WO2025221809A1 - 2-aryl-quinazolin-4(3h)-one inhibitors for the treatment of diseases - Google Patents

Abstract

Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions, for example, in treating inflammatory dermatitis diseases, proliferative diseases, and cancer, including, but not limited to breast cancer, ovarian cancer, colon cancer, prostate cancer, melanoma, and fibrosarcoma.

Description

2-ARYL-QUINAZOLIN-4(3H)-ONE INHIBITORS FOR THE TREATMENT OF DISEASES

CROSS-REFERNCE TO RELATED APPLICATIONS

[0001] This application is a PCT International Application that claims the benefit of U.S. Provisional Application No. 63/634,664 filed April 16, 2024, the contents of which are hereby incorporated by reference in its entirety.

FIELD

[0002] Provided herein are compounds, pharmaceutical compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds and compositions, for example, in treating inflammatory dermatitis diseases, proliferative diseases, and cancer, including, but not limited to breast cancer, ovarian cancer, colon cancer, prostate cancer, melanoma, and fibrosarcoma.

BACKGROUND

[0003] Poly(adenosine diphosphate-ribose) polymerases (PARPs) are a family of highly conserved enzymes involved in DNA damage repair. In humans, the PARP family consists of 17 proteins and three subfamilies based on catalytic activity (polyP ARPs, monoP ARPs and inactive).

[0004] Two widely studied PARP family members are PARP-1 and PARP -2. These are nuclear enzymes that, upon activation in response to DNA strand breaks, synthesize and transfer long branches of poly(ADP -ribose) (PAR) onto DNA-associated proteins via poly(ADP-ribosyl)ation. This results in a negatively charged environment that facilitates recruitment of repair machinery and accelerates DNA damage repair by re-building bridges between the open ends of DNA. Supporting studies have shown that inhibition of PARPs exerts a cytotoxic effect by suppressing PARP-1 and PARP -2 catalytic activity, which traps the PARP -DNA complexes, thereby preventing DNA replication and transcription. The mechanism of action of many anti-cancer therapies hinges on the ability of a therapeutic to induce DNA damage in tumor cells, thus inhibiting the repair process itself and forcing the cancer to self-destruct. Since PARPs are at the center of DNA repair, their regulation is of high therapeutic interest.

[0005] Other commonly studied PARPs are PARP-5a and PARP-5b (also known as Tankyrases TNK-1 and TNK-2, respectively). Tankyrases contain an ANK domain, which contains 16-24 ankyrin repeat units. The ANK domain interacts with a variety of proteins, including the telomeric protein telomere repeat-binding factor-1 (TRF-1). Thus, the proteins are called TRF-1 -interacting, ankyrin-related ADP -ribose polymerases, or TNKs. These enzymes act via mono- or poly(ADP-ribosyl)ation (“parsylation”) of substrate proteins. Poly(ADP-ribosyl)ation of TRF-1 inhibits the ability of TRF-1 to bind to telomeric DNA and leads to release of TRF-1 from the telomeres. The telomeric complex is opened, allowing access to telomerases. Therefore, TNKs function as positive regulators of telomere length, permitting elongation of the telomeres by telomerase to play key roles in various cellular processes including, but not limited to regulation of telomere length, Wnt/p-catenin signaling, and mitotic spindle organization. Inhibition of these enzymes can disrupt cancer cell proliferation and survival, offering a therapeutic strategy for cancers with aberrant tankyrase activity.

[0006] Another important substrate of TNKs is AXIN, a key regulator in the Wnt/p-catenin signal transduction pathway. The Wnt/p-catenin pathway plays essential roles in embryonic development and adult tissue homeostasis, and deregulation of this pathway can lead to cancer and fibrosis. Inhibitors of TNKs have been shown to result in efficient stabilization and increased levels of AXIN-GSK3P complex protein, which increases P-catenin phosphorylation and destruction. Tankyrases are also proposed to have roles in the regulation of the mitotic spindle and in vesicle trafficking.

[0007] The Wnt pathway has been recently shown to play a key role in dermal fibrosis and scarring. It is an evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell polarity, cell migration, neural patterning, and organogenesis during embryonic development. This pathway is instrumental in ensuring proper tissue development in embryos and tissue maintenance in adults. Wnt signaling is involved at the beginning stages of skin development. Following gastrulation, embryonic cells of the ectoderm and the mesoderm differentiate to form the epidermis and dermis, respectively. Although there are at least three distinct Wnt signaling pathways involved in the signal transduction process, the canonical (or P-catenin-dependent) Wnt pathway is the most understood. P-Catenin is the key effector molecule resulting from the signaling of the canonical Wnt pathway, and its protein levels are regulated through a "destruction complex." In the absence of a Wnt signal, the transcriptional activator P-catenin is actively degraded in the cell by the actions of a protein complex, designated the “destruction complex.” Within this complex, Axin-1 and -2 form a scaffold with adenomatous polypsis coli that facilitates P-catenin phosphorylation by caseinkinase 19a and glycogen synthase kinase 3p. Phosphorylated P-catenin is recognized and ubiquitinylated, resulting in its proteosomal degradation. [0008] Tankyrase-1 and Tankyrase-2 (TNK-1 and TNK-2) function to parsylate and destabilize Axin-1 and -2 proteins, thus destabilizing the P-catenin destruction complex. Once the destruction complex is destabilized, this allows P-catenin to remain dephosphorylated, and subsequently stabilized and allowed to accumulate in the cytoplasm, where it enters the cell nucleus and interacts with members of the Tcf/Lef family. P-Catenin converts the Tcf proteins into potent transcriptional activators by recruiting co-activator proteins, thus ensuring efficient activation of Wnt target genes. The Wnt pathway, once activated by the Wnt family of natural ligands, upregulates TNK1 and TNK2 to help destabilize the destruction complex. Studies have shown that TNK1 and TNK2 are critical regulators of canonical Wnt.

[0009] Because PARP inhibitors work by exploiting the defective DNA repair mechanisms in cancer cells, targeted inhibition of specific PARPs offers an attractive approach to customized cancer therapy. These inhibitors block PARP enzymes, which are involved in single-strand break (SSB) DNA repair. Cancer cells that rely on PARP due to their inability to use homologous recombination (HR) for DNA repair are particularly vulnerable to PARP inhibition, leading to their death. In particular, PARP inhibitors have been shown to be effective in cancer cells lines with BRCA1/2 mutations, common in triple negative breast cancer. Studies have also linked PARP-1 with anti-androgen prostate cancer and ovarian cancer; PARP -2 with anti-androgen prostate cancer, B-cell lymphoma, and triple negative breast cancer; and, PARP- 5a/5b with colorectal cancer metastasis.

[0010] Moreover, the combination of PARP inhibition with other targeted therapies can enhance the efficacy of treatment. For instance, the combination of PARP inhibitors with PI3K/AKT/mTOR pathway inhibitors has shown promise in preclinical studies and early-phase clinical trials. This combination is based on the hypothesis that effective blockade of the PI3K/mT0R pathway can induce a homologous recombination deficiency (HRD)-like phenotype, sensitizing tumors to PARP inhibition, even in the absence of HRD.

[0011] In the context of cMYC-driven cancers, PARP inhibitors could disrupt the interaction between PARP enzymes and cMYC, inhibiting the transcriptional activity of cMYC and leading to reduced tumor growth and proliferation.

