (m, 6H), 3.56-3.40 (m, 2H). ESI-MS: m / z 428.2 (C23H21N7O2, requires 428.2, [M + H]+). (14) Synthesis of 2-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 14 was prepared according to Scheme 3 and Method C section using 2-(3- (piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (this was prepared in the same manner as compound 1A using 2,3-diaminobenzamide and 3-formylbenzoic acid and subsequently coupling with N-Boc piperazine and Boc deprotection) and 2-chloropyrimidine.1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.33 (s, 1H), 8.40 (d, J = 4.7 Hz, 2H), 8.36 (dt, J = 7.7, 1.5 Hz, 1H), 8.31 (s, 1H), 7.90 (dd, J = 7.6, 1.2 Hz, 1H), 7.81 (s, 1H), 7.76 (dd, J = 8.1, 1.2 Hz, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.63 (dt, J = 7.6, 1.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 6.68 (t, J = 4.7 Hz, 1H), 3.98-3.67 (m, 6H), 3.58-3.43 (m, 2H). ESI-MS: m / z 428.2 (C23H21N7O2, requires 428.2, [M + H]+). (15) Synthesis of methyl 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2- yl)benzoyl)piperazin-1-yl)pyrimidine-5-carboxylate Compound 15 was prepared according to Scheme 3 and Method C using compound 1A and methyl 2-chloropyrimidine-5-carboxylate.1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.35 (s, 1H), 8.81 (s, 2H), 8.34 (d, J = 8.2 Hz, 2H), 7.91 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.05-3.84 (m, 4H), 3.84- 3.71 (m, 5H), 3.59-3.43 (m, 2H). ESI-MS: m / z 486.2 (C25H23N7O4, requires 486.2, [M + H]+). (16) Synthesis of ethyl 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin- 1-yl)pyrimidine-5-carboxylate The title compound was prepared according to the method described for preparation of compound 15. Mp 267 – 269 °C;1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.34 (s, 1H), 8.83 (s, 2H), 8.34 (d, J = 7.8 Hz, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 4.28 (q, J = 7.0 Hz, 3H), 4.08 – 3.87 (m, 4H), 3.85 – 3.69 (m, 2H), 3.61 – 3.44 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H);13C NMR (101 MHz, DMSO-d6) δ 169.10, 166.57, 164.41, 162.17, 159.92, 151.57, 141.89, 137.86, 135.84, 130.62, 128.42, 127.44, 123.62, 123.13, 123.07, 115.65, 112.91, 60.83, 47.14, 44.15, 43.74, 41.89, 14.65; HRMS (ESI): m / z, calcd. for C26H26N7O4 [M+H]+500.2046, found 500.2064; HPLC purity: 98.5% (tR = 0.60 min). (17) Synthesis of 2-(4-(4-(5-acetylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide

[0007] The title compound was prepared according to the method described for preparation of compound 15. Mp 290 – 292 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (s, 1H), 8.90 (s, 2H), 8.34 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.08 – 3.89 (m, 4H), 3.83 – 3.71 (m, 2H), 3.60 – 3.46 (m, 2H), 2.47 (s, 3H);13C NMR (101 MHz, DMSO-d6) δ 194.79, 169.10, 166.57, 161.87, 159.69, 151.58, 145.35, 141.88, 137.88, 135.84, 130.61, 128.43, 127.44, 123.62, 123.14, 120.41, 115.67, 26.64; HRMS (ESI): m / z, calcd. for C25H24N7O3 [M+H]+470.1941, found 470.1962; HPLC purity: 97.0% (tR= 3.20 min). (18) Synthesis of 2-(4-(4-(5-(methylthio)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 287 – 289 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.46 (s, 2H), 8.33 (d, J = 7.9 Hz, 2H), 7.89 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 3.95 – 3.67 (m, 6H), 3.58 – 3.43 (m, 2H), 2.39 (s, 3H); HRMS (ESI): m / z, calcd. for C24H24N7O2S [M+H]+474.1712, found 474.1720; HPLC purity: 100.0% (tR= 1.45 min). (19) Synthesis of 2-(4-(4-(5-(methylsulfonyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 276 – 278 °C;1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.34 (s, 1H), 8.76 (s, 2H), 8.34 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 4.08 – 3.88 (m, 4H), 3.83 – 3.71 (m, 2H), 3.58 – 3.48 (m, 2H), 3.25 (s, 3H); HRMS (ESI): m / z, calcd. for C24H24N7O4S [M+H]+506.1610, found 506.1649; HPLC purity: 97.7% (tR = 1.04 min). (20) Synthesis of 2-(4-(4-(4-(methylsulfonyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 286 – 288 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.78 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 4.01 – 3.83 (m, 4H), 3.82 – 3.73 (m, 2H), 3.80 – 3.45 (m, 2H), 3.31 (s, 3H); HRMS (ESI): m / z, calcd. for C24H24N7O4S [M+H]+506.1610, found 506.1624; HPLC purity: 100.0% (tR = 1.03 min). (21) Synthesis of 2-(4-(4-(5-sulfamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 226 – 228 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.35 (s, 1H), 8.69 (s, 2H), 8.34 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.45 – 7.35 (m, 3H), 4.05 – 3.84 (m, 4H), 3.82 – 3.70 (m, 2H), 3.59 – 3.44 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 169.09, 166.54, 161.44, 156.61, 151.58, 141.89, 137.89, 135.85, 130.62, 128.42, 127.95, 127.45, 127.29, 123.62, 123.14, 123.10, 115.65, 47.18, 44.23, 43.78, 42.04; HRMS (ESI): m / z, calcd. for C23H23N8O4S [M+H]+507.1563, found 507.1565; HPLC purity: 97.4% (tR = 0.99 min). (22) Synthesis of 2-(4-(4-(5-(methylsulfonamido)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide N-(2-Chloropyrimidin-5-yl)methanesulfonamide (22A) To a stirred solution of methanesulfonyl chloride (47 µL, 0.60 mmol) in DCM at 0 °C, subsequently K2CO3 (61 mg, 0.44 mmol), and N,N-diisopropylethylamine (210 µL, 1.20 mmol) were added. While maintaining the temperature, the reaction mixture was stirred for 45 min before 2-chloropyrimidin-5-amine (52 mg, 0.40 mmol) was added. After complete consuming of starting compound, the reaction was quenched with sat. aqueous NaHCO3and extracted with dichloromethane (2 X 5.0 mL). The combined organic layers were washed with brine (2 X 5.0 mL), water (2 X 5.0 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and purified by flash chromatography (silica gel) using ethyl acetate / hexanes gradient to furnish compound 22A (65 mg, 78% yield) as white solid.1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.06 (s, 1H), 3.11 (s, 2H); LC-MS (ESI): m / z, 207.9. 2-(4-(4-(5-(methylsulfonamido)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide (22B) The title compound was prepared according to the method described for preparation of compound 15 using compound 22A. Mp 222 – 224 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.35 (s, 2H), 8.33 (d, J = 8.2 Hz, 2H), 8.28 (s, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 3.95 – 3.64 (m, 6H), 3.58 – 3.45 (m, 2H), 2.96 (s, 3H); HRMS (ESI): m / z, calcd. for C24H25N8O4S [M+H]+521.1719, found 521.1716; HPLC purity: 100.0% (tR= 1.03 min). (23) Synthesis of 2-(4-(4-(5-bromopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 295 – 297 °C;1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.34 (s, 1H), 8.51 (s, 1H), 8.34 (d, J = 7.3 Hz, 2H), 7.90 (d, J = 6.9 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.68 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 3.94 – 3.65 (m, 6H), 3.57 – 3.43 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 167.27, 164.83, 158.12, 156.74, 149.81, 140.01, 136.14, 134.09, 128.78, 126.56, 125.68, 121.76, 121.27, 113.89, 104.53, 45.37, 42.42, 42.35, 40.01; HRMS (ESI): m / z, calcd. for C23H21BrN7O2 [M+H]+506.0940, 508.0920 found 506.0957, 508.0938; HPLC purity: 98.9% (tR = 0.99 min). (24) Synthesis of 2-(4-(4-(5-cyanopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp >300 °C (decomposes at this temperature);1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (d, J = 2.9 Hz, 1H), 8.81 (s, 2H), 8.33 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.68 = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.05 – 3.85 (m, 4H), 3.81 – 3.70 (m, 2H), 3.59 – 3.46 (m, 2H); HRMS (ESI): m / z, calcd. for C24H21N8O2 [M+H]+453.1787, found 453.1816; HPLC purity: 95.6% (tR = 1.11 min). (25) Synthesis of 2-(4-(4-(5-ethynylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp >300 °C (decomposes at this temperature);1H NMR (400 MHz, DMSO-d6) δ 13.58 (br s, 1H), 9.39 (s, 1H), 8.53 (s, 2H), 8.34 (d, J = 8.1 Hz, 2H), 7.86 (d, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.34 (t, J = 7.7 Hz, 1H), 4.33 (s, 1H), 4.00 – 3.80 (m, 4H), 3.79 – 3.67 (m, 2H), 3.58 – 3.43 (m, 2H);13C NMR (101 MHz, DMSO) δ 169.16, 166.84, 160.97, 159.68, 152.23, 141.27, 137.64, 136.84, 131.22, 128.32, 127.42, 123.24, 122.68, 122.62, 116.36, 106.06, 84.29, 79.22, 47.27, 44.01, 43.63, 41.88; HRMS (ESI): m / z, calcd. for C25H22N7O2 [M+H]+452.1835, found 452.1836; HPLC purity: 98.7% (tR = 1.20 min). (26) Synthesis of 2-(4-(4-(5-cyano-4-methoxypyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 296 – 298 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.62 (s, 1H), 8.34 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 4.10 – 3.86 (m, 7H), 3.84 – 3.68 (m, 2H), 3.60 – 3.43 (m, 2H); HRMS (ESI): m / z, calcd. for C25H23N8O3 [M+H]+483.1893, found 483.1938; HPLC purity: 98.3% (tR= 1.14 min). (27) Synthesis of 2-(4-(4-(5-ethoxypyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 270 – 272 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (s, 1H), 8.33 (d, J = 8.0 Hz, 2H), 8.24 (s, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 4.04 (dd, J = 6.9 Hz, 2H), 3.83 – 3.59 (m, 6H), 3.53 – 3.41 (m, 2H), 1.30 (t, J = 6.9 Hz, 3H);13C NMR (101 MHz, DMSO-d6) δ 169.00, 167.09, 166.55, 157.54, 151.60, 146.08, 141.88, 138.09, 135.85, 130.51, 128.37, 127.43, 123.60, 123.12, 123.08, 115.64, 65.38, 41.89, 38.54, 15.12; HRMS (ESI): m / z, calcd. for C25H26N7O3 [M+H]+472.2097, found 472.2089; HPLC purity: 96.8% (tR = 1.367min). (28) Synthesis of 2-(4-(4-(5-(cyclopropylmethoxy)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0008] The title compound was prepared according to the method described for preparation of compound 15. Mp 275 – 277 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 8.24 (s, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 3.83 (d, J = 7.1 Hz, 2H), 3.81 – 3.62 (m, 6H), 3.53 – 3.41 (m, 2H), 1.28 – 1.13 (m, 1H), 0.60 – 0.53 (m, 2H), 0.33 – 0.27 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 168.98, 166.52, 157.51, 151.58, 146.26, 146.21, 141.87, 138.07, 135.82, 130.50, 128.34, 127.41, 123.58, 123.09, 123.06, 115.62, 74.38, 47.30, 44.84, 44.36, 41.88, 10.63, 3.55; HRMS (ESI): m / z, calcd. for C27H28N7O3[M+H]+498.2254, found 498.2264; HPLC purity: 99.0 % (tR = 1.72 min). (29) Synthesis of 2-(4-(4-(5-(hydroxymethyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 288 – 290 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.35 (s, 1H), 8.35 (s, 2H), 8.34 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 7.4 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 5.12 (t, J = 5.5 Hz, 1H), 4.35 (d, J = 5.4 Hz, 2H), 3.94 – 3.66 (m, 6H), 3.59 – 3.41 (m, 2H); HRMS (ESI): m / z, calcd. for C24H24N7O3 [M+H]+458.1941, found 458.1924; HPLC purity: 96.6% (tR = 1.07 min). (30) Synthesis of 2-(4-(4-(5-(1-hydroxyethyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 212 – 214 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (s, 1H), 8.37 (s, 2H), 8.33 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 5.19 (d, J = 4.0 Hz, 1H), 4.70 – 4.61 (m, 1H), 3.93 – 3.66 (m, 6H), 3.55 – 3.41 (m, 2H), 1.34 (d, J = 6.5 Hz, 3H); HRMS (ESI): m / z, calcd. for C25H26N7O3 [M+H]+472.2097, found 472.2115; HPLC purity: 96.9% (tR = 1.04 min). (31) Synthesis of 2-(4-(4-(5-isopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 212 – 214 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.35 (s, 1H), 8.37 – 8.28 (m, 3H), 7.90 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 3.92 – 3.64 (m, 6H), 3.56 – 3.41 (m, 2H), 2.85 – 2.72 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H);13C NMR (101 MHz, DMSO-d6) δ 169.02, 166.55, 160.77, 156.60, 151.60, 141.89, 138.08, 135.85, 130.52, 129.82, 128.38, 127.43, 123.61, 123.11, 123.08, 115.65, 47.38, 44.32, 43.74, 41.90, 28.70, 23.92; HRMS (ESI): m / z, calcd. for C26H28N7O2[M+H]+470.2304, found 470.2338; HPLC purity: 93.5% (tR = 1.58 min). (32) Synthesis of 2-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 258 – 260 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (s, 1H), 8.33 (d, J = 8.2 Hz, 2H), 8.21 (s, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 3.91 – 3.64 (m, 6H), 3.56 – 3.40 (m, 2H), 1.83 – 1.74 (m, 1H), 0.94 – 0.84 (m, 2H), 0.69 – 0.60 (m, 2H); HRMS (ESI): m / z, calcd. for C26H26N7O2 [M+H]+468.2148, found 468.2176; HPLC purity: 99.6% (tR = 1.45 min). (33) Synthesis of 2-(4-(4-(4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide

[0009] The title compound was prepared according to the method described for preparation of compound 15. Mp >300 °C (decomposes at this temperature);1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 5.9 Hz, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 6.13 (d, J = 6.1 Hz, 1H), 3.85 – 3.67 (m, 6H), 3.66 – 3.60 (m, 4H), 3.55 – 3.48 (4H), 3.47 – 3.39 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 167.90, 165.46, 161.65, 160.22, 156.03, 150.52, 140.80, 137.05, 134.76, 129.40, 127.27, 126.33, 122.52, 122.03, 122.00, 114.56, 92.88, 65.24, 46.43, 43.12, 43.01, 42.53, 40.97, 39.53, 39.32, 39.11, 38.91, 38.70, 38.49, 38.28; HRMS (ESI): m / z, calcd. for C27H29N8O3[M+H]+513.2363, found 513.2369; HPLC purity: 93.3% (tR= 0.804min). (34) Synthesis of 2-(4-(4-(5-bromo-4-morpholinopyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 274 – 276 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.33 (s, 1H), 8.32 (d, J = 8.1 Hz, 2H), 8.15 (s, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 2.7 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 3.85 – 3.71 (m, 4H), 3.69 – 3.64 (m, 6H), 3.56 – 3.50 (m, 4H), 3.48 – 3.40 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 169.05, 166.58, 161.63, 160.60, 159.67, 151.59, 141.88, 138.02, 135.84, 130.52, 128.36, 127.42, 123.62, 123.14, 123.04, 115.67, 93.72, 66.26, 48.13, 47.32, 44.24, 43.76, 41.84; HRMS (ESI): m / z, calcd. for C27H28BrN8O3[M+H]+591.1468, 593.1447 found 593.1470, 593.1454; HPLC purity: 99.0% (tR = 2.39 min). (35) Synthesis of 2-(4-(4-(5-fluoro-4-morpholinopyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 295 – 297 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.33 (s, 1H), 8.32 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 6.6 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 3.81 – 3.57 (m, 14H), 3.51 – 3.39 (m, 2H); HRMS (ESI): m / z, calcd. for C27H28FN8O3[M+H]+531.2268, found 531.2271; HPLC purity: 99.0% (tR = 2.36 min). (36) Synthesis of 2-(4-(4-(4-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0010] The title compound was prepared according to the method described for preparation of compound 15. Mp 212 – 214 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (s, 1H), 8.32 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 6.14 (d, J = 6.3 Hz, 1H), 4.74 (d, J = 4.2 Hz), 4.07 – 3.91 (m, 2H), 3.84 – 3.62 (m, 6H), 3.52 – 3.37 (m, 2H), 3.13 (t, J = 10.2 Hz, 2H), 1.81 – 1.69 (m, 2H), 1.38 – 1.23 (m, 2H); HRMS (ESI): m / z, calcd. for C28H31N8O3[M+H]+572.2519, found 572.2527; HPLC purity: 94.6% (tR = 0.82 min). (37) Synthesis of 2-(4-(4-(5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2- yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 263 – 265 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 12.12 (s, 1H), 9.34 (s, 1H), 8.68 (br s, 1H), 8.34 (d, J = 7.8 Hz, 2H), 8.05 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 6.29 (br s, 1H), 3.90 – 3.63 (m, 6H), 3.57 – 3.42 (m, 2H), 2.21 (s, 3H); HRMS (ESI): m / z, calcd. for C27H26ClN10O2[M+H]+557.1929, found 557.1955; HPLC purity: 95.4% (tR= 0.60 min). (38) Synthesis of 2-(4-(4-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 270 – 272 °C;1H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 9.34 (s, 1H), 8.42 – 8.38 (s, 1H), 8.34 (d, J = 8.4 Hz, 2H), 8.32 (d, J = 6.0 Hz, 1H), 8.07 (s, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.81 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 6.92 (d, J = 5.1 Hz, 1H), 4.02 – 3.66 (m, 4H), 3.89 (s, 3H), 3.57 – 3.42 (m, 2H), 3.42 – 3.33 (m, 2H); LC-MS (ESI): m / z, 508.3 ([M+H]+calcd. for C27H25N9O2, 508.2); HPLC purity: 100.0% (tR= 1.07 min). (39) Synthesis of 2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0011] The title compound was prepared according to the method described for preparation of compound 15. Mp 272 – 274 °C;1H NMR (400 Hz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.64 (s, 2H), 8.34 (d, J = 8.2 Hz, 2H), 8.10 (s, 1H), 7.90 (d, J = 7.2 Hz, 1H), 7.84 (s, 2H), 7.78 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.93 – 3.70 (m, 6H), 3.57 – 3.44 (m, 2H); HRMS (ESI): m / z, calcd. for C27H26N9O2 [M+H]+508.2209, found 508.2213; HPLC purity: 99.6% (tR = 1.12 min). (40) Synthesis of 2-(4-(4-(5-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 293 – 295 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.82 (s, 2H), 8.34 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 6.8 Hz, 2H), 7.85 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.35 (s, 1H), 4.02 – 3.84 (m, 4H), 3.83 – 3.69 (m, 2H), 3.58 – 3.42 (m, 2H);13C NMR (101 MHz, DMSO) δ 166.87, 164.34, 163.45, 159.72, 156.26, 149.39, 139.69, 135.75, 133.65, 128.39, 126.21, 125.24, 121.41, 120.92, 120.89, 114.54, 113.45, 45.04, 41.84, 41.41, 39.75; HRMS (ESI): m / z, calcd. for C24H22N8O3 [M+H]+471.1893, found 471.1922; HPLC purity: 100.0% (tR = 1.02 min). (41) Synthesis of 2-(4-(4-(4-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 241 – 243 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.35 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 7.9 Hz, 2H), 8.25 (s, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.84 (s, 1H), 7.82 – 7.75 (m, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.38 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 4.07 – 3.84 (m, 4H), 3.83 – 3.66 (m, 2H), 3.58 – 3.42 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 169.06, 166.55, 165.74, 161.20, 160.80, 158.35, 151.64, 141.90, 138.05, 130.59, 128.35, 127.44, 123.61, 115.66, 107.28, 47.39, 47.02, 44.10, 41.93; HRMS (ESI): m / z, calcd. for C24H23N8O3 [M+H]+471.1893, found 471.1921; HPLC purity: 95.0% (tR = 3.14 min). (42) Synthesis of 2-(4-(4-(5-(3-cyanoazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 246 – 248 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.64 (s, 2H), 8.34 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 4.77 – 4.50 (m, 2H), 4.44 – 4.11 (m, 2H), 4.05 – 3.83 (m, 5H), 3.80 – 3.68 (m, 2H), 3.61 – 3.44 (m, 2H); HRMS (ESI): m / z, calcd. for C28H26N9O3 [M+H]+536.2159, found 536.2181; HPLC purity: 100.0% (tR = 1.03 min). (43) Synthesis of 2-(4-(4-(5-(3-hydroxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 286 – 288 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.35 (s, 1H), 8.65 (s, 1H), 8.34 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 5.78 (d, J = 5.3 Hz, 1H), 4.60 – 4.45 (m, 2H), 4.30 – 4.08 (m, 2H), 4.05 – 3.84 (m, 4H), 3.83 – 3.70 (m, 4H), 3.60 – 3.43 (m, 2H); HRMS (ESI): m / z, calcd. for C27H27N8O4 [M+H]+527.2155, found 527.2158; HPLC purity: 97.6% (tR = 1.03 min). (44) Synthesis of 2-(4-(4-(5-(methylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0012] The title compound was prepared according to the method described for preparation of compound 15. Mp 253 – 255 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.79 (s, 2H), 8.37 (q, J = 4.7 Hz, 1H), 8.34 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.7 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 4.02 – 3.83 (m, 4H), 3.81 – 3.67 (m, 2H), 3.58 – 3.45 (m, 2H), 2.77 (d, J = 4.4 Hz, 3H);13C NMR (101 MHz, DMSO-d6) δ 169.07, 166.54, 164.34, 161.83, 157.95, 151.59, 141.89, 137.95, 135.85, 130.59, 128.41, 127.44, 123.61, 123.12, 123.09, 117.09, 115.65, 47.33, 44.03, 43.66, 41.90, 26.34; HRMS (ESI): m / z, calcd. for C25H25N8O3485.2050 [M+H]+found 485.2046; HPLC purity: 100.0% (tR= 1.06 min). (45) Synthesis of 2-(4-(4-(5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 293 – 295 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 9.00 (t, J = 6.2 Hz, 1H), 8.85 (s, 2H), 8.34 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.15 – 4.04 (m, 2H), 4.03 – 3.85 (m, 4H), 3.82 – 3.69 (m, 2H), 3.59 – 3.45 (m, 2H), 3.17 (d, J = 5.2 Hz, 3H);13C NMR (101 MHz, DMSO-d6) δ 169.06, 166.53, 164.63, 161.97, 158.43, 151.57, 141.88, 137.91, 135.84, 130.59, 128.41, 127.43, 125.25 (d, J = 279.5 Hz), 123.60, 123.11, 123.08, 115.82, 115.64, 55.38, 47.25, 44.13, 43.71, 41.88; HRMS (ESI): m / z, calcd. for C26H24F3N8O3[M+H]+553.1923, found 500.2064; HPLC purity: 100% (tR = 0.99 min). (46) Synthesis of 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 295 – 297 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (s, 1H), 8.77 (s, 2H), 8.36 (d, J = 5.9 Hz, 1H), 8.33 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.02 – 3.84 (m, 4H), 3.82 – 3.68 (m, 2H), 3.58 – 3.45 (m, 2H), 2.83 – 2.75 (m, 1H), 0.73 – 0.66 (m, 2H), 0.58 – 0.51 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 169.07, 166.56, 165.16, 161.85, 158.03, 151.58, 141.89, 137.93, 135.84, 130.59, 128.41, 127.44, 123.62, 123.13, 123.08, 116.96, 115.65, 47.25, 44.04, 43.64, 41.88, 23.19, 6.25; HRMS (ESI): m / z, calcd. for C27H27N8O3[M+H]+511.2206, found 511.2227; HPLC purity: 95.6% (tR = 1.11 min). (47) Synthesis of 2-(4-(4-(5-((3,3-difluorocyclobutyl)carbamoyl)pyrimidin-2-yl)piperazine- 1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0013] The title compound was prepared according to the method described for preparation of compound 15. Mp 248 – 250 °C;1H NMR (400 MHz, DMSO-d6) 13.56 (s, 1H), 9.34 (s, 1H), 8.80 (s, 2H), 8.72 (d, J = 6.4 Hz, 1H), 8.34 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 7.8 Hz, 1H), 4.00 – 3.85 (m, 4H), 3.80 – 3.70 (m, 2H), 3.55 – 3.45 (m, 2H), 3.02 – 2.89 (m, 2H), 2.78 – 2.64 (m, 2H), 1.29 – 1.23 (m, 1H); HRMS (ESI): m / z, calcd. for C28H27F2N8O3 [M+H]+561.2174, found 561.2175; HPLC purity: 94.8 % (tR= 0.97 min). (48) Synthesis of 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2- yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 286 – 288 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.87 (s, 1H), 8.78 (s, 2H), 8.34 (d, J = 7.3 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.39 (t, J = 7.0 Hz, 1H), 4.03 – 3.84 (m, 4H), 3.81 – 3.69 (m, 2H), 3.58 – 3.44 (m, 2H), 2.46 (s, 1H), 2.08 (s, 6H);13C NMR (101 MHz, DMSO-d6) δ 169.07, 166.56, 164.14, 161.83, 158.14, 151.58, 141.89, 137.94, 135.85, 130.60, 128.41, 127.44, 123.62, 123.12, 123.09, 116.90, 115.65, 52.92, 49.42, 47.41, 44.17, 43.66, 41.98, 25.17; HRMS