[0012] Several small molecule drugs that inhibit both PARP-1 and PARP-2 have already been approved by the FDA for cancer treatments. One approach to improving effectiveness is to enhance therapeutic potency based on a better understanding of PARP functionality. For instance, conventional wisdom has been that PARP-1 and PARP-2 are highly similar and work in tandem with overlapping functionality. More recent work, however, has provided more insight into the mechanisms of these two PARPs and has revealed that they appear to have completely opposite effects with regard to at least one aspect of cancer growth: proliferation (Galindo-Campos, et al. Blood, 2022, 139(2), 228). Specifically, PARP-1 inhibition promotes cancer proliferation while PARP-2 inhibition reduces proliferation.

[0013] Therefore, what are needed are inhibitors that could inhibit PARP-2 or TNK-2, but have different selectivity profiles from known PARP inhibitors to control cancer growth, metastasis, and overall proliferation.

SUMMARY

[0014] In the first aspect, provided herein is a compound of Formula (I), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof: wherein

R¹ is selected from hydrogen; Ci-ealkyl optionally substituted with -OH, -OCi-ealkyl, -OC(O)R⁶, -C(O)OR⁶, -NR^4aR^4b, -NR^4aC(O)R^4b, or -C(O)NR^4aR^4b; -OH; -B(OH)₂; -OCi-₆alkyl; halo; -NR^4aR^4b; -NR^4aC(O)R^4b, and -C(O)NR^4aR^4b;

Cy is absent, cycloalkyl, or heterocycloalkyl;

X¹, X², X³, and X⁴ are independently N or CR² wherein at least 2 of X¹ to X⁴ are CR²; each R² is independently selected from hydrogen, Ci-ealkyl, -OH, -B(OH)₂, -OCi-ealkyl, halo, -NR^4aR^4b, -NR^4aC(O)R^4b, and -C(O)NR^4aR^4b;

R³ is -B(OH)₂, -(Co-6alkylene)-X⁵-R⁵, or -(Ci-3alkylene)-X⁵-R⁵ wherein the Ci-3alkylene is substituted with R^7a and R^7b;

R^4a and R^4b are independently selected from hydrogen and Ci-ealkyl;

R⁵ is Ci-ealkoxycarbonyl-NH-Ci-ealkyl-;

X⁵ is bond, O, or NR^4a;

R⁶ is hydrogen or Ci-ealkyl; and

R^7a and R^7b are joined together with the atom or atoms to which they are attached to form a C3-5cycloalkyl. [0015] In one embodiment, provided is a compound of Formula (la), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof:

(la).

[0016] In one embodiment, provided is a compound of Formula (la-1), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof:

[0017] In one embodiment, provided is a compound of Formula (lb), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof:

(lb).

[0018] In one embodiment, provided is a compound of Formula (Ic), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof:

(Ic).

[0019] In some embodiments, provided is a compound of Formula (I), (la), (la-1), (lb), or (Ic) (or any embodiments thereof) or a single stereoisomer or mixture of stereoisomers thereof; a single tautomer or mixture of tautomers thereof; and/or a pharmaceutically acceptable salt thereof.

[0020] In a second aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I), (la), (la-1), (lb), or (Ic) (or any embodiments thereof), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof; and a pharmaceutically acceptable carrier. In one or more embodiments, provided is a compound of Formula (I), (la), (la-1), (lb), or (Ic) (or any embodiments thereof) or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0021] In a third aspect, provided is a method for inhibiting PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a subject comprising contacting an effective amount of a compound of Formula (I), (la), (la-1), (lb), or (Ic) (or any embodiments thereof), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof. In some embodiments, the compound of Formula (I), (la-1 ), (lb), or (Ic) (or any embodiments thereof) is provided as a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof. In some embodiments, the method is for inhibiting PARP-2 signaling pathway activity in a subject. In some embodiments, the method is for inhibiting PARP-5A and PARP-5B signaling pathway activity in a subject.

[0022] In a fourth aspect, provided herein is a method of treating a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a mammal in need thereof, comprising administering a compound of Formula (I), (la), (la-1), (lb), or (Ic), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof (or any embodiments thereof) or administering a pharmaceutical composition comprising a compound of Formula (I), (la), (la-1), (lb), or (Ic), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof. In some embodiments, the compound of Formula (I), (la), (la-1), (lb), or (Ic) (or any embodiments thereof) is provided as a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof. In some embodiments, the disease, disorder, or condition is associated with PARP-2 signaling pathway activity. In some embodiments, the disease, disorder, or condition is associated with PARP-5A and PARP-5B signaling pathway activity. In some embodiments, the disease, disorder, or condition is a proliferative disease, disorder, or condition. In some embodiments, the disease, disorder, or condition is cancer, including, but not limited to, prostate cancer, ovarian cancer, B-cell lymphoma, breast cancer, colorectal cancer, melanoma, and fibrosarcoma. In some embodiments, the breast cancer is triple negative breast cancer. In some embodiments, the prostrate cancer is anti-androgen prostate cancer. In some embodiments, the disease, disorder, or condition is an inflammatory dermatitis disease, including, but not limited to acne, psoriasis, rosacea, and scleroderma.

DETAILED DESCRIPTION

[0023] The present disclosure provides for novel PARP inhibitor compounds, compositions, and methods of using the compounds and compositions, for example, in treating proliferative diseases and cancer, including, but not limited to breast cancer, ovarian cancer, colon cancer, prostate cancer, B-cell lymphoma, melanoma, and fibrosarcoma, and in treating inflammatory dermatitis diseases, including, but not limited to acne, psoriasis, rosacea, and scleroderma. PARP inhibitors help to inhibit DNA repair, and because cancer cells and inflamed cells are constantly attempting to repair themselves, PARP inhibitors are of therapeutic interest in the treatment of cancer and inflammatory dermatitis diseases. The PARP family consists of 17 proteins in humans, and it would be therapeutically beneficial to administer inhibitors that are selective for one PARP over the other, for example inhibitors that are selective for PARP -2 over PARP-1 because it has been shown that PARP-1 inhibition tends to promotes cancer proliferation, while PARP -2 inhibition reduces proliferation. It would also be beneficial to administer a single pan-PARP inhibitor that could target multiple pathways at once.

Definitions

[0024] When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. Unless specified otherwise, where a term is defined as being substituted, the groups in the list of substituents are themselves unsubstituted. For example, a substituted alkyl group can be substituted, for example, with a -OCi-ealkyl group, and the -OCi-ealkyl group is not further substituted unless specified otherwise.

[0025] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with temperatures, doses, amounts, or weight percent of ingredients of a composition or a dosage form, mean a dose, amount, or weight percent that is recognized by those of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. Specifically, the terms “about” and “approximately,” when used in this context, contemplate a dose, amount, or weight percent within 15%, within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose, amount, or weight percent.

[0026] The terms “a” or “an,” as used in herein means one or more, unless context clearly dictates otherwise. For example, “pharmaceutically acceptable carrier” includes one or more ingredients as provided herein.

[0027] The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight or branched, monovalent hydrocarbon. In one or more embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. An alkyl may be linear or branched, and may contain, for example, from one to eight carbon atoms. In one or more embodiments, the alkyl group has one to six carbon atoms, i.e., Ci to Ce alkyl. In one or more embodiments, the alkyl is a Ci-3alkyl. In one or more embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, /-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3 -methylpentyl, 2,2-dimethylbutyl, and 2,3- dimethylbutyl. Examples of alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl isomers (e.g. n-butyl, iso-butyl, tert-butyl, etc.) pentyl isomers, hexyl isomers, and the like.

[0028] As used herein, the term “linear alkyl” refers to a chain of carbon and hydrogen atoms (e.g., ethane, propane, butane, pentane, hexane, etc.).

[0029] As used herein, the term “branched alkyl” refers to a chain of carbon and hydrogen atoms, without double or triple bonds that contains a fork, branch, and/or split in the chain. “Branching” refers to the divergence of a carbon chain, whereas “substitution” refers to the presence of non-carbon/non-hydrogen atoms in a moiety.

[0030] The term “alkylene,” as used herein, unless otherwise specified, refers to a divalent alkyl group, as defined herein. When Co-Cealkylene is used, Coalkylene indicates a bond.

[0031] As used herein, the term “cycloalkyl” refers to a completely saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. In some or any embodiments, the cycloalkyl group includes three to six carbon atoms, i.e., C3 to Ce cycloalkyl. In some or any embodiments, the cycloalkyl has 3, 4, 5, or 6 (C3-6) 3, 4, or 5 (C3-5); 3 or 4 (C3-4); 3 (C3); 4 (C4); or 5 (C5) carbon atoms. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some or any embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl. In one or more embodiments, the cycloalkyl group is cyclobutyl. In some or any embodiments, the cycloalkyl group is cyclopropyl. In some or any embodiments, the cycloalkyl group is cyclopentyl. In some or any embodiments, the cycloalkyl group is bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2.]decyl, bicyclo[2.2.2]octyl, or adamantyl. In one or more embodiments, the cycloalkyl group is cyclobutyl.

[0032] The term “alkoxycarbonyl-NH-alkyl,” as used herein, and unless otherwise specified, refers to an alkyl group substituted with -NH-C(O)O(alkyl), wherein alkyl is as defined herein. In some or any embodiments, alkoxycarbonyl-NH-alkyl is Ci- Cealkoxycarbonyl-NH-Ci-Cealkyl-.

[0033] The terms “halogen” and “halo,” as used herein, and unless otherwise specified, are synonymous and refer to chloro, bromo, fluoro, or iodo.

[0034] The term “heterocycloalkyl,” as used herein, and unless otherwise specified, refers to a monovalent monocyclic saturated ring system or a monovalent multicyclic saturated ring system; wherein one or more (in some or any embodiments, 1, 2, 3, or 4) of the ring atoms is a heteroatom independently selected from O, S(0)o-2, and N, and the remaining ring atoms are carbon atoms. In some or any embodiments, the heterocycloalkyl ring comprises one or two heteroatom(s) which are independently selected from nitrogen and oxygen. In some or any embodiments, the heterocycloalkyl ring comprises one or two heteroatom(s) which are nitrogen (where the nitrogen is substituted as described in any aspect or embodiment described herein). In some or any embodiments, the heterocycloalkyl group has from 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In one or more embodiments, the heterocycloalkyl is a 4- to 10-membered heterocyclic. In one or more embodiments, the heterocycloalkyl is a 5- to 10-membered heterocyclic. In some or any embodiments, the heterocyclic is a monocyclic or bicyclic ring system. In some or any embodiments, the heterocycloalkyl group may be a bridged or non-bridged, spirocyclic or not spirocyclic, and/or fused or not fused. One or more of the nitrogen and sulfur atoms may be optionally oxidized, one or more of the nitrogen atoms may be optionally quaternized, one or more of the carbon atoms may be optionally replaced with ⁰ . The heterocycloalkyl may be attached to the main structure at any heteroatom or carbon atom which results in a stable compound. In some or any embodiments, heterocycloalkyl is 3- to 6-membered heterocycloalkyl. In some or any embodiments, heterocycloalkyl is 3- to 8-membered heterocycloalkyl. In some or any embodiments, heterocycloalkyl is 3- to 9- membered heterocycloalkyl. When heterocycloalkyl and heterocycloalkyl are substituted, they can be substituted on any ring. In some or any embodiments, such heterocycloalkyl includes, but is not limited to, azepinyl, isoxazolidinyl,

3-oxo-isoxazolidinyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxo- oxadiazolyl (including but not limited to 5-oxo-l,2,4-oxadiazol-3-yl), oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6-dioxo-piperidinyl,

4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiomorpholinyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, . In some or any embodiments, heterocyclic is piperidinyl or piperazinyl. In some embodiments, heterocycloalkyl is piperazinyl. In some embodiments, heterocycloalkyl is an N-linked heterocycloalkyl.

[0035] In some embodiments, the term “pharmaceutically acceptable carrier” includes any and all and/or one or more solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, excipients, diluents, disintegrants, lubricants, adjuvants, and the like which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. In addition, various adjuvants such as are commonly used in the art may be included. These and other such compounds are described in the literature, e.g., in the Merck Index (Merck & Company, Rahway, N.J.), considerations for the inclusion of various components in pharmaceutical compositions are described, (e.g., Gilman et al. (Eds.), 2010, Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies).

[0036] In some embodiments, the term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the compounds provided herein and which are not biologically or otherwise undesirable. In many cases, the compounds provided herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, tri ethyl amine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297.

[0037] In some embodiments, the term “pharmaceutically acceptable salt,” as used herein, and unless otherwise specified, refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise desirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2 -hydroxy ethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-l -carboxylic, glucoheptonic, 3 -phenylpropionic, trimethylacetic, tert-butyl acetic, lauryl sulfuric, gluconic, benzoic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, muconic acid and the like acids; and (2) base addition salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, ammonia or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 7V-methylglucamine tris(hydroxymethyl)-aminomethane, piperazine, tetramethylammonium hydroxide, and the like.

[0038] In some embodiments, pharmaceutically acceptable salts further include, in some or any embodiments, and without limitation, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts and the like. When the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, e.g. hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, tri chloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate,

2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylate, glucoheptonate, 3 -phenylpropionate, trimethylacetate, tert-butyl acetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate and the like. [0039] In some embodiments, a “therapeutically effective amount” or “pharmaceutically effective amount” of a compound as provided herein, is one which is sufficient to achieve the desired effect and may vary according to the nature and severity of the disease condition, and the potency of the compound. The combination of compounds is preferably a synergistic combination. Synergy, as described in the art (for example, Chou, 2010, Cane. Res. 70(2):440- 446), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at sub-optimal concentrations of the compounds. This amount can further depend upon the patient's height, weight, sex, age and medical history.

[0040] The term “mammal” specifically includes humans, cattle, horses, dogs, and cats, but also includes many other mammalian species like pigs, rats, mice, primates (e.g., a monkey such as a cynomolgous monkey, a chimpanzee and a human). In some embodiments, the mammal is a human. [0041] The term “subject” refers to a mammal, as provided herein, as well as to a cell or biological sample.

[0042] The term “substantially free of’ stereoisomers with respect to a composition refers to a composition that includes at least 85 or 90% by weight, in some or any embodiments 95%, 98%, 99% or 100% by weight, of a designated stereoisomer of a compound in the composition. In some or any embodiments, in the methods and compounds provided herein, the compounds are substantially free of stereoisomers.

[0043] Similarly, the term “isolated” with respect to a composition refers to a composition that includes at least 85, 90%, 95%, 98%, 99% to 100% by weight, of a specified compound, the remainder comprising other chemical species or stereoisomers.

[0044] The term “isotopic composition,” as used herein, and unless otherwise specified, refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural isotopic composition.