[0014] (ESI): m / z, calcd. for C29H29N8O3 [M+H]+537.2363, found 537.2356; HPLC purity: 94.7% (tR = 1.30 min). (49) Synthesis of 2-(4-(4-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp >300 °C (decomposes at this temperature);1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 9.00 (d, J = 6.5 Hz, 1H), 8.84 (s, 2H), 8.34 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 7.1 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 5.06 – 4.94 (m, 1H), 4.78 (t, J = 6.8 Hz, 2H), 4.57 (t, J = 6.4 Hz, 2H), 4.05 – 3.84 (m, 4H), 3.82 – 3.70 (m, 2H), 3.58 – 3.44 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 169.08, 166.56, 163.67, 161.91, 158.28, 151.58, 141.89, 137.93, 135.85, 130.60, 128.41, 127.44, 123.62, 123.13, 123.08, 116.44, 115.65, 77.44, 47.21, 44.78, 44.11, 43.71, 41.98; HRMS (ESI): m / z, calcd. for C27H27N8O4 [M+H]+527.2155, found 527.2150; HPLC purity: 100% (tR = 0.84 min). (50) Synthesis of 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2- yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide 111

[0015] N-(bicyclo[1.1.1]pentan-1-yl)-2-chloropyrimidine-4-carboxamide (50A) To a solution of 2-chloropyrimidine-4-carboxylic acid (200 mg, 1.26 mmol) in dichloromethane (5.0 mL), oxalyl chloride (162 μL, 1.89 mmol) was added dropwise. A catalytic amount of DMF was added and the reaction mixture was refluxed for two hours. Upon reaction completion, the reaction mixture was concentrated under reduced pressure and obtained residue was re-dissolved in tetrahydrofuran (5.0 mL). Bicyclo[1.1.1]pentan-1-amine hydrochloride (185 mg, 1.51 mmol) was added to the reaction mixture and solution was stirred overnight. Then, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine (2 X 5.0 mL) and dried over anhydrous Na2SO4. Organic solvent was removed under reduced pressure and formed residue was purified by flash chromatography (silica gel) using ethyl acetate / hexanes (1:19 to 1:3) to obtain the title compound (191 mg, 68%) as white solid.1H NMR (400 MHz, DMSO-d6) 9.50 (s, 1H), 9.00 (d, J = 4.9 Hz, 1H), 7.97 (d, J = 4.9 Hz, 1H), 2.50 (s, 6H), 2.47 (s, 1H); LC-MS (ESI): m / z, 223.1 ([M]+calcd. for C10H10ClN3O, 223.1). 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide (50B)

[0016] The title compound was prepared according to the method described for preparation of compound 15 using compound 50A. Mp 280 – 282 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.34 (s, 1H), 9.10 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 4.9 Hz, 1H), 4.05 – 3.85 (m, 4H), 3.82 – 3.71 (m, 2H), 3.57 – 3.44 (m, 2H), 2.47 (s, 1H), 2.12 (s, 6H);13C NMR (101 MHz, DMSO-d6) δ 169.07, 166.60, 163.95, 161.14, 160.79, 158.15, 151.62, 141.91, 138.01, 135.90, 130.58, 128.32, 127.48, 123.58, 123.07, 115.68, 107.19, 53.00, 49.17, 47.46, 44.15, 43.70, 42.01, 25.15; HRMS (ESI): m / z, calcd. for C29H29N8O3 [M+H]+537.2363, found 537.2385; HPLC purity: 94.7% (tR = 1.30 min). (51) Synthesis of 2-(4-(4-(4-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide 2-chloro-N-(oxetan-3-yl)pyrimidine-4-carboxamide (51A) Compound 51A was synthesized following the procedure for the synthesis of compound 50A using 2-chloropyrimidine-4-carboxylic acid (300 mg, 1.89 mmol), oxalyl chloride (243 μL, 2.94 mmol), a catalytic amount of DMF, and 3-aminooxetane (166 mg, 159 µl, 2.27 mmol) and obtained the amide (286 mg, 71%) as white solid.1H NMR (400 MHz, DMSO- d6) δ 9.72 (d, J = 6.5 Hz, 1H), 9.02 (d, J = 4.9 Hz, 1H), 8.00 (d, J = 4.9 Hz, 1H), 5.08 – 4.97 (m, 1H), 4.77 – 4.65 (m, 4H); LC-MS (ESI): m / z, 213.1 ([M+H]+calcd. for C8H8ClN3O2, 213.1). 2-(4-(4-(4-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide (51B) The title compound was prepared according to the method described for preparation of compound 15 using compound 51A. Mp 280 – 282 °C;1H NMR (400 MHz, DMSO-d6) ; LC- MS (ESI): m / z, 527.3 ([M+H]+calcd. for C27H26N8O4, 527.3); HPLC purity: 94.7% (tR= 1.30 min). (52) Synthesis of 2-(4-(4-(4-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0017] 2-chloro-N-cyclopropylpyrimidine-4-carboxamide (52A) Compound 52A was synthesized following the procedure for the synthesis of compound 50A using 2-chloropyrimidine-4-carboxylic acid (200 mg, 1.26 mmol), oxalyl chloride (162 μL, 1.89 mmol), a catalytic amount of DMF, and cyclopropylamine (86 mg, 105µl, 1.51 mmol) and obtained the amide (191 mg, 68%) as white solid.1H NMR (400 MHz, DMSO- d6) δ 9.00 (d, J = 4.5 Hz, 1H), 8.00 (d, J = 5.0 Hz, 1H), 2.97 – 2.88 (m, 1H), 0.76 – 0.66 (m, 4H); LC-MS (ESI): m / z, 197.0 ([M+H]+calcd. for C8H8ClN3O, 197.0). 2-(4-(4-(4-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide (52B) The title compound was prepared according to the method described for preparation of compound 15 using compound 52A.1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.34 (s, 1H), 8.62 (s, 1H), 8.59 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 7.8 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 4.7 Hz, 1H), 4.08 – 3.84 (m, 4H), 3.82 – 3.70 (m, 2H), 3.56 – 3.44 (m, 2H), 2.88 – 2.77 (m, 1H), 0.77 – 0.59 (m, 4H);13C NMR (101 MHz, DMSO-d6) δ 169.07, 166.70, 164.87, 161.10, 160.82, 157.98, 151.71, 137.92, 130.72, 128.31, 127.46, 123.52, 122.94, 107.25, 47.39, 44.15, 43.74, 42.07, 23.22, 6.37; HRMS (ESI): m / z, calcd. for C27H27N8O3 [M+H]+511.2206, found 511.2201; HPLC purity: 94.9% (tR= 1.30 min). (53) Synthesis of 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine- 1-carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 244 – 246 °C;1H NMR (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 9.30 (s, 1H), 8.88 (s, 1H), 8.78 (s, 2H), 8.33 (d, J = 7.7 Hz, 2H), 8.04 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 9.6 Hz, 2H), 4.02 – 3.83 (m, 4H), 3.82 – 3.70 (m, 2H), 3.57 – 3.45 (m, 2H), 2.46 (s, 1H), 2.08 (s, 6H); HRMS (ESI): m / z, calcd. for C29H28FN8O3 [M+H]+555.2268, found 555.2273; HPLC purity: 95.8% (tR = 2.08 min). (54) Synthesis of 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2- yl)piperazine-1-carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide

[0018] The title compound was prepared according to the method described for preparation of compound 15. Mp 247 – 249 °C;1H NMR (400 MHz, DMSO-d6) δ 13.70 (s, 1H), 9.30 (s, 1H), 9.11 (s, 1H), 8.60 (d, J = 5.2 Hz, 1H), 8.33 (d, J = 8.1 Hz, 2H), 8.05 (s, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 9.1 Hz, 2H), 7.13 (d, J = 4.7 Hz, 1H),4.09 – 3.83 (m, 4H), 3.82 – 3.68 (m, 2H), 3.56 – 3.41 (m, 2H), 2.47 (s, 1H), 2.11 (s, 6H); HRMS (ESI): m / z, calcd. for C29H28FN8O3 [M+H]+555.2268, found 555.2277; HPLC purity: 97.5% (tR = 1.03 min). (55) Synthesis of 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp >300 °C (decomposes at this temperature); (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 9.29 (s, 1H), 8.77 (s, 2H), 8.37 (d, J = 3.4 Hz, 1H), 8.33 (d, J = 7.9 Hz, 2H), 8.04 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 9.0 Hz, 2H), 4.03 – 3.82 (m, 4H), 3.80 – 3.68 (m, 2H), 3.58 – 3.43 (m, 2H), 2.84 – 2.74 (m, 1H), 0.73 – 0.65 (m, 2H), 0.59 – 0.49 (m, 2H); HRMS (ESI): m / z, calcd. for C27H26FN8O3 [M+H]+529.2112, found 529.2093; HPLC purity: 99.3% (tR = 1.18 min). (56) Synthesis of 6-fluoro-2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine- 1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15.. Mp >300 °C (decomposes at this temperature);1H NMR (400 MHz, DMSO-d6) δ 13.69 (s, 1H), 9.29 (s, 1H), 8.64 (s, 2H), 8.32 (d, J = 8.0 Hz, 2H), 8.10 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 10.3 Hz, 2H), 3.94 – 3.69 (m, 6H), 3.86 (s, 3H), 3.55 – 3.42 (m, 2H); HRMS (ESI): m / z, calcd. for C27H25FN9O2 [M+H]+526.2115, found 526.2119; HPLC purity: 99.4% (tR = 1.20 min). (57) Synthesis of ethyl 2-(4-((4-(4-carbamoyl-1H-benzo[d]imidazol-2- yl)benzamido)methyl)piperidin-1-yl)pyrimidine-5-carboxylate The title compound was prepared according to the method described for preparation of compound 15. Mp 247 – 249 °C;1H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H), 9.31 (s, 1H), 8.77 (s, 2H), 8.70 (t, J = 5.2 Hz, 1H), 8.32 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.80 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 4.77 (d, J = 13.2 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.23 (t, J = 5.9 Hz, 2H), 3.01 (t, J = 11.8 Hz, 2H), 2.04 – 1.90 (m, 1H), 1.88 – 1.78 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.21 – 1.07 (m, 2H);13C NMR (101 MHz, DMSO-d6) δ 166.55, 166.16, 164.49, 162.02, 159.87, 151.51, 141.90, 136.53, 135.84, 131.79, 128.47, 127.17, 123.66, 123.17, 123.12, 115.62, 111.99, 60.63, 45.09, 43.97, 36.38, 30.00, 14.66; HRMS (ESI): m / z, calcd. for C28H30N7O4[M+H]+528.2359, found 528.2354; HPLC purity: 97.8% (tR= 1.70 min). (58) Synthesis of ethyl 2-(3-((4-(4-carbamoyl-1H-benzo[d]imidazol-2- yl)benzamido)methyl)azetidin-1-yl)pyrimidine-5-carboxylate The title compound was prepared according to the method described for preparation of compound 15. Mp 211 – 213 °C;1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.31 (s, 1H), 8.86 (t, J = 5.1 Hz, 1H), 8.75 (s, 2H), 8.33 (d, J = 8.1 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 4.31 – 4.19 (m, 4H), 3.98 (dd, J = 9.7, 5.0 Hz, 2H), 3.60 (t, J = 6.2 Hz, 2H), 3.06 – 2.93 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H);13C NMR (101 MHz, DMSO-d6) δ 166.53, 164.63, 162.78, 159.79, 151.44, 141.88, 136.26, 135.84, 131.93, 128.47, 127.20, 123.67, 123.21, 123.12, 115.64, 112.61, 60.72, 53.56, 42.69, 29.66, 14.64; HRMS (ESI): m / z, calcd. for C26H26N7O4 [M+H]+500.2046, found 500.2044; HPLC purity: 96.8% (tR= 1.24 min). (59) Synthesis of ethyl 2-(3-(4-(4-carbamoyl-1H-benzo[d]imidazol-2- yl)benzamido)azetidin-1-yl)pyrimidine-5-carboxylate