[0045] The term “isotopic enrichment,” as used herein, and unless otherwise specified, refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance. In some or any embodiments, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0046] The term “isotopically enriched,” as used herein, and unless otherwise specified, refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. [0047] As used herein, and unless otherwise specified, the term “IC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0048] In some embodiments, the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In some or any embodiments, the term “therapeutic agent” includes a compound provided herein. In some or any embodiments, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.

[0049] In some embodiments, “treating” or “treatment” of any condition or disorder refers, in some or any embodiments, to ameliorating a condition or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the condition or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying the onset of the condition or disorder. In yet another embodiment, “treating” or “treatment” includes the reduction or elimination of either the condition or one or more symptoms of the condition, or to retard the progression of the condition or of one or more symptoms of the condition, or to reduce the severity of the condition or of one or more symptoms of the condition.

Compounds

[0050] The aspects and embodiments described herein include the recited compounds as well as any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof. For instance, aspects and embodiments described herein include a pharmaceutically acceptable salt thereof, and/or a single stereoisomer of mixture of stereoisomers thereof, and/or tautomer thereof.

[0051] Included herein, if chemically possible, are all stereoisomers of the compounds, including diastereomers and enantiomers. Also included are mixtures of possible stereoisomers in any ratio, including, but not limited to, racemic mixtures. Unless stereochemistry is explicitly indicated in a structure at a particular atom, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated. It will be apparent that certain structures recite specific stereochemistry at particular atoms.

[0052] Included herein, if chemically possible, are all tautomers of the compounds. Also included are mixtures of possible tautomers in any ratio.

[0053] In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), R¹ is selected from hydrogen; Ci-ealkyl optionally substituted with -OH; -OH; and -B(OH)2. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), R¹ is hydrogen. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), R¹ is Ci-ealkyl optionally substituted with -OH. In certain embodiments of Formula (I), (la), (lb), and (Ic), R¹ is -OH. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), R¹ is -B(OH)2.

[0054] In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of formula. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, [0055] In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the

[0056] In certain embodiments of Formula (I) and (lb), including any of the foregoing, Cy is absent or heterocycloalkyl. In certain embodiments of Formula (I) and (lb), including any of the foregoing, Cy is absent. In certain embodiments of Formula (I) and (lb), including any of the foregoing, Cy is heterocycloalkyl. In certain embodiments of Formula (I) and (lb), including any of the foregoing, Cy is heterocycloalkyl comprising 1 or 2 nitrogen atoms wherein the remaining ring atoms are carbon. In certain embodiments of Formula (I) and (lb), including any of the foregoing, Cy is a 4- to 10-membered heterocycloalkyl comprising 1 or 2 nitrogen atoms wherein the remaining ring atoms are carbon. In certain embodiments of Formula (I) and (lb), including any of the foregoing, Cy is a 5- to 6-membered heterocycloalkyl comprising 1 or 2 nitrogen atoms wherein the remaining ring atoms are carbon. In certain wherein each of the Cy ring indicates an attachment to the rest of the formula and either

A \f3^xi <x1^² of the Cy ring is attached to X^{4 r3} . In certain embodiments of Formula (I) and

(lb), including any of the foregoing, Cy is [0057] In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of indicates attachment to the R³ group. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, wherein each R² is independently selected from -Ci-ealkyl, -OH, -B(OH)2, -OCi-ealkyl, halo,

-NR^4aR^4b, -NR^4aC(O)R^4b, and -C(O)NR^4aR^4b. In certain embodiments of Formula (I), (la), (la-

1), (lb), and (Ic), including any of the foregoing, . In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including . In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing,

[0058] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)₂.

[0059] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -(Co-6alkylene)-X⁵-R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -(Co-6alkylene)-0-R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -(Co-6alkylene)-NR^4aR⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -(Co-6alkylene)-NHR⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -(Co-6alkylene)-R⁵.

[0060] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2OCi-6alkyl-NH-C(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2OC2alkyl-NHC(O)Ci- ealkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2OCi-6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2OC2alkyl-NHC(O)OCH3.

[0061] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2Ci-6alkyl-NH-C(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2-CH2-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2Ci-6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -C(CH3)2-CH2-NHC(O)OCH3.

[0062] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -OCi-6alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -OC2alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -OCi- 6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -OC2alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(0H)2 or

-OC₂alkyl-NHC(O)OCH₃.

[0063] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -Ci-6alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -CH2-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)2 or -Ci- 6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -B(OH)₂ or -CH₂-NHC(O)OCH₃.

[0064] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2X⁵-R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2OR⁵ or -C(CH₃)2R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2OR⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH2CH₃)2OR⁵ or -C(CH2CH₃)2R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH2CH₃)2OR⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH2CH₃)2R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -CH(CH₃)OR⁵ or -CH(CH₃)R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -CH(CH₃)OR⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -CH(CH₃)R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -CH(CH2CH₃)OR⁵ or -CH(CH2CH₃)R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -CH(CH2CH₃)OR⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -CH(CH2CH₃)R⁵.

[0065] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2OCi-6alkyl-NH-C(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2OC2alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2OCi-6alkyl-NHC(O)OCH₃. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2OCH2-NHC(O)OCH₃.

[0066] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2Ci-6alkyl-NH-C(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2-CH2-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)2Ci-6alkyl- NHC(O)OCH3. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -C(CH₃)₂-CH2-NHC(O)OCH3.

[0067] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -(Ci-C3alkylene)-X⁵-R⁵ and the Ci-Csalkylene is substituted with R^7a and R^7b. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is -CR^7aR^7b-X⁵-R⁵. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is . in certain embodiments of Formula (I) and (Ic), including any of the foregoing, R³ is i_n certain embodiments of Formula (I) and (Ic), including any of the foregoing,

[0068] In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R^7a and R^7b are joined together with the atom or atoms to which they are attached to form a C₃-

4cycloalkyl. In certain embodiments of Formula (I) and (Ic), including any of the foregoing, R^7a and R^7b are joined together with the atom or atoms to which they are attached to form a Cscycloalkyl.

[0069] In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing,

-X⁵-R⁵ is -OCi-6alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing, -X⁵-R⁵ is -OC2alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing, -X⁵-R⁵ is -OCi- 6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing, -X⁵-R⁵ is -OC2alkyl-NHC(O)OCH3.

[0070] In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing,

-X⁵-R⁵ is -Ci-6alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing, -X⁵-R⁵ is -CH2-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing, -X⁵-R⁵ is -Ci-6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I), (la), and (Ic), including any of the foregoing, -X⁵-R⁵ is

-CH2-NHC(O)OCH₃.

[0071] In certain embodiments of Formula (I), (la), (la-1), and (Ic), including any of the foregoing, R⁵ is -C2alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I), (la), (la- 1), and (Ic), including any of the foregoing, R⁵ is -Ci-6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I), (la), (la-1), and (Ic), including any of the foregoing, R⁵ is - C2alkyl-NHC(O)OCH3. In certain embodiments of Formula (I), (la), (la- 1), and (Ic), including any of the foregoing, R⁵ is -Ci-6alkyl-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I), (la), (la-1), and (Ic), including any of the foregoing, R⁵ is -CH2-NHC(O)Ci-6alkoxy. In certain embodiments of Formula (I), (la), (la-1), and (Ic), including any of the foregoing, R⁵ is -Ci-6alkyl-NHC(O)OCH3. In certain embodiments of Formula (I), (la), (la-1), and (Ic), including any of the foregoing, R⁵ is -CH2-NHC(O)OCH3.

[0072] In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, R^4a and R^4b are both hydrogen. In certain embodiments of Formula (I), (la), (la- 1), (lb), and (Ic), including any of the foregoing, R^4a is hydrogen. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, R⁶ is Ci-ealkyl. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, R⁶ is Ci-3alkyl. In certain embodiments of Formula (I), (la), (la-1), (lb), and (Ic), including any of the foregoing, R⁶ is CH .

[0073] In one embodiment of Formula (la), including any of the foregoing, X⁵ is O. In one embodiment of Formula (la), including any of the foregoing, are each CH. In one embodiment of Formula (la), including any of the foregoing, are each CH. In one embodiment of Formula (la), including any of the foregoing, are each CH. In one embodiment of Formula (la), including any of the foregoing, are each CH; X⁵ is O; and R⁵ is -Ci-6alkyl-NHC(O)OCi-6alkyl. In one embodiment of Formula (la), including any of the foregoing, are each CH; X⁵ is O; and

R⁵ is -Ci-6alkyl-NHC(O)OCi-6alkyl. In one embodiment of Formula (la), including any of the foregoing, are each CH; X⁵ is O; and R⁵ is -

C2alkyl-NHC(O)OCi-6alkyl. In one embodiment of Formula (la), including any of the R¹ is Ci-ealkyl,

-B(0H)2, or hydrogen, wherein the Ci-ealkyl is substituted with -OH; X¹ to X⁴ are each CH; X⁵ is O; and, R⁵ is -C2alkyl-NHC(O)OCi-6alkyl. In one embodiment of Formula (la) or (la-1), including any of the foregoing, are each

CH; and R⁵ is -C2alkyl-NHC(O)OCi-6alkyl. In one embodiment of Formula (la), including any [0074] In one embodiment of Formula (lb), Cy is . In one embodiment of

Formula (lb), R¹ is hydrogen, Cy is and X³ and X⁴ are each CH. In one embodiment of Formula (lb), R¹ is hydrogen, X¹ is N, and X² to X⁴ are each CH. In one embodiment of Formula (lb), R¹ is hydrogen, X² is CR², and X¹, X³, and X⁴ are each CH. In one embodiment of Formula (lb), R¹ is hydrogen, X² is C-OH, and X¹, X³, and X⁴ are each . , y , , , , and X⁴ are each CH.

[0075] In one embodiment of Formula (Ic), R¹ is hydrogen and X¹ to X⁴ are each CH. In one embodiment of Formula (Ic), R¹ is hydrogen; X² is CR²; and, X¹, X³, and X⁴ are each CH. In one embodiment of Formula (Ic), R¹ is hydrogen, X² is C-OH, and X¹, X³, and X⁴ are each CH. In one embodiment of Formula (Ic), R¹ is hydrogen, X¹ to X⁴ are each CH, and R³ is -C(CH₃)₂R⁵. In one embodiment of Formula (Ic), R¹ is hydrogen; X² is CR²; X¹, X³, and X⁴ are each CH; and R³ is -C(CH3)2R⁵. In one embodiment of Formula (Ic), R¹ is hydrogen, X¹ to X⁴ are CH, R³ is -C(CH3)2R⁵, and R⁵ is -CH2-NHC(O)OCi-6alkyl. In one embodiment of Formula (Ic), R¹ is hydrogen; X² is CR²; X¹, X³, and X⁴ are each CH; R³ is -C(CH3)2R⁵; and, R⁵ is -CH₂-NHC(O)OCi-₆alkyl.

[0076] In one embodiment of Formula (I), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof; R¹ is selected from hydrogen and Ci-ealkyl optionally substituted with -OH, or -B(OH)2;

Cy is absent or heterocycloalkyl;

X¹, X², X³, and X⁴ are independently N or CR² wherein at least 2 of X¹ to X⁴ are CR²; each R² is independently hydrogen or -OH;

R³ is -B(OH)2 or -(Co-Cealkylene)-X⁵-R⁵;

R⁵ is Ci-ealkoxycarbonyl-NH-Ci-ealkyl; and

X⁵ is bond or O.

[0077] In one embodiment, the compound of Formula (I) is a compound of Table 1 : or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof: [0078] In some or any embodiments, provided herein are:

(a) compounds as described herein, e.g., of Formula (I), (la), (la-1), (lb), or (Ic) or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof and Compounds 1-7 or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof ;

(b) compounds as described herein, e.g., of Formula (I), (la), (la-1), (lb), or (Ic) or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof and Compounds 1-7 or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof and compositions (including pharmaceutical compositions) thereof for use in inhibiting PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a subject;

(c) pharmaceutical compositions comprising a compound as described herein, e.g., of Formula (I), (la), (la-1), (lb), or (Ic) or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof or a Compound 1-7 or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof together with a pharmaceutically acceptable carrier (e.g. diluent);

(d) a method for the treatment of a disease, disorder, or condition associated with PARP- 1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a mammal that includes the administration of a therapeutically effective amount of a compound as described herein, e.g., of Formula (I), (la), (la-1), (lb), or (Ic) or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof or a Compound 1-7 or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof or compositions (including pharmaceutical compositions) thereof;

(e) pharmaceutical compositions comprising a compound as described herein, e.g., of Formula (I), (la), (la-1), (lb), or (Ic) or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof or a Compound 1-7 or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof together with one or more other effective agents for treating a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity, optionally in a pharmaceutically acceptable carrier (e.g. diluent);

(f) embodiments (d) or (e), wherein the disease, disorder, or condition is cancer or a cellular proliferative disease, disorder, or cancer;

(g) embodiment (g) wherein the cancer is selected from prostate cancer, ovarian cancer, B- cell lymphoma, breast cancer, colorectal cancer, melanoma, and fibrosarcoma;

(h) embodiments (d) or (e), wherein the disease, disorder, or condition is an inflammatory dermatitis disease; and

(i) embodiment (h) wherein the inflammatory dermatitis disease is selected from the group consisting of acne, psoriasis, rosacea, and scleroderma.

Optically Active Compounds

[0079] It is appreciated that in certain embodiments, the compounds provided herein have several chiral centers and may exist in and be isolated in optically active and racemic forms. It is to be understood that any racemic, optically-active, diastereomeric, tautomeric, or stereoisomeric form, mixture, or combination thereof, of a compound provided herein, which possess the useful properties described herein is within the scope of the invention. It being well known in the art how to prepare optically active forms (in some or any embodiments, by resolution of the racemic form by recrystallization techniques, by synthesis from optically- active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0080] In some or any embodiments, methods to obtain optically active materials are known in the art, and include at least the following. i) physical separation of crystals - a technique whereby macroscopic crystals of the individual stereoisomers are manually separated. This technique can be used if crystals of the separate stereoisomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization - a technique whereby the individual stereoisomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions - a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the stereoisomers with an enzyme; iv) enzymatic asymmetric synthesis - a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain a stereoisomerically pure or enriched synthetic precursor of the desired stereoisomer; v) chemical asymmetric synthesis - a synthetic technique whereby the desired stereoisomer is synthesized from an achiral precursor under conditions that produce asymmetry i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations - a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations - a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions - this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the stereoisomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) stereospecific synthesis from non-racemic precursors - a synthetic technique whereby the desired stereoisomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography - a technique whereby the stereoisomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography - a technique whereby the racemate is volatilized and stereoisomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents - a technique whereby the stereoisomers are separated by virtue of preferential dissolution of one stereoisomer into a particular chiral solvent; xiii) transport across chiral membranes - a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane which allows only one stereoisomer of the racemate to pass through.