[0019] The title compound was prepared according to the method described for preparation of compound 15. Mp 275 – 277 °C;1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.31 (s, 1H), 9.28 (d, J = 7.1 Hz, 2H), 8.81 (s, 2H), 8.36 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.3 Hz, 2H), 7.89 (d, J = 6.9 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 4.98 – 4.88 (m, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.21 (dd, J = 9.9, 5.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H);13C NMR (101 MHz, DMSO-d6) δ 166.54, 165.95, 164.62, 162.66, 159.86, 151.40, 141.88, 135.84, 135.73, 132.17, 128.60, 127.24, 123.70, 123.24, 123.12, 115.67, 112.92, 60.81, 57.26, 40.51, 14.66; HRMS (ESI): m / z, calcd. for C25H24N7O4 [M+H]+486.1890, found 486.1879; HPLC purity: 97.6% (tR= 1.68 min). (60) Synthesis of ethyl 2-(6-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyrimidine-5-carboxylate The title compound was prepared according to the method described for preparation of compound 15. Mp 260 – 262 °C;1H NMR (400 MHz, DMSO) δ 13.56 (s, 1H), 9.31 (s, 1H), 8.77 (s, 2H), 8.33 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.3 Hz, 1H), 7.87 – 7.80 (m, 3H), 7.77 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 4.61 (s, 2H), 4.39 – 4.27 (m, 6H), 4.26 (q, J = 7.0 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H);13C NMR (101 MHz, DMSO-d6) δ 168.55, 166.54, 164.59, 162.41, 159.78, 151.41, 141.88, 135.85, 135.09, 131.70, 128.98, 127.31, 123.67, 123.20, 123.12, 115.67, 112.91, 63.05, 60.78, 60.22, 59.05, 33.58, 14.64; HRMS (ESI): m / z, calcd. for C27H26N7O4 [M+H]+512.2046, found 512.2063; HPLC purity: 96.9% (tR= 1.23 min). (61) Synthesis of 2-(4-(((1-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 240 – 242 °C;1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 9.32 (s, 1H), 8.87 (t, J = 5.5 Hz, 1H), 8.70 (s, 2H), 8.38 – 8.30 (m, 3H), 8.03 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.4 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.38 (t, J = 7.7 Hz, 1H), 4.18 (t, J = 8.7 Hz, 2H), 3.98 – 3.87 (m, 2H), 3.65 – 3.55 (m, 2H), 3.04 – 2.92 (m, 1H), 2.82 – 2.72 (m, 1H), 0.72 – 0.63 (m, 2H), 0.57 – 0.47 (m, 2H).13C NMR (101 MHz, DMSO-d6) δ 166.53, 165.37, 162.78, 157.90, 151.56, 141.87, 136.31, 135.95, 131.93, 130.33, 128.32, 127.24, 123.60, 123.11, 116.75, 115.66, 53.58, 42.83, 29.65, 23.17, 6.21; HRMS (ESI): m / z, calcd. for C27H27N8O3[M+H]+511.2206, found 511.2217; HPLC purity: 95.1% (tR= 1.18 min). (62) Synthesis of 2-(4-(((1-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0020] The title compound was prepared according to the method described for preparation of compound 15. Mp 231 – 233 °C;1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 9.32 (s, 1H), 8.95 (d, J = 6.4 Hz, 1H), 8.87 (t, J = 5.2 Hz, 1H), 8.76 (s, 2H), 8.33 (d, J = 8.3 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.84 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 5.01 – 4.91 (m, 1H), 4.74 (t, J = 6.9 Hz, 2H), 4.54 (t, J = 6.4 Hz, 2H), 4.20 (t, J = 8.6 Hz, 2H), 3.94 (dd, J = 9.1, 5.0 Hz, 2H), 3.63 – 3.54 (m, 2H), 3.04 – 2.94 (m, 1H);13C NMR (101 MHz, DMSO-d6) δ 166.60, 166.55, 163.84, 162.78, 158.08, 151.57, 141.87, 136.22, 135.91, 132.09, 128.43, 127.24, 123.51, 123.08, 116.24, 115.71, 77.43, 53.59, 44.71, 42.79, 29.61; HRMS (ESI): m / z, calcd. for C27H27N8O4 [M+H]+527.2155, found 527.2141; HPLC purity: 99.1% (tR = 1.03 min). (63) Synthesis of 2-(4-(((1-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2- yl)azetidin-3-yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide The title compound was prepared according to the method described for preparation of compound 15. Mp 247 – 249 °C;1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 9.32 (s, 1H), 8.92 (s, 1H), 8.87 (t, J = 4.1 Hz, 1H), 8.54 (d, J = 4.6 Hz, 1H), 8.34 (d, J = 8.2 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 7.2 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 5.1 Hz, 1H), 4.20 (t, J = 8.4 Hz, 2H), 3.98 – 3.88 (m, 2H), 3.65 – 3.56 (m, 2H), 3.05 – 2.93 (m, 1H), 2.51 (s, 6H), 2.46 (s, 1H);13C NMR (101 MHz, DMSO-d6) δ 166.54, 166.46, 164.03, 162.50, 160.73, 158.04, 151.42, 141.89, 136.30, 135.94, 131.86, 128.44, 127.24, 123.66, 123.13, 115.72, 106.91, 53.90, 52.95, 49.04, 43.02, 29.69, 25.10; HRMS , calcd. for C29H29N8O3 [M+H]+537.2363, found 537.2381; HPLC purity: 95.7% (tR = 1.65 min). (64) Synthesis of 2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine- 7-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 64 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 9.34 (s, 1H), 8.37 (d, J = 7.9 Hz, 2H), 7.95-7.70 (m, 5H), 7.39 (t, J = 7.8 Hz, 1H), 5.00 (s, 2H), 4.42-3.76 (m, 4H). ESI-MS: m / z 456.1 (C21H16F3N7O2, requires 456.1, [M + H]+). (65) Synthesis of 2-(3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine-7-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 65 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 9.29 (s, 1H), 8.46-8.33 (m, 2H), 7.90 (d, J = 7.5 Hz, 1H), 7.81-7.63 (m, 4H), 7.37 (t, J = 7.8 Hz, 1H), 5.04 (s, 2H), 4.42-3.80 (m, 4H). ESI-MS: m / z 456.1 (C21H16F3N7O2, requires 456.1, [M + H]+). (66) Synthesis of ethyl 7-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-5,6,7,8- tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate Compound 66 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 9.35 (s, 1H), 8.36 (d, J = 8.0 Hz, 2H), 7.98-7.67 (m, 5H), 7.39 (t, J = 7.8 Hz, 1H), 5.01 (s, 2H), 4.46-4.32 (m, 4H), 3.92 (s, 2H), 1.34 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 460.2 (C23H21N7O4, requires 460.2, [M + H]+). (67) Synthesis of 2-(4-(3-cyclopentyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 67 was prepared according to Scheme 4. (68) Synthesis of 2-(4-(3-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0021] Compound 68 was prepared according to Scheme 4. (69) Synthesis of 2-(4-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 69 was prepared according to Scheme 4. (70) Synthesis of 2-(3-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- Compound 70 was prepared according to Scheme 4. (71) Synthesis of 2-(4-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine-7-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0022] Compound 71 was prepared according to Scheme 4. (72) Synthesis of 2-(3-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- Compound 72 was prepared according to Scheme 4. (73) Synthesis of 2-(4-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyrazine-7-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 73 was prepared according to Scheme 4. (74) Synthesis of 2-(3-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine- 7-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 74 was prepared according to Scheme 4. (75) Synthesis of 2-(4-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 75 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 12.34 (s, 1H), 9.33 (s, 1H), 8.88 (t, J = 5.7 Hz, 1H), 8.33 (d, J = 8.1 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H), 7.94-7.74 (m, 3H), 7.62-7.34 (m, 3H), 7.13 (dd, J = 6.2, 2.9 Hz, 2H), 3.77 (q, J = 6.7 Hz, 2H), 3.13 (t, J = 7.4 Hz, 2H). ESI-MS: m / z 425.2 (C24H20N6O2, requires 425.2, [M + H]+). (76) Synthesis of 2-(3-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 76 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 12.35 (s, 1H), 9.37 (s, 1H), 8.95 (t, J = 5.6 Hz, 1H), 8.73 (t, J = 1.8 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.93-7.80 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.61-7.32 (m, 3H), 7.19-7.07 (m, 2H), 3.79 (q, J = 6.9 Hz, 2H), 3.15 (t, J = 7.4 Hz, 2H). ESI-MS: m / z 425.2 (C24H20N6O2, requires 425.2, [M + H]+). (77) Synthesis of 2-(4-(4-(1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 77 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 11.51 (s, 1H), 9.35 (s, 1H), 8.35 (d, J = 8.1 Hz, 2H), 7.95-7.74 (m, 3H), 7.69 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.30-7.17 (m, 2H), 7.04-6.84 (m, 2H), 3.94-3.46 (m, 8H). HRMS (m / z): [M + H]+calcd for C26H23N7O2, requires 466.1992; found: 466.1976. HPLC tR= 2.78 min (95.70% purity). (78) Synthesis of 2-(3-(4-(1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 78 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 11.51 (s, 1H), 9.34 (s, 1H), 8.42-8.26 (m, 2H), 7.90 (dd, J = 7.6, 1.1 Hz, 1H), 7.86- 7.61 (m, 4H), 7.38 (t, J = 7.8 Hz, 1H), 7.32-7.13 (m, 2H), 7.08-6.80 (m, 2H), 3.97-3.46 (m, 8H). ESI-MS: m / z 466.2 (C26H23N7O2, requires 466.2, [M + H]+). (79) Synthesis of 2-(4-((1-(1H-benzo[d]imidazol-2-yl)-2-methylpropan-2- yl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide

[0023] Compound 79 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 12.33 (s, 1H), 9.34 (s, 1H), 8.43 (s, 1H), 8.40-8.29 (m, 2H), 8.07-7.98 (m, 2H), 7.91 (dd, J = 7.6, 1.1 Hz, 1H), 7.87-7.74 (m, 2H), 7.65-7.44 (m, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.21-7.10 (m, 2H), 3.32 (s, 2H), 1.51 (s, 6H). ESI-MS: m / z 453.2 (C26H24N6O2, requires 453.2, [M + H]+). (80) Synthesis of methyl 2-(2-(4-(4-carbamoyl-1H-benzo[d]imidazol-2- yl)benzamido)ethyl)-1H-benzo[d]imidazole-5-carboxylate Compound 80 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 12.74 (s, 1H), 9.33 (s, 1H), 8.89 (s, 1H), 8.33 (d, J = 8.0 Hz, 2H), 8.21 – 7.99 (m, 3H), 7.90 (d, J = 7.5 Hz, 1H), 7.87 – 7.71 (m, 3H), 7.59 (s, 1H), 7.39 (t, J = 7.7 Hz, 1H), 3.86 (s, 3H), 3.83 – 3.72 (m, 2H), 3.18 (t, J = 7.2 Hz, 2H). ESI-MS: m / z 483.2 (C26H22N6O4, requires 483.2, [M + H]+). (81) Synthesis of Sodium 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2- yl)benzoyl)piperazin-1-yl)pyrimidine- 5-carboxylate