[0081] In some or any embodiments, provided is a composition of a compound that comprises a substantially pure designated stereoisomer of the compound. In some or any embodiments, in the methods and compounds, the compounds are substantially free of other stereoisomer. In some or any embodiments, a composition includes a compound that is at least 85%, 90%, 95%, 98%, 99% or 100% by weight, of the designated stereoisomer, the remainder comprising other chemical species or stereoisomers.

Isotopically Enriched Compounds

[0082] Also provided herein are isotopically enriched compounds.

[0083] Isotopic enrichment (in some or any embodiments, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117: 191 (1999).

[0084] Isotopic enrichment of a drug can be used, in some or any embodiments, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrees the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.

[0085] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C-H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). See, e.g., Foster et aL, Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al.. Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999).

[0086] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C-H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. High DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon.

[0087] Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T2O. Tritium decays slowly (half-life = 12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements, including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen, may lead to a similar kinetic isotope effect.

[0088] For example, the DKIE was used to decrease the hepatotoxicity of halothane by presumably limiting the production of reactive species such as trifluoroacetyl chloride. However, this method may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching asserts that xenogens, when sequestered by Phase I enzymes, may bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively vast size of binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity.

[0089] In some embodiments, the compounds described herein may be used as radiopharmaceuticals such as, for example, imaging agents. In one instance, radiopharmaceuticals are positron emission tomography (PET) imaging agents. In such embodiments, substitution of radionuclides (e.g., positron emitting isotopes) for atoms in the compounds allows for the syntheses of radiopharmaceuticals that can function as imaging agents. In some embodiments, radionuclides which can be substituted in the compounds described herein include, and are not limited to, ¹⁸F, ⁿC, ¹³N, ¹⁵O, ⁷⁶Br, and ¹²⁴I. In some embodiments, the compound is isotopically enriched at one or more atoms, one atom, two atoms, or three atoms. In some embodiments, the compound is administered as an isotopic composition.

[0090] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. In some or any embodiments, such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or carbon-carbon (C-C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and longterm toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. These drugs therefore often require the administration of multiple or high daily doses. [0091] Therefore, isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacokinetic, pharmacologic, and/or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition.

Preparation of Compounds

[0092] The compounds provided herein can be prepared, isolated or obtained by any method apparent to those of skill in the art. Compounds provided herein can be prepared according to the Exemplary Preparation Schemes provided below. Reaction conditions, steps and reactants not provided in the Exemplary Preparation Schemes would be apparent to, and known by, those skilled in the art.

[0093] One of skill will understand that the order of steps for any process described herein may be changed. Other variations will be apparent to one of skill in the art and all such variations are contemplated within the scope of embodiments presented herein.

Pharmaceutical Compositions and Methods of Administration

[0094] The compounds provided herein can be formulated into pharmaceutical compositions using methods available in the art and those disclosed herein. Any of the compounds disclosed herein can be provided in the appropriate pharmaceutical composition and be administered by a suitable route of administration. Provided herein are pharmaceutical compositions comprising a compound of Formula (I), (la), (la-1), (lb), or (Ic) as described herein in some and any embodiments, or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, and a pharmaceutically acceptable carrier.

[0095] The methods provided herein encompass administering pharmaceutical compositions containing at least one compound as described herein, including a compound of Formula (I), (la), (la-1), (lb), or (Ic) or any stereoisomer and/or tautomer thereof, and if appropriate in a salt form, either used alone or in the form of a combination with one or more compatible and pharmaceutically acceptable carriers, such as diluents or adjuvants, or with another agent for the treatment of cancer or a proliferative disease, disorder, or condition. In some embodiments, the disease, disorder, or condition is associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity. In some embodiments, the disease, disorder, or condition is associated with PARP-2 signaling pathway activity. In some embodiments, the disease, disorder, or condition is associated with PARP-5a and PARP-5b signaling pathway activity.

[0096] In some embodiments, the compositions can include a second medication or therapeutic agent. These therapeutic agents can be delivered as separate dosage forms from the compositions described herein, or may be included as additional components of the compositions described herein, hence delivered together with the compound of Formula (I), (la), (la-1), (lb), or (Ic) or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof (or any embodiments thereof, including in some embodiments, a Compound 1-7 or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof).

[0097] In some or any embodiments, the second agent can be formulated or packaged with the compound provided herein. Of course, the second agent will only be formulated with the compound provided herein when, according to the judgment of those of skill in the art, such co-formulation should not interfere with the activity of either agent or the method of administration. In some or any embodiments, the compound provided herein and the second agent are formulated separately. They can be packaged together, or packaged separately, for the convenience of the practitioner of skill in the art.

[0098] In clinical practice the active agents provided herein may be administered by any conventional route, in particular parenterally, rectally, orally, by inhalation (e.g. in the form of aerosols), or topically.

[0099] Use may be made, as solid compositions for oral administration, of tablets, pills, hard gelatin capsules, powders or granules. In these compositions, the active product is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch.

[00100] These compositions can comprise substances other than diluents, for example a lubricant, such as magnesium stearate, or a coating intended for controlled release.

[00101] Use may be made, as liquid compositions for oral administration, of solutions which are pharmaceutically acceptable, suspensions, emulsions, syrups and elixirs containing inert diluents, such as water or liquid paraffin. These compositions can also comprise substances other than diluents, in some or any embodiments, wetting, sweetening or flavoring products.

[00102] The compositions for parenteral administration can be emulsions or sterile solutions. Use may be made, as solvent or vehicle, of propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, or injectable organic esters, in some or any embodiments, ethyl oleate. These compositions can also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterilization can be carried out in several ways, in some or any embodiments, using a bacteriological filter, by radiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other injectable sterile medium.

[00103] The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active principle, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.

[00104] The compositions can also be aerosols. For use in the form of liquid aerosols or sprays, the compositions can be stable sterile solutions or solid compositions dissolved at the time of use in apyrogenic sterile water, in saline or any other pharmaceutically acceptable vehicle. For use in the form of dry aerosols intended to be directly inhaled, the active principle is finely divided and combined with a water-soluble solid diluent or vehicle, in some or any embodiments, dextran, mannitol or lactose. In one or more embodiments, a pharmaceutical composition provided herein is a spray.

[00105] In some or any embodiments, a composition provided herein is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and single unit dosage forms provided herein comprise a therapeutically effective amount of one or more therapeutic agents (e.g., a compound provided herein, or other therapeutic agent), and a typically one or more pharmaceutically acceptable carriers (e.g. excipients). In a specific embodiment and in this context, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. In some embodiments, the term “carrier” includes a diluent, disintegrant, lubricant, adjuvant (e.g., Freund’ s adjuvant (complete and incomplete)), excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[00106] Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well-known to those skilled in the art of pharmacy, and in some or any embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a mammal and the specific active ingredients in the dosage form. The composition or single unit dosage form, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[00107] Lactose free compositions provided herein can comprise excipients that are well known in the art and are listed, in some or any embodiments, in the U.S. Pharmacopeia (USP 36-NF 31 S2). In general, lactose free compositions comprise an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose free dosage forms comprise an active ingredient, microcrystalline cellulose, pre gelatinized starch, and magnesium stearate.

[00108] Further encompassed herein are anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long term storage in order to determine characteristics such as shelf life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, New York, 1995, pp. 379 80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.

[00109] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine can be anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.

[00110] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions can be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. In some or any embodiments, suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. [00111] Further provided are pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as “stabilizers,” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[00112] Further provided are pharmaceutical compositions and dosage forms that comprise one or more chemical permeation enhancer. In some or any embodiments, chemical permeation enhancers include but are not limited to ethanol, amides (such as Ozone, Laurocapram), alkyl and benzoate esters, fatty acid esters (such as isopropyl myristate, propylene glycol monocaprylate and propyleneglycomonolaurate), Transcutol (Registered name), fatty acids (oleic acid), glycols, pyrrolidone (N-methyl-2-pyrrolidone and 2-pyrrolidone, dimethylsulfoxide (DMSO), terpenes (such as essential oils comprising terpenes), phospholipids, and/or cyclodeextrines.

[00113] The pharmaceutical compositions and single unit dosage forms can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like. Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such compositions and dosage forms will contain a prophylactically or therapeutically effective amount of a prophylactic or therapeutic agent, in some or any embodiments, in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the mammal. The formulation should suit the mode of administration. In a some or any embodiment, the pharmaceutical compositions or single unit dosage forms are sterile and in suitable form for administration to a mammal, in some or any embodiments, a human.

[00114] A pharmaceutical composition is formulated to be compatible with its intended route of administration. In some or any embodiments, routes of administration include, but are not limited to, parenteral, e.g., intrathecal, epidural, local or regional for peripheral nerve block, intravenous, intradermal, subcutaneous, intramuscular, subcutaneous, oral, buccal, sublingual, inhalation, intranasal, transdermal, topical (including administration to the eye, and in some embodiments to the cornea), transmucosal, intra-tumoral, intra-synovial, and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical (including administration to the eye, and in some embodiments to the cornea) administration to human beings. In a specific embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocamne to ease pain at the site of the injection.

[00115] In some or any embodiments, dosage forms include, but are not limited to: sprays, tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a mammal, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil in water emulsions, or a water in oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a mammal; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a mammal.

[00116] The composition, shape, and type of dosage forms provided herein will typically vary depending on their use. In some or any embodiments, a dosage form used in the initial treatment of the disease, disorder, or condition may contain larger amounts of one or more of the active ingredients it comprises than a dosage form used in the maintenance treatment of the same disease, disorder, or condition. Similarly, a parenteral dosage form may contain smaller amounts of one or more of the active ingredients it comprises than an oral dosage form used to treat the same disease or disorder. These and other ways in which specific dosage forms encompassed herein will vary from one another will be readily apparent to those skilled in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[00117] Generally, the ingredients of compositions are supplied either separately or mixed together in unit dosage form, in some or any embodiments, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[00118] Typical dosage forms comprise a compound provided herein, or a pharmaceutically acceptable salt, solvate or hydrate thereof lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose in the morning or as divided doses throughout the day taken with food. Particular dosage forms can have about 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 2.5, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 100, 200, 250, 500 or 1000 mg of the active compound.

Oral Dosage Forms

[00119] Pharmaceutical compositions that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[00120] In some or any embodiments, the oral dosage forms are solid and prepared under anhydrous conditions with anhydrous ingredients, as described in detail herein. However, the scope of the compositions provided herein extends beyond anhydrous, solid oral dosage forms. As such, further forms are described herein.

[00121] Typical oral dosage forms are prepared by combining the active ingredient(s) in an intimate admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. In some or any embodiments, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. In some or any embodiments, excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.

[00122] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or non-aqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.

[00123] In some or any embodiments, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00124] In some or any embodiments, one or more of the following can be used in the pharmaceutical composition: benzyl alcohol, butyl paraben, butylated hydroxy toluene, calcium carbonate, candelilla wax, colloidal silicone dioxide, calcium stearate, calcium disodium EDTA, copolyvidone or copovidone, calcium hydrogen phosphate dihydrate, crosspovidone, calcium phosphate (di and tri basic), emollients (glyceryl monostearate), iron oxide ivyyellow yellow, and iron.

[00125] In some or any embodiments, excipients that can be used in oral dosage forms include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, copolyvidone or copovidone, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[00126] In some or any embodiments, fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.

[00127] In some or any embodiments, suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL PH 101, AVICEL PH 103 AVICEL RC 581, AVICEL PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC 581. Suitable anhydrous or low moisture excipients or additives include AVICEL PH 103™ and Starch 1500 LM.

[00128] Disintegrants are used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.

[00129] Disintegrants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, crosspovidone, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.

[00130] Lubricants that can be used in pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, in some or any embodiments, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, TX), CAB O SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.

Delayed Release Dosage Forms

[00131] Active ingredients such as the compounds provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. In some or any embodiments, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500; each of which is incorporated herein by reference in its entirety. Such dosage forms can be used to provide slow or controlled release of one or more active ingredients using, in some or any embodiments, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. Thus encompassed herein are unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gel caps, and caplets that are adapted for controlled release.

[00132] All controlled release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled release formulations include extended activity of the drug, reduced dosage frequency, and increased compliance. In addition, controlled release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[00133] Most controlled release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[00134] In some or any embodiments, the drug may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some or any embodiments, a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321 :574 (1989)). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in a mammal at an appropriate site determined by a practitioner of skill, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). Other controlled release systems are discussed in the review by Langer (Science 2 9A52^rl- 1533 (1990)). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethyl ene/propylene copolymers, ethyl ene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the mammal.

Parenteral Dosage Forms

[00135] In some or any embodiments, provided are parenteral dosage forms. Parenteral dosage forms can be administered to mammals by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial. Because their administration typically bypasses the mammal’s natural defenses against contaminants, parenteral dosage forms are typically, sterile or capable of being sterilized prior to administration to a mammal. In some or any embodiments, parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.

[00136] Suitable vehicles that can be used to provide parenteral dosage forms are well known to those skilled in the art. In some or any embodiments, suitable vehicles include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer’s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer’s Injection; water miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[00137] Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms.

Transdermal, Topical & Mucosal Dosage Forms

[00138] Also provided are transdermal, topical, and mucosal dosage forms. Transdermal, topical, and mucosal dosage forms include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include “reservoir type” or “matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.

[00139] Suitable carriers (e.g., excipients and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed herein are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane 1,3 diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are nontoxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).

[00140] Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients provided. In some or any embodiments, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).

[00141] The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery enhancing or penetration enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.

Dosage and Unit Dosage Forms

[00142] In human therapeutics, the doctor will determine the posology which the doctor considers most appropriate according to the treatment needed (e.g. preventative or curative) and according to the age, weight, stage of the disease, disorder, or condition and other factors specific to the mammal to be treated. In some or any embodiments, topical doses are described as mg per cm² of treatment site (e.g. a wound) and are from about 0.001 to about 50 mg/cm², or from about 0.005 to about 50 mg/cm², or from about 0.01 to about 50 mg/cm², or from about 0.01 to about 40 mg/cm², or from about 0.01 to about 30 mg/cm², or from about 0.01 to about 20 mg/cm², or from about 0.01 to about 10 mg/cm², or from about 0.05 to about 10 mg/cm², or from about 0.05 to about 1 mg/cm².