[0024] Compound 81 was prepared by treating compound 15 (100 mg, 0.21 mmol) with NaOH (17 mg, 0.42 mmol) and THF / H2O in 1:1 ratio. The reaction was then subjected to reverse phase flash purification by using 0-100% methanol in water as the mobile phase, in a gradient manner to obtain 81 as a pale-yellow powder which was re-dissolved in water and subjected to freeze drying process. (50 mg, 49% yield), mp >310 °C.1H NMR (400 MHz, DMSO-d6) o 9.43 (s, 1H), 8.77 (s, 2H), 8.56-8.35 (m, 2H), 7.87 (ddd, J = 13.9, 7.8, 1.2 Hz, 2H), 7.81-7.71 (m, 1H),7.71-7.58 (m, 2H),7.32 (t, J = 7.8 Hz, 1H), 4.02-3.36 (m, 8H); HRMS (m / z): [M + H]+ calcd forC24H22N7O4(due to neutralization of salt by solvent), requires 472.1728; found 472.1748.(82) Synthesis of2-(3-((2-Amino-4,5-dimethylphenyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide A mixture of carboxylic acid (4-(4-carbamoyl-1h-benzo[d]imidazol-2-yl)benzoicacid), HBTU (1.1 eq), EtN(i-Pr)2(2 eq),appropriate amine (1.1 eq) and DMF were added toa flask and stirred overnight. Subsequently, DMF was removed via addition of ethyl acetateinto the reaction mixture and extraction of themixture three times with saturated NaHCO3and three times with brine solution. The resultant organic layer was dried using MgSO4. A slurry of filtrate with silica was prepared and concentrated. The mixture was then purified by flash chromatography using DMC:MeOH (~ 9:1) as eluent to obtain 82 as a white powder. The mixture was then subjected to flash chromatographic purification using DCM:MeOH (usually in the ratio of 90:10; run time varied depending on column size) as mobile phase, with gradient elution to obtain products in 23-63% yields (60 mg, 42% yield).1H NMR (400 MHz, DMSO-d6) o 13.60 (s, 1H), 9.84 (s, 1H), 9.38 (d, J = 3.5 Hz, 1H), 8.82 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.93 – 7.87 (m, 1H), 7.85 (s, 1H), 7.80 – 7.69 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 6.97 (s, 1H), 6.62 (s, 1H), 4.76 (s, 2H), 2.12 (d,J =9.9 Hz, 6H). 13C NMR (101 MHz, DMSO-d6) o 166.55, 165.81, 151.70, 144.23, 141.86,135.86, 135.77, 130.20, 129.74, 129.68, 128.73, 128.38, 126.98, 123.60, 123.32, 123.09, 123.05, 116.43, 116.40, 115.65, 55.38. ESI-MS (low resolution) (m / z): [M + H]+calcd for C23H21N5O2, requires 399.17; found: 399.17. (83) Synthesis of 2-(4-((2-(5-methyl-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 83 was prepared as a white solid according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 12.17 (s, 1H), 9.32 (s, 1H), 8.86 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 8.04 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 7.5 Hz, 1H), 7.81 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.44 – 7.37 (m, 1H), 7.36 – 7.28 (m, 1H), 7.21 (s, 1H), 6.95 (t, J = 8.7 Hz, 1H), 3.74 (dd, J = 12.6, 6.7 Hz, 2H), 3.09 (t, J = 7.2 Hz, 2H), 2.40 (s, 3H). HRMS (m / z): [M + H]+calcd for C25H23N6O2, requires 439.1883; found 439.1877: HPLC tR= 2.35 min (100 % purity). (84) Synthesis of 2-(4-((2-(5-chloro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 84 was prepared as a white solid according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ13.54 (s, 1H), 12.53 (s, 1H), 9.32 (s, 1H), 8.86 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 7.4 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.63 – 7.52 (m, 1H), 7.52 – 7.42 (m, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.6 Hz, 1H), 3.74 (dd, J = 13.4, 6.7 Hz, 2H), 3.12 (dd, J = 13.3, 10.2 Hz, 2H). (85) Synthesis of tert-butyl 4-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H- 1,2,3-triazol-1-yl)piperidine-1-carboxylate Compound 85 was prepared according to the procedures used to prepare compound 9 using tert-butyl 4-azidopiperidine-1-carboxylate.1HNMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 9.37 (s, 1H), 8.90 (s, 1H), 8.34 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.35 (t, J = 7.9 Hz, 1H), 3.16 – 2.86 (m, 4H), 2.15 (d, J = 10.8 Hz, 3H), 1.89 (d, J = 11.8 Hz, 2H), 1.42 (s, 9H); HRMS (m / z): [M + H]+calcd for C26H30N7O3, requires 488.2332; found: 488.2377. HPLC tR= 2.20 min (100 % purity). (86) Synthesis of 2-(4-(4-methoxypiperidine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide Compound 86 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.52 (s, 1H), 9.34 (s, 1H), 8.30 (d, J = 7.7 Hz, 2H), 7.88 (d, J = 7.0 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.8 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 3.95 (s, 1H), 3.46 (s, 1H), 3.41 – 3.37 (m, 1H), 3.27 (s, 3H), 3.21 – 3.15 (m, 1H), 1.86 (d, J = 34.1 Hz, 2H), 1.47 (s, 2H), 1.09 (t, J = 7.0 Hz, 1H). (87) Synthesis of 2-(4-(4,7-diazaspiro[2.5]octane-4-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide Compound 87 was synthesized using compound 1A (500 mg, 1.78 mmol) and tert-butyl 4,7-diazaspiro[2.5]octane-7-carboxylate (416 mg, 1.96 mmol) following steps and using procedure similar to that described for the synthesis of compound 1, and was obtained as a white solid (507 mg, 73%).1H NMR (400 MHz, DMSO-d6) δ13.69 (s, 1H), 9.33 (s, 1H), 8.35 (d, J = 7.8 Hz, 2H), 7.98 – 7.80 (m, 3H), 7.77 = 7.8 Hz, 2H), 7.41 (t, J = 7.7 Hz, 1H), 3.73 (t, J = 6.2 Hz, 2H), 3.19 (d, J = 7.3 Hz, 4H), 1.15 (dd, J = 6.9, 7.6 Hz, 5H). (88) Synthesis of 2-(4-(2,2-dimethylpiperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide Compound 88 was synthesized using compound 1A (0.1 g, 0.35 mmol), DIPEA (0.17 mL, 1.30 mmol), HBTU (0.148 g, 0.29 mmol), and tert-butyl 3,3-dimethylpiperazine-1- carboxylate (0.077 g, 0.36 mmol) following steps and using procedure similar to that described for the synthesis of compound 1 and was obtained as a white solid (0.07 g, 88% yield).1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 2H), 9.17 (s, 1H), 8.36 (d, J = 7.9 Hz, 2H), 7.97 – 7.72 (m, 4H), 7.71 (d, J = 7.9 Hz, 2H), 7.41 (t, J = 7.7 Hz, 2H), 3.51 (d, J = 4.1 Hz, 2H), 3.20 (d, J = 6.2 Hz, 4H), 1.53 (d, J = 7.7 Hz, 6H). (89) Synthesis of 2-(4-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 89 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 9.36 (s, 1H), 8.35 (d, J = 7.0 Hz, 1H), 7.92 (d, J = 6.8 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 5.8 Hz, 4H), 7.40 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 7.03 (s, 1H), 6.77 (d, J = 7.0 Hz, 1H), 3.81 (s, 2H), 3.55 (s, 4H), 3.38 (s, 2H), 2.33 (s, 3H). (90) Synthesis of 2-(4-(4-(5-chloro-1H-benzo[d]imidazol-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 90 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6)1H NMR (400 MHz, DMSO) δ 13.55 (s, 1H), 11.67 (d, J = 4.3 Hz, 1H), 9.34 (s, 1H), 8.34 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 6.8 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.74 – 7.65 (m, 3H), 7.39 (t, J = 7.8 Hz, 1H), 7.26 – 7.16 (m, 1H), 7.01 – 6.91 (m, 1H), 3.80 (s, 2H), 3.59 (s, 6H). (91) Synthesis of 2-(4-(4-(5-bromo-1H-benzo[d]imidazol-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide Compound 91 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 11.68 (s, 1H), 9.34 (s, 1H), 8.34 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.39 (dd, J = 9.2, 6.2 Hz, 1H), 7.31 (s, 1H), 7.21 – 7.10 (m, 1H), 7.05 (d, J = 8.0 Hz, 1H), 3.80 (s, 2H), 3.59 (s, 6H). (92) Synthesis of 2-(4-((2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide Compound 92 was prepared according to Scheme 4.1H NMR (400 MHz, DMSO-d6) δ13.54 (s, 1H), 12.56 (s, 1H), 9.31 (s, 1H), 8.84 (s, 1H), 8.33 (d, J = 8.1 Hz, 2H), 8.04 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.4 Hz, 1H), 7.57 (s, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.32 (t, J = 8.6 Hz, 1H), 3.73 (dd, J = 13.4, 6.7 Hz, 2H), 3.10 (dd, J = 13.3, 10.2 Hz, 2H). Example 2: PARP inhibitors (PARPis) for treating cancer and / or neurodegenerative disease(s) The inhibition assay described herein and a PARP isoform selectivity assays were used to study the activity of certain exemplary compounds disclosed herein. In one aspect, the data provided herein regarding inhibition of one or more PARP isoforms demonstrates that certain compounds provided herein are useful for treating cancer (Tables 2-3). In another aspect, the data provided herein regarding inhibition of one or more PARP isoforms demonstrates that certain compounds provided herein are useful for treating neurodegenerative disease(s) (Tables 2-3). In certain embodiments, a compound which demonstrates at least about 10-fold greater inhibition for a first PARP isoform as compared to a second PARP isoform is considered a selective inhibitor of the first PARP isoform over the second PARP isoform. In certain embodiments, a compound which demonstrates at least about 100-fold greater inhibition for a first PARP isoform as compared to a second PARP isoform is considered a selective inhibitor of the first PARP isoform over the second PARP isoform. In certain embodiments, a compound which inhibits a first PARP isoform and does not significantly inhibit a second PARP isoform is considered selective. Table 2. Biological activities for certain compounds of the disclosurea a IC50data shown are mean values obtained from two independent experiments performed in duplicate; IC50< 1 nM (A); IC50= 1-5 nM (B); IC50> 5 nM (C). Table 3. Selectivity profile of certain exemplary compounds against selected PARP-isoforms Example 3: Biochemical analysis of pro-retention behavior on DNA damage The catalytic inhibition of all target compounds was analyzed using a PARP1 enzyme assay (BPS Bioscience, San Diego, CA) and their potency was largely comparable to the inhibition demonstrated by veliparib except for compound 76 which showed a ~100-fold decrease in potency. PARP1 affinity for DNA damage in the presence of target compounds was assessed via anequilibrium binding constant (KD) obtained with a fluorescencepolarization (FP) DNA binding assay performed in solution (FIG.1B). In addition, an FP DNA competition assay was used to test the ability of target compounds to promote PARP1 DNA retention in the presence of competitor DNA breaks in solution (FIG.1A). An SDS- PAGE activity assay was conducted to ensure that saturating amounts of target compounds were used in both FP assays. The results obtained for certain target compounds with the PARP1 enzyme assay, DNA binding affinity assay, and DNA competition assay are provided herein (Table 4). Table 4. Exemplary data for certain compounds Substitution at the 4-carboxy group of the pyrimidin-2-yl-piperazine to obtain 13 resulted in an approximately nine-fold decrease in the PARP1 inhibition compared to veliparib. Compound 13 did not display significant DNA retention phenotype although it mildly increased PARP1 DNA binding affinity. The equivalent substituent at the 3-carboxy group led to 14 which also did not display any pro-retention phenotype and increased PARP1 DNA binding affinity to a lesser extent than compound 13. Next, a methyl ester group was introduced on the pyrimidine ring to potentially destabilize the HD and trigger PARP1 reverse allostery due to the bulkiness and electronegative property of the substituent. Adding a methyl ester group at the C5-position of the pyrimidine ring of 13 led to 15 with PARP1 inhibitory activity that was comparable to veliparib. When tested, 15 drastically increased PARP1 retention on DNA breaks akin to other type I PARPis such as BAD and EB-47, two NAD+analogs. PARP1 DNA binding affinity in the presence of 15 was also greatly increased. Hydrolysis of the methyl ester group led to compound 81 which promoted a rather mild DNA pro-retention phenotype compared to 15. Given that 13, 15 and 81 all share the same pyrimidin- 2-yl-piperazine motif, it appears that the addition of a non-hydrolyzed methyl ester group is essential to trigger the intense pro-retention phenotype seen with 15. An alternative of pyrimidin-2-yl-piperazine was incorporated in the form of a benzimidazol-2-yl-piperazine motif either in para-(77) or meta-(78) position. Compound 77 showed a good retention phenotype, as compared to its meta-counterpart. It appears that both para- and meta-substituted compounds increased PARP1 DNA binding affinity to the same extent despite their different retention phenotype. Although compound 77 showed a promising retention phenotype, the level of retention was comparatively less than that which was observed for compound 15. Replacement of the piperazine motif for a more flexible ethylamine motif led to compound 75. Compound 75 displayed a slightly increased PARP1 DNA binding affinity and promoted DNA retention in a manner similar to its rigid counterpart 77. Again, compound 75 meta-counterpart (compound 76) did not display the same phenotype. It was that introducing a rigid and bulky substituent either in the para- or meta- position could potentially induce allosteric clashes with the HD, subsequently destabilizing its structure to drive PARP1 reverse allostery. Another isostere of pyrimidin-2-yl-piperazine was incorporated inthe form of 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (with electronegative CF3substitution),which led tocompound 64 in the para- and 65 in the meta-position. Interestingly, both compounds showeda four-fold decreased PARP1 inhibitory activity and did not display pro-retention ability.Despite the presence of an electronegative group (i.e., CF3) in 64 and 65, these derivatives did not recapitulate the level of retention seen with 15. Compound 82, bearing a unique 4,5-dimethyl-ortho-aminobenzamide substituent at the meta- position also showed PARP1 enzyme inhibition that was comparable to the analogues discussed above. However, compound 82 was only found to mildly promote PARP1 retention and did not significantly increase PARP1 DNA binding affinity. Taken together, these results highlight that a bulky substituent will not necessarily promote PARP1 retention. Example 4: Crystal structures of target compounds bound to PARP1 Next, X-ray crystallography studies were employed to gain insights into target compound binding poses in the PARP1 active site. The active site pocket of PARP1 is located in the ART fold and is composed of two distinct binding sites: the nicotinamide (N) binding pocket and the adenosine (A) binding pocket (FIG.2A). PARPi that contact these two sites include EB-47 (FIG.2B), BAD and olaparib, while veliparib being a relatively small compound only contacts the N binding pocket. Talazoparib, niraparib and rucaparib all protrude from the N binding pocket and shoulder helix αF of the HD on its central region. Co-crystallization of compounds 75, 82 and 65 with PARP1 CATΔHD was attempted, thus representing the minimal catalytic region. The co-crystal structure of compound 82 (2.7 Å resolution, 2 molecules per asymmetric unit) bound to PARP1 ART fold showed that the inhibitor core was binding the N binding site, however it appears that its 4,5-dimethyl-ortho- aminobenzamide substituent does not contact the A binding site stably given the lack of electron density in this portion of the molecule (FIG.2E and FIG.2G). Similarly, the co- crystal structure of compound 65 (3.4 Å resolution, 2 molecules per asymmetric unit) revealed that the bulky substituent of the compound was not stably interacting with the A binding pocket, as shown by the non-continuous electron density of the molecule despite the core being firmly anchored in the N binding pocket (FIGs.2F-2G). Accordingly, the substituents of both compounds also display high crystallographic B- factors relative to their respective compound core, which indicates that both substituents have a high degree of motion relative to a more stable core. Therefore, without wishing to be bound by any theory, it is possible that the poor pro-retention behavior of compounds 82 and 65 stems from their flexible interaction with the ART fold. The co-crystal structure of 15 with PARP1 ART fold was previously disclosed. The co-crystal structure revealed that while compound 15 was indeed interacting with the N binding pocket, it was not bound to the A binding pocket. Rather, compound 15 extends towards the active site loop (ASL) of the ART fold, a binding pose that would presumably severely clash with the HD. The co-crystal structure of compound 15 with the complete CAT domain showed the compound extending to a position between helices αF and αD of the HD and the ASL region located in the ART (FIG.2C). Helix αF also bent slightly to better accommodate the inhibitor. This surprising and unexpected binding mode could explain the compound’s ability to trigger PARP1 reverse allostery by means of destabilizing the HD given the poor electron density observed for this subdomain in the crystal structure. Mutations made on the C-terminal region of helix αF did not impact the increased retention of PARP1 on DNA breaks induced by 15, which confirmed that the compound is indeed interacting with the N-terminal portion of helix αF. It appears that compound 81 lower pro-retention ability could derive from the fact that a hydrolyzed methyl ester group bearing a negative charge cannot be easily accommodated in the groove formed in between the helices of the HD and the ASL. The co-crystal structure of compound 75 (2.8 Å resolution, 1 molecule per asymmetric unit) bound to the ART fold revealed a similar binding mode to 15 with the compound benzimidazole group extending towards the ASL (FIG.2D). Of note, the electron density of compound 75 appears continuous throughout the inhibitor (FIG.2G). It was expected that, in the presence of the HD, compound 75 would shoulder the N-terminal portion of helix αF, explaining its somewhat similar effect to compound 15 in terms of pro- retention ability. To address how compound 75 contacts the HD domain, the crystal structure of compound 75 bound to PARP1ΔVal687-Glu688 (ΔVE), a PARP1 mutant bearing a two- residue deletion in helix αB of the HD, was solved. ΔVE favors the active PARP1 conformation and was recently used as a model to better characterize PARP1 allosteric communication. As ΔVE represents an open and active conformation of PARP1, it was reasoned that changes induced upon compound 75 binding could further inform the influence of this compound on PARP1 allostery. PARP1ΔVE in complex with compound 75 was crystallized using a minimal arrangement of domains (i.e. Zn1, Zn3, WGR and CAT domains) that diffracted to 3.9 Å (FIG.3A; 2 molecules per asymmetric unit). The crystal structure shows that compound 10 has inserted itself in between the HD and the ASL following a repositioning of its benzimidazole group (FIGs.3B-3C). The electron density confirms this distinct binding pose (FIG.3D). Compound 75 contacts helices αD and αF but in a manner that differs from 75, which could explain compound 75 milder phenotype. While compound 75 extends towards the hydrophobic core of the HD and appears buried (FIG.3E), 15 specifically shoulders the very N-terminal portion of helix αF, and is exposed to the solvent (FIG.3F). Taken together, these crystal structures highlight that compound 10 stably contacts both the ART fold and the HD. Example 5: HXMS and PARP1 dynamics in the presence of the target compounds Next, HXMS was employed to measure the changes in the protein backbone dynamics of PARP1 in the presence of PARPi. HXMS has successfully identified the allosteric communication that drives PARP1 activation upon binding to a DNA break and the reverse allostery from PARPi compounds EB-47 and 15. These findings were key to defining these two compounds as Type I PARPi. Type I behavior has been clearly observed at a timepoint of 100 s of HX, so that timepoint was monitored for three compounds: 75, 65, and 82 (FIGs.4A- 4G). It was found that compound 75 destabilized αB, the adjacent linker region, and the C- terminal portion of αF (FIG.4A), in a manner similar to that of 15. It also stabilized other regions of the HD, namely αD, αE, the N-terminal portion of αF, and nearby linker residues bridging these helices. Moreover, compound 75 appears to protect other regions of PARP1 such as portions of both the Zn3 and WGR domains (FIG.4A and FIGs.4D-4E). Indeed, similar HX behavior is conferred by EB-47 and BAD when PARP1 is bound to a DNA break: i.e., destabilizing the critical regions within HD (αB and αF helices) and strengthening the contacts between DNA-binding domain, WGR and HD, thereby confirming that compound 75 displays type I behavior. Compound 65, on the other hand, displayed HX behavior more consistent with a Type II inhibitor (FIG.4B) talazoparib. It confers modest deprotection in the HD of helix αB and the adjacent linker region, which includes αC, and strong deprotection of the C-terminal portion of αF (FIG.4B, FIG.4D, and FIG.4F). Unlike compound 75, 65 did not strongly transmit towards the stability of DNA binding domains (FIG.4B and FIG.4D). Although compound 65 might appear to favor PARP1 release from DNA damage (FIG.1A), it cannot be classified as a type III inhibitor as it does increase PARP1 affinity for DNA damage in sharp contrast to veliparib (FIG.1B). Compound 82 has yet a third outcome on the HX behavior of PARP1. It neither destabilizes any regions of PARP1 HD (FIGs.4C-4D and FIG.4G), nor stabilizes the inter- domain contacts. This behavior is reminiscent of the HX behavior of PARP1 when bound to olaparib, a type II inhibitor. Indeed, compound 82 displayed mild pro-retention behavior (FIG.1A), which did not translate to a clear increase in PARP1 affinity for DNA damage (FIG.1B), and therefore agrees with a type II behavior. None of the target compounds exhibited protection of PARP1 active site peptides at the timepoint measured (100 s), which is consistent at this early timepoint with what is observed with 15. That said, biochemical assay data provides support for PARPi binding saturation. Taken together, these results confirm compounds 82 and 65 as being modulators of PARP1 allostery, albeit to different extents. Crystal structures of targeted PARPi with CATΔHD (FIGs.2A-2G) suggests that clashing the N-terminal of αF helix could make a PARPi act like a type I inhibitor. Although compounds 75 and 15 both exhibit type I behavior, they appear to influence PARP1 allostery in different ways. While both compounds do stabilize portions of the Zn3 and WGR domains, 15 does not stabilize the central portion of the HD, which hints at compound 75 contacting the HD domain differently. This observation is confirmed by the crystal structure of compound 75 bound to ΔVE in which the compound substituent is buried at the interface of αD and αF (FIGs.3E-3F). Overall, it appears that PARP1 allostery and retention on DNA damage can be triggered by the insertion of a compound in between the HD and the ART fold, whether this compound participates to the HD hydrophobic core or to the groove at the interface of the two subdomains. Example 6: Additional exemplary compounds which exhibit Type I PARPi behavior In certain embodiments, certain triazolyl-piperidinyl compounds of the present disclosure exhibited Type I PARPi behavior, including carbamate, urea, amide, and N-alkyl piperidine triazolyl-piperidinyl compounds. Non-limiting generic formulae for exemplary compounds exhibiting Type I PARPi behavior include: , wherein RCis independently selected from the group consisting of methyl, cyclopropyl, cyclobutyl, bicyclopentyl, oxetanyl, alkenyl, and alkynyl. In certain embodiments, certain benzimidazolyl compounds of the present disclosure exhibited Type I PARPi behavior, including ethylenimine- and piperazine-linked compounds. Non-limiting generic formulae for exemplary compounds exhibiting Type I PARPi behavior include: , wherein each occurrence of R7is independently selected from the group consisting of H, CH3, F, Cl, Br, CN, C(=O)NH2, C(=O)NHCH3, C(=O)NH(cyclopropyl), C(=O)NH(bicyclopentyl), C(=O)OH, CF3, OCH3, OCF3, and OCHF2. In certain embodiments, R7is R7aor R7b: , wherein R7aand R7bare each independently selected from the group consisting of H, CH3, F, Cl, Br, CN, C(=O)NH2, C(=O)NHCH3, C(=O)NH(cyclopropyl), C(=O)NH(bicyclopentyl), C(=O)OH, CF3, OCH3, OCF3, and OCHF2. In certain embodiments, R7ais H and R7bis CH3. In certain embodiments, R7ais H and R7bis Cl. In certain embodiments, R7ais Cl and R7bis H. In certain embodiments, R7ais H and R7bis F. In certain embodiments, R7ais F and R7bis H. In certain embodiments, R7ais H and R7bis Br. In certain embodiments, R7ais Br and R7bis H. In certain embodiments, R7ais H and R7bis CF3. In certain embodiments, R7ais CF3 and R7bis H. In certain embodiments, R7ais H and R7bis OCF3. In certain embodiments, R7ais OCF3and R7bis H. In certain embodiments, R7ais H and R7bis OCHF2. In certain embodiments, R7ais OCHF2and R7bis H. In certain embodiments, R7ais H and R7bis CN. In certain embodiments, R7ais CN and R7bis H. In certain embodiments, R7ais H and R7bis C(=O)NH2. In certain embodiments, R7ais C(=O)NH2and R7bis H. In certain embodiments, R7ais H and R7bis C(=O)OH. In certain embodiments, R7ais C(=O)OH and R7bis H. In certain embodiments, R7ais H and R7bis C(=O)NHCH3. In certain embodiments, R7ais C(=O)NHCH3 and R7bis H. In certain embodiments, R7ais H and R7bis C(=O)NH(cyclopropyl). In certain embodiments, R7ais C(=O)NH(cyclopropyl) and R7bis H. In certain embodiments, R7ais H and R7bis C(=O)NH(bicyclopentyl). In certain embodiments, R7ais C(=O)NH(bicyclopentyl) and R7bis H. In certain embodiments, R7ais CH3 and R7bis CH3. In certain embodiments, R7ais F and R7bis F. In certain embodiments, R7ais Cl and R7bis Cl. In certain embodiments, R7ais F and R7bis CF3. In certain embodiments, R7ais CF3and R7bis F. In certain embodiments, R7ais CF3and R7bis Br. In certain embodiments, R7ais Br and R7bis CF3. In certain embodiments, R7ais Br and R7bis F. In certain embodiments, R7ais F and R7bis Br. In certain embodiments, R7ais OCH3and R7bis Br. In certain embodiments, R7ais Br and R7bis OCH3. In certain embodiments, R7ais CN and R7bis Cl. In certain embodiments, R7ais Cl and R7bis CN. In certain embodiments, R7ais CN and R7bis F. In certain embodiments, R7ais F and R7bis CN. In certain embodiments, R7ais Cl and R7bis Br. In certain embodiments, R7ais Br and R7bis Cl. In certain embodiments, R7ais Cl and R7bis OCH3. In certain embodiments, R7ais OCH3and R7bis Cl. Sequence Listing SEQ ID NO:1

[0025] Enumerated Embodiments The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof: , wherein: R1a, R1b, and R1care each independently selected from the group consisting of H, C1-C6alkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB); R2a, R2b, and R2care each independently selected from the group consisting of H and C1- C6 alkyl; R3is ; A is selected from the group consisting of: ; L1is selected from the group consisting of a bond, -C(=O)-, -C(=O)N(R6)-, and - C(=O)N(R6)-C1-C3 alkylenyl-; L2is selected from the group consisting of a bond, -C2-C8heterocycloalkylenyl-, and -C2- C8 heteroarylenyl-; R4is selected from the group consisting of H, C1-C6 alkoxy, -C2-C8 heterocycloalkyl, - C6-C10aryl, and heteroaryl, wherein the -C2-C8heterocycloalkyl is independently substituted with 0, 1, 2, or 3 of R8or R9, and each of -C6-C10 aryl and heteroaryl is independently substituted with 0, 1, 2, or 3 of R7or R9; wherein when both L1and L2are a bond, R4is not H, or L2and R4can combine with the atoms to which they are bound to form a monocyclic or bicyclic C2-C12 heterocyclyl substituted with 0, 1, 2, or 3 R7; R5a, R5b, R5c, and R5d, if present, are each independently selected from the group consisting of H, C1-C6alkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB); R6is selected from the group consisting of H and C1-C6 alkyl; and each occurrence of RAand RBis independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, and heteroaryl; each R7is independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, C2-C6alkynyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); each R8is independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C(=O)ORC, C(=O)RC, and C(=O)N(RC)(RD); each R9is independently selected from the group consisting of H and C1-C6 alkyl; and RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 hydroxyheterocycloalkyl, C6-C10aryl, and heteroaryl; with the proviso that the compound is not methyl 2-(4-(4-(4-carbamoyl-1H- benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5-carboxylate. Embodiment 2 provides the compound of Embodiment 1, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R5a, R5b, R5c, and R5d, if present, are each independently H. Embodiment 3 provides the compound of Embodiment 2, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein A is selected from the group consisting of: . Embodiment 4 provides the compound of any one of Embodiments 1-3, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L1is selected from the group consisting of: . Embodiment 5 provides the compound of any one of Embodiments 1-4, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L2is selected from the group consisting of: , Embodiment 6 provides the compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (II): Embodiment 7 provides the compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (III): ,wherein: m is 0, 1, 2, or 3; nais 0, 1, 2, or 3; nbis 0, 1, 2, or 3; and and the sum of na+ nbis 2, 3, or 4. Embodiment 8 provides the compound of any one of Embodiments 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (IVA): . Embodiment 9 provides the compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: (a) at least one of R1a, R1b, and R1cis H; (b) at least two of R1a, R1b, and R1care H; or (c) each of R1a, R1b, and R1care H. Embodiment 10 provides the compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R1a, R1b, and R1care each independently selected from the group consisting of H and F. Embodiment 11 provides the compound of any one of Embodiments 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein one of the following applies: (a) R1aand R1bare H and R1cis F; and (b) R1a, R1b, and R1care each H. Embodiment 12 provides the compound of any one of Embodiments 1-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R2a, R2b, and R2care each independently H. Embodiment 13 provides the compound of any one of Embodiments 1-9, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: * a) R4p( is selected from the group consisting of H, C1-C6 alkoxy, , (b) L2and R4combine to form: wherein: each R7is independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C2-C6 alkynyl, C2-C8 heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); R8is selected from the group consisting of H, C1-C6 alkyl, and C(=O)ORC; each R9is independently C1-C6 alkyl; and RCand RDare each independently selected from the group consisting of H, C1-C6alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, and heteroaryl; p is 0, 1, or 2; and q is 0, 1, or 2. Embodiment 14 provides the compound of any one of Embodiments 1-13, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein each R7is independently selected from the group consisting of CH3, CH2OH, CH(OH)CH3, CH(CH3)2, CH2CH2OMe, CF3, CH2CH2CH3, cyclopentyl, OCH3, OCH2CH3, NH2, C(=O)OH, C(=O)OCH3, C(=O)OCH2CH3, C(=O)CH3, SCH3, S(=O)2CH3, S(=O)2NH2, NHS(=O)2CH3, Cl, Br, CN, C≡CH, C(=O)NH2, C(=O)NHCH3, C(=O)NHCH2CF3, , Embodiment 15 provides the compound of Embodiment 13 or 14, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R8is selected from the group consisting of H, CH3, C(=O)O(C1-C6alkyl), C(=O)O(C3-C8cycloalkyl), C(=O)NH(C1-C6 alkyl), and C(=O)NH(C3-C8 cycloalkyl). Embodiment 16 provides the compound of any one of Embodiments 13-15, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein q is 0. Embodiment 17 provides the compound of any one of Embodiments 13-16, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is selected from the group consisting of H, OCH3, , . Embodiment 18 provides the compound of any one of Embodiments 1-6 and 9-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (V): , wherein: p is 1 or 2; each R7is independently selected from the group consisting of C1-C6alkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, C2-C6alkynyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); and RCand RDare each independently selected from the group consisting of H, C1-C6alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 hydroxyheterocycloalkyl, C6-C10 aryl, and heteroaryl. Embodiment 19 provides the compound of Embodiment 18, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: (a) each R7is independently selected from the group consisting of C2-C8 hydroxyheterocycloalkyl, heteroaryl, CN, ORC, C(=O)RC, C(=O)ORC, and C(=O)N(RC)(RD); and (b) RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, and C2-C8hydroxyheterocycloalkyl. Embodiment 20 provides the compound of any one of Embodiments 1-5, 7, and 9-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (VI): , wherein: p is 1 or 2; each R7is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkyl- OH, C3-C8 cycloalkyl, C2-C6 alkynyl, C2-C8 heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); and RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8cycloalkyl, C1-C6alkyl-C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, C6-C10aryl, and heteroaryl. Embodiment 21 provides the compound of Embodiment 20, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: (a) each R7is independently selected from the group consisting of C(=O)ORCand C(=O)N(RC)(RD); and (b) RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8cycloalkyl, and C2-C8heterocycloalkyl. Embodiment 22 provides the compound of Embodiment 20 or 21, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein nais 1 and nbis 1. Embodiment 23 provides the compound of any one of Embodiments 1, 9-11, and 14, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (VII): , each R7is independently selected from the group consisting C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C2-C6 alkynyl, C2-C8 heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); and RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8cycloalkyl, C1-C6alkyl-C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, C6-C10aryl, and heteroaryl. Embodiment 24 provides the compound of any one of Embodiments 1-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is H. Embodiment 25 provides the compound of any one of Embodiments 7 and 9-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is H and m is 0 or 1, and one of the following applies: (a) nais 1 and nbis 1; (b) nais 2 and nbis 2; or (c) nais 2 and nbis 1. Embodiment 26 provides the compound of any one of Embodiments 8 and 9-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is C2-C8heterocycloalkyl. Embodiment 27 provides the compound of Embodiment 26, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the C2-C8 heterocycloalkyl is pyrrolidinyl. Embodiment 28 provides the compound of any one of Embodiments 1, 10-13, and 23, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L2and R4combine to form , , , Embodiment 29 provides the compound of any one of Embodiments 1-4 and 10-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, ,

[0026] ,

[0027] ,

[0028] , Embodiment 30 provides the compound of any one of Embodiments 1-3 and 8-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (IVB): , wherein R8is selected from the group consisting of H, C1-C3alkyl, C(=O)O(C1-C6alkyl), C(=O)O(C3-C8cycloalkyl), C(=O)(C1-C6alkyl), C(=O)(C3-C8cycloalkyl), C(=O)NH(C1- C6 alkyl), and C(=O)NH(C3-C8 cycloalkyl). Embodiment 31 provides the compound of any one of Embodiments 1, 4, 9-11, and 13, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (VIII): (VIII), wherein: p is 1 or 2; each R7is independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, C2-C6alkynyl, C2-C8heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); R8is selected from the group consisting of H and C1-C6 alkyl; and RCand RDare each independently selected from the group consisting of H, C1-C6alkyl, C1-C6 alkenyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, and heteroaryl. Embodiment 32 provides the compound of Embodiment 31, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L1is - C(=O)-. Embodiment 33 provides the compound of Embodiment 31, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L1is - C(=O)N(R6)(C1-C3 alkylenyl). Embodiment 34 provides the compound of any one of Embodiments 1-33, which is selected from the group consisting of: 2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 6-fluoro-2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((azetidin-3-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(azetidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-((piperidin-4-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (R)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (S)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (R)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; (S)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; ethyl 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1- yl)pyrimidine-5-carboxylate; 2-(4-(4-(5-acetylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-(methylthio)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(methylsulfonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(methylsulfonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-sulfamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(methylsulfonamido)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-cyanopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-ethynylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(5-cyano-4-methoxypyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-ethoxypyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(5-(cyclopropylmethoxy)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(hydroxymethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(1-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-isopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromo-4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-fluoro-4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(3-cyanoazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(3-hydroxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(methylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-((3,3-difluorocyclobutyl)carbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-6- fluoro-1H-benzo[d]imidazole-4-carboxamide; 6-fluoro-2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; ethyl 2-(4-((4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)methyl)piperidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(3-((4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)methyl)azetidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(3-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)azetidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(6-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyrimidine-5-carboxylate; 2-(4-(((1-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(((1-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(((1-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; ethyl 7-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate; 2-(4-(3-cyclopentyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(3-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(1H-benzo[d]imidazole-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(3-(4-(1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-((1-(1H-benzo[d]imidazol-2-yl)-2-methylpropan-2-yl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; methyl 2-(2-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)ethyl)-1H- benzo[d]imidazole-5-carboxylate; 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5- carboxylic acid; 2-(3-((2-amino-4,5-dimethylphenyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-((2-(5-methyl-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-((2-(5-chloro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; tert-butyl 4-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H-1,2,3-triazol-1- yl)piperidine-1-carboxylate; 2-(4-(4-methoxypiperidine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4,7-diazaspiro[2.5]octane-4-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(2,2-dimethylpiperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-chloro-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromo-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; and 2-(4-((2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide. Embodiment 35 provides a pharmaceutical composition comprising at least one compound of any one of Embodiments 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, and at least one pharmaceutically acceptable carrier. Embodiment 36 provides the composition of Embodiment 35, further comprising at least one additional therapeutic agent that treats, ameliorates, or prevents cancer. Embodiment 37 provides the composition of Embodiment 35, further comprising at least one additional therapeutic agent that treats, ameliorates, or prevents a neurodegenerative disease or disorder. Embodiment 38 provides a method of inhibiting at least one PARP, the method comprising contacting the PARP with the compound of any one of Embodiments 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of any one of Embodiments 35-37. Embodiment 39 provides the method of Embodiment 38, wherein the at least one PARP comprises PARP-1 and / or PARP-2. Embodiment 40 provides the method of Embodiment 38 or 39, wherein the PARP is within a cell. Embodiment 41 provides the method of Embodiment 40, wherein the cell is in vivo. Embodiment 42 provides a method of treating, ameliorating, and / or preventing a PARP- mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any one of Embodiments 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of any one of Embodiments 35-37. Embodiment 43 provides the method of Embodiment 42, wherein the disease or disorder is cancer. Embodiment 44 provides the method of Embodiment 43, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, liver cancer, melanoma, lung cancer, malignant pancreatic cancer, stomach cancer, colon cancer, neuroblastoma, glioblastoma, multiple myeloma, Kaposi’s sarcoma, skin cancer, and prostate cancer. Embodiment 45 provides the method of Embodiment 42, wherein the disease or disorder is a neurodegenerative disease or disorder. Embodiment 46 provides the method of Embodiment 45, wherein the neurodegenerative disease or disorder is selected from the group consisting of Parkinson’s disease (PD), Alzheimer’s disease (AD), Lewy body dementia, Alzheimer’s disease related dementia, and Amyotrophic lateral sclerosis (ALS). Embodiment 47 provides the method of any one of Embodiments 38-46, wherein the at least one compound or pharmaceutical composition is administered to the subject by at least one route selected from the group consisting of oral, topical, nasal, inhalational, vaginal, buccal, rectal, peritoneal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous. Embodiment 48 provides the method of any one of Embodiments 38-47, wherein the subject is a mammal. Embodiment 49 provides the method of Embodiment 48, wherein the mammal is a human. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application.

Claims

Attorney Docket No.046483-7368WO1 CLAIMS What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof:, wherein: R1a, R1b, and R1care each independently selected from the group consisting of H, C1-C6 alkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB); R2a, R2b, and R2care each independently selected from the group consisting of H and C1- C6 alkyl; R3is ; A is selected from the group consisting of: ;L1is selected from the group consisting of a bond, -C(=O)-, -C(=O)N(R6)-, and - C(=O)N(R6)-C1-C3 alkylenyl-; L2is selected from the group consisting of a bond, -C2-C8 heterocycloalkylenyl-, and -C2- C8heteroarylenyl-; R4is selected from the group consisting of H, C1-C6alkoxy, -C2-C8heterocycloalkyl, - C6-C10 aryl, and heteroaryl, wherein the -C2-C8 heterocycloalkyl is independently substituted with 0, 1, 2, or 3 of R8or R9, and each of -C6-C10aryl and heteroaryl is independently substituted with 0, 1, 2, or 3 of R7or R9; wherein when both L1and L2are a bond, R4is not H, orAttorney Docket No.046483-7368WO1 L2and R4can combine with the atoms to which they are bound to form a monocyclic or bicyclic C2-C12 heterocyclyl substituted with 0, 1, 2, or 3 R7; R5a, R5b, R5c, and R5d, if present, are each independently selected from the group consisting of H, C1-C6 alkyl, halogen, CN, NO2, ORA, N(RA)(RB), C(=O)ORA, and C(=O)N(RA)(RB); R6is selected from the group consisting of H and C1-C6alkyl; and each occurrence of RAand RBis independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C6-C10 aryl, and heteroaryl; each R7is independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, C2-C6alkynyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); each R8is independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C(=O)ORC, C(=O)RC, and C(=O)N(RC)(RD); each R9is independently selected from the group consisting of H and C1-C6 alkyl; and RCand RDare each independently selected from the group consisting of H, C1-C6alkyl, C1-C6haloalkyl, C3-C8cycloalkyl, C1-C6alkyl-C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, C6-C10 aryl, and heteroaryl; with the proviso that the compound is not methyl 2-(4-(4-(4-carbamoyl-1H- benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5-carboxylate.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R5a, R5b, R5c, and R5d, if present, are each independently H.

3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein A is selected from the group consisting of: .Attorney Docket No.046483-7368WO1 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L1is selected from the group consisting of:.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L2is selected from the group consisting of: ,6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (II):

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (III):Attorney Docket No.046483-7368WO1,wherein: m is 0, 1, 2, or 3; nais 0, 1, 2, or 3; nbis 0, 1, 2, or 3; and and the sum of na+ nbis 2, 3, or 4.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (IVA):.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: (a) at least one of R1a, R1b, and R1cis H; (b) at least two of R1a, R1b, and R1care H; or (c) each of R1a, R1b, and R1care H.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R1a, R1b, and R1care each independently selected from the group consisting of H and F.Attorney Docket No.046483-7368WO1 11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein one of the following applies: (a) R1aand R1bare H and R1cis F; and (b) R1a, R1b, and R1care each H.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R2a, R2b, and R2care each independently H.

13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: p(a) R4is selected from the group consisting of H, C1-C6 alkoxy,, r, wherein: each R7is independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, C2-C6alkynyl, C2-C8heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); R8is selected from the group consisting of H, C1-C6alkyl, and C(=O)ORC; each R9is independently C1-C6 alkyl; and RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6alkenyl, C3-C8cycloalkyl, C1-C6alkyl-C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10Attorney Docket No.046483-7368WO1 aryl, and heteroaryl; p is 0, 1, or 2; and q is 0, 1, or 2.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein each R7is independently selected from the group consisting of CH3, CH2OH, CH(OH)CH3, CH(CH3)2, CH2CH2OMe, CF3, CH2CH2CH3, cyclopentyl, OCH3, OCH2CH3, NH2, C(=O)OH, C(=O)OCH3, ,15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R8is selected from the group consisting of H, CH3, C(=O)O(C1-C6 alkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)NH(C1-C6 alkyl), and C(=O)NH(C3-C8 cycloalkyl).

16. The compound of any one of claims 13-15, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein q is 0.

17. The compound of any one of claims 13-16, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is selected from the group consisting,Attorney Docket No.046483-7368WO1 ,Attorney Docket No.046483-7368WO1.

18. The compound of any one of claims 1-6 and 9-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (V):, wherein: p is 1 or 2; each R7is independently selected from the group consisting of C1-C6alkyl, C1-C6hydroxyalkyl, C3-C8cycloalkyl, C2-C6alkynyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); and RCand RDare each independently selected from the group consisting of H, C1-C6alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 hydroxyheterocycloalkyl, C6-C10 aryl, and heteroaryl.

19. The compound of claim 18, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: (a) each R7is independently selected from the group consisting of C2-C8hydroxyheterocycloalkyl, heteroaryl, CN, ORC, C(=O)RC, C(=O)ORC, and C(=O)N(RC)(RD); and (b) RCand RDare each independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C2-C8heterocycloalkyl, and C2-C8hydroxyheterocycloalkyl.Attorney Docket No.046483-7368WO1 20. The compound of any one of claims 1-5, 7, and 9-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (VI):, wherein: p is 1 or 2; each R7is independently selected from the group consisting of C1-C6alkyl, C1-C6alkyl- OH, C3-C8 cycloalkyl, C2-C6 alkynyl, C2-C8 heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); and RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl-C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, C2-C8 hydroxyheterocycloalkyl, C6-C10aryl, and heteroaryl.

21. The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein: (a) each R7is independently selected from the group consisting of C(=O)ORCand C(=O)N(RC)(RD); and (b) RCand RDare each independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, and C2-C8heterocycloalkyl.

22. The compound of claim 20 or 21, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein nais 1 and nbis 1.Attorney Docket No.046483-7368WO1 23. The compound of any one of claims 1, 9-11, and 14, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (VII):each R7is independently selected from the group consisting C1-C6 alkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C2-C6 alkynyl, C2-C8 heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); and RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C3-C8cycloalkyl, C1-C6alkyl-C3-C8cycloalkyl, C2-C8heterocycloalkyl, C2-C8hydroxyheterocycloalkyl, C6-C10aryl, and heteroaryl.

24. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is H.

25. The compound of any one of claims 7 and 9-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is H and m is 0 or 1, and one of the following applies: (a) nais 1 and nbis 1; (b) nais 2 and nbis 2; or (c) nais 2 and nbis 1.

26. The compound of any one of claims 8 and 9-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein R4is C2-C8heterocycloalkyl.Attorney Docket No.046483-7368WO1 27. The compound of claim 26, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the C2-C8 heterocycloalkyl is pyrrolidinyl.

28. The compound of any one of claims 1, 10-13, and 23, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L2and R4combine to ,29. The compound of any one of claims 1-4 and 10-12, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein B is selected from the group ,Attorney Docket No.046483-7368WO1 ,Attorney Docket No.046483-7368WO1 ,Attorney Docket No.046483-7368WO1 ,Attorney Docket No.046483-7368WO1 ,30. The compound of any one of claims 1-3 and 8-11, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (IVB):, wherein R8is selected from the group consisting of H, C1-C3alkyl, C(=O)O(C1-C6alkyl), C(=O)O(C3-C8 cycloalkyl), C(=O)(C1-C6 alkyl), C(=O)(C3-C8 cycloalkyl), C(=O)NH(C1- C6 alkyl), and C(=O)NH(C3-C8 cycloalkyl).

31. The compound of any one of claims 1, 4, 9-11, and 13, or a pharmaceutically acceptableAttorney Docket No.046483-7368WO1 salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein the compound has a structure of Formula (VIII):, wherein: p is 1 or 2; each R7is independently selected from the group consisting of C1-C6alkyl, C1-C6haloalkyl, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, C2-C6 alkynyl, C2-C8 heterocycloalkyl, heteroaryl, CN, NO2, halogen, ORC, SRC, N(RC)(RD), N(RC)S(=O)2RD, C(=O)RC, C(=O)ORC, C(=O)N(RC)(RD), S(=O)2RC, and S(=O)2N(RC)(RD); R8is selected from the group consisting of H and C1-C6 alkyl; and RCand RDare each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6alkenyl, C3-C8cycloalkyl, C1-C6alkyl-C3-C8cycloalkyl, C2-C8heterocycloalkyl, C6-C10aryl, and heteroaryl.

32. The compound of claim 31, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L1is -C(=O)-.

33. The compound of claim 31, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, wherein L1is -C(=O)N(R6)(C1-C3alkylenyl).

34. The compound of any one of claims 1-33, which is selected from the group consisting of: 2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 6-fluoro-2-(4-(piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((azetidin-3-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(azetidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide;Attorney Docket No.046483-7368WO1 2-(4-((piperidin-4-ylmethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (R)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (S)-2-(4-(pyrrolidin-3-ylcarbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; (R)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; (S)-2-(4-(1-(pyrrolidin-3-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; ethyl 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1- yl)pyrimidine-5-carboxylate; 2-(4-(4-(5-acetylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-(methylthio)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(methylsulfonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(methylsulfonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-sulfamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(methylsulfonamido)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(5-cyanopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide;Attorney Docket No.046483-7368WO1 2-(4-(4-(5-ethynylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(5-cyano-4-methoxypyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-ethoxypyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole- 4-carboxamide; 2-(4-(4-(5-(cyclopropylmethoxy)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(hydroxymethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(1-hydroxyethyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-isopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-cyclopropylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromo-4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-fluoro-4-morpholinopyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(4-hydroxypiperidin-1-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H-Attorney Docket No.046483-7368WO1 benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-carbamoylpyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(3-cyanoazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(3-hydroxyazetidine-1-carbonyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(methylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-((2,2,2-trifluoroethyl)carbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-((3,3-difluorocyclobutyl)carbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-6-fluoro-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-6- fluoro-1H-benzo[d]imidazole-4-carboxamide;Attorney Docket No.046483-7368WO1 6-fluoro-2-(4-(4-(5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)piperazine-1- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; ethyl 2-(4-((4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)methyl)piperidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(3-((4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)methyl)azetidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(3-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)azetidin-1- yl)pyrimidine-5-carboxylate; ethyl 2-(6-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-2,6- diazaspiro[3.3]heptan-2-yl)pyrimidine-5-carboxylate; 2-(4-(((1-(5-(cyclopropylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(((1-(5-(oxetan-3-ylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(((1-(4-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)pyrimidin-2-yl)azetidin-3- yl)methyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; ethyl 7-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate; 2-(4-(3-cyclopentyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)- 1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-propyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(pyridin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-Attorney Docket No.046483-7368WO1 carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(3-(3-(2-methoxyethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(3-((2-(1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-(4-(1H-benzo[d]imidazole-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(3-(4-(1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-((1-(1H-benzo[d]imidazol-2-yl)-2-methylpropan-2-yl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; methyl 2-(2-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzamido)ethyl)-1H- benzo[d]imidazole-5-carboxylate; 2-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)pyrimidine-5- carboxylic acid; 2-(3-((2-amino-4,5-dimethylphenyl)carbamoyl)phenyl)-1H-benzo[d]imidazole-4- carboxamide; 2-(4-((2-(5-methyl-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-((2-(5-chloro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; tert-butyl 4-(4-(4-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)phenyl)-1H-1,2,3-triazol-1- yl)piperidine-1-carboxylate; 2-(4-(4-methoxypiperidine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4,7-diazaspiro[2.5]octane-4-carbonyl)phenyl)-1H-benzo[d]imidazole-4-Attorney Docket No.046483-7368WO1 carboxamide; 2-(4-(2,2-dimethylpiperazine-1-carbonyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-methyl-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-chloro-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; 2-(4-(4-(5-bromo-1H-benzo[d]imidazol-2-yl)piperazine-1-carbonyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide; and 2-(4-((2-(5,6-difluoro-1H-benzo[d]imidazol-2-yl)ethyl)carbamoyl)phenyl)-1H- benzo[d]imidazole-4-carboxamide.

35. A pharmaceutical composition comprising at least one compound of any one of claims 1- 34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, and at least one pharmaceutically acceptable carrier.

36. The composition of claim 35, further comprising at least one additional therapeutic agent that treats, ameliorates, or prevents cancer.

37. The composition of claim 35, further comprising at least one additional therapeutic agent that treats, ameliorates, or prevents a neurodegenerative disease or disorder.

38. A method of inhibiting at least one PARP, the method comprising contacting the PARP with the compound of any one of claims 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of any one of claims 35-37.

39. The method of claim 38, wherein the at least one PARP comprises PARP-1 and / or PARP-2.

40. The method of claim 38 or 39, wherein the PARP is within a cell.Attorney Docket No.046483-7368WO1 41. The method of claim 40, wherein the cell is in vivo.

42. A method of treating, ameliorating, and / or preventing a PARP-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of at least one compound of any one of claims 1-34, or a pharmaceutically acceptable salt, stereoisomer, isotopologue thereof, or any mixtures thereof, or the pharmaceutical composition of any one of claims 35-37.

43. The method of claim 42, wherein the disease or disorder is cancer.

44. The method of claim 43, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, liver cancer, melanoma, lung cancer, malignant pancreatic cancer, stomach cancer, colon cancer, neuroblastoma, glioblastoma, multiple myeloma, Kaposi’s sarcoma, skin cancer, and prostate cancer.

45. The method of claim 42, wherein the disease or disorder is a neurodegenerative disease or disorder.

46. The method of claim 45, wherein the neurodegenerative disease or disorder is selected from the group consisting of Parkinson’s disease (PD), Alzheimer’s disease (AD), Lewy body dementia, Alzheimer’s disease related dementia, and Amyotrophic lateral sclerosis (ALS).

47. The method of any one of claims 38-46, wherein the at least one compound or pharmaceutical composition is administered to the subject by at least one route selected from the group consisting of oral, topical, nasal, inhalational, vaginal, buccal, rectal, peritoneal, intramuscular, subcutaneous, transdermal, epidural, intrathecal, and intravenous.

48. The method of any one of claims 38-47, wherein the subject is a mammal.

49. The method of claim 48, wherein the mammal is a human.

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