[00143] In some or any embodiments, topical and non-topical doses are from about 1 to about 1000 mg per day for an adult, or from about 5 to about 250 mg per day or from about 10 to about 50 mg per day for an adult. In some or any embodiments, doses are from about 5 to about 400 mg per day or about 25 to about 200 mg per day per adult. In some or any embodiments, dose rates of from about 50 to about 500 mg per day are also contemplated. In some or any embodiments, doses for subcutaneous administration are from about 1 to about 50 mg per day, or from about 1 to about 25 mg per day, or from about 1 to about 10 mg per day, or from about 1 to about 20 mg per day, or from about 5 to about 25 mg per day, or from about 5 mg to about 20 mg per day, or from about 10 to about 20 mg per day. In some or any embodiments, doses for oral administration are from about 0.01 mg to about 100 mg per day, from about 0.01 to about 100 mg per day, or from about 0.01 mg to about 50 mg per day, from about 0.01 to about 25 mg per day, from about 0.01 to about 15 mg per day, from about 0.01 to about 10 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.05 to about 1 mg per day, from about 0.1 to about 100 mg per day, from about 0.1 to about 50 mg per day, from about 0.1 to about 25 mg per day, from about 0.1 to about 15 mg per day, from about 0.1 to about 10 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 mg to about 1 mg per day, or from about 10 mg to about 200 mg per day. In some or any embodiments, including any of the foregoing embodiments, the daily dose can be administered once a day. In some or any embodiments, including any of the foregoing embodiments, the daily dose can be divided and administered twice a day. In some or any embodiments, including any of the foregoing embodiments, the daily dose can be divided and administered three times a day.

[00144] In some embodiments, the mg/day amounts are for an adult. In further aspects, provided are methods of treating a disease, disorder, or condition associated with Wnt signaling pathway activity in a mammal by administering to a mammal in need thereof, a therapeutically or prophylactically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof. The amount of the compound or composition which will be therapeutically or prophylactically effective in the treatment of a disorder or one or more symptoms thereof will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each mammal depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the mammal. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[00145] In some or any embodiments, exemplary doses of a composition include milligram or microgram amounts of the active compound per kilogram of mammal or sample weight (e.g., about 10 micrograms per kilogram to about 50 milligrams per kilogram, about 100 micrograms per kilogram to about 25 milligrams per kilogram, or about 100 microgram per kilogram to about 10 milligrams per kilogram). For compositions provided herein, in some or any embodiments, the dosage administered to a mammal is 0.01 mg/kg to 3 mg/kg of the mammal’s body weight, or 0.10 mg/kg to 3 mg/kg of the mammal’s body weight, based on weight of the active compound. In some or any embodiments, the dosage administered to a mammal is between 0.20 mg/kg and 2.00 mg/kg, or between 0.30 mg/kg and 1.50 mg/kg of the mammal’s body weight. In some embodiments, the dosage is administered subcutaneously to a mammal and is between about 0.01 mg/kg to 1 mg/kg (inclusive), or between about 0.03 mg/kg to 0.5 mg/kg (inclusive) of the mammal’s body weight, based on weight of the active compound. In some embodiments, the dosage is administered orally to a mammal and is between about 0.10 mg/kg to 5 mg/kg (inclusive) of the mammal’s body weight, or between about 0.10 mg/kg to 2 mg/kg (inclusive) of the mammal’s body weight, based on weight of the active compound. In some or any embodiments, the recommended daily topical dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.01 mg to about 100 mg per day, given as a single once-a-day dose or as divided doses (e.g. in two or three doses) throughout a day.

[00146] In some or any embodiments, the recommended daily dose range of a composition provided herein for the conditions described herein lie within the range of from about 0.1 mg to about 1000 mg per day, given as a single once-a-day dose or as divided doses throughout a day. In some or any embodiments, the daily dose is administered twice daily in equally divided doses. In some or any embodiments, the daily dose is administered thrice daily in equally divided doses. In some or any embodiments, the daily dose is administered four times daily in equally divided doses. In some or any embodiments, a daily dose range should be from about 0.01 mg to about 400 mg per day, from about 0.1 mg to about 250 mg per day, from about 10 mg to about 200 mg per day, in other embodiments, or from about 10 mg and about 150 mg per day, in further embodiments, between about 25 and about 100 mg per day. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with the response of the mammal.

[00147] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the herein described dosage amounts and dose frequency schedules. Further, when a mammal is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. In some or any embodiments, the dosage administered to the mammal may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular mammal is experiencing.

[00148] In some or any embodiment, the dosage of the composition provided herein, based on weight of the active compound, administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a mammal is about 0.01 mg/kg, about 0.1 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 10 mg/kg, or about 15 mg/kg or more of a mammal’s body weight. In another embodiment, the dosage of the composition or a composition provided herein administered to prevent, treat, manage, or ameliorate a disorder, or one or more symptoms thereof in a mammal is a unit dose selected from about 0.01 mg/kg to about 100 mg/kg, selected from about 0.1 mg to about 200 mg, selected from about 0.1 mg to about 100 mg, selected from about 0.1 mg to about 50 mg, selected from about 0.1 mg to about 25 mg, selected from about 0.1 mg to about 20 mg, selected from about 0.1 mg to about 15 mg, selected from about 0.1 mg to about 10 mg, selected from about 0.1 mg to about 7.5 mg, selected from about 0.1 mg to about 5 mg, 0.1 to about 2.5 mg, selected from about 0.25 mg to about 20 mg, selected from about 0.25 to about 15 mg, selected from about 0.25 to 12 mg, selected from about 0.25 to about 10 mg, selected from about 0.25 mg to about 7.5 mg, selected from about 0.25 mg to about 5 mg, selected from about 0.5 mg to about 2.5 mg, 1 mg to about 20 mg, selected from about 1 mg to about 15 mg, selected from about 1 mg to about 12 mg, 1 mg to about 10 mg, selected from about 1 mg to about 7.5 mg, selected from about 1 mg to about 5 mg, or selected from about 1 mg to about 2.5 mg.

[00149] In some or any embodiments, a dose of a compound or composition provided herein can be administered to achieve a steady-state concentration of the active ingredient in blood or serum of the mammal. The steady-state concentration can be determined by measurement according to techniques available to those of skill or can be based on the physical characteristics of the mammal such as height, weight and age. In some or any embodiments, administration of the same composition may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[00150] In some or any embodiments, provided herein are unit dosages comprising a compound, or a pharmaceutically acceptable salt thereof, in a form suitable for administration. Such forms are described in detail herein. In some or any embodiments, the unit dosage comprises 1 to 1000 mg, 1 to 100 mg or 10 to 50 mg active ingredient. In particular embodiments, the unit dosages comprise about 1, 5, 10, 25, 50, 100, 125, 250, 500 or 1000 mg active ingredient. Such unit dosages can be prepared according to techniques familiar to those of skill in the art.

[00151] In some or any embodiments, dosages of the second agents to be used in a combination therapy are provided herein. In some or any embodiments, dosages lower than those which have been or are currently being used to treat the disease, disorder, or condition are used in the combination therapies provided herein. The recommended dosages of second agents can be obtained from the knowledge of those of skill in the art. For those second agents that are approved for clinical use, recommended dosages are described in, for example, Hardman etal., eds., 1996, Goodman & Gilman’s The Pharmacological Basis Of Therapeutics 9^th Ed, Mc-Graw-Hill, New York; Physician’s Desk Reference (PDR) 57^th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ; which are incorporated herein by reference in their entirety.

[00152] In various embodiments, the therapies (e.g., a compound provided herein and the second agent) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours apart. In various embodiments, the therapies are administered no more than 24 hours apart or no more than 48 hours apart. In some or any embodiments, two or more therapies are administered within the same patient visit. In other embodiments, the compound provided herein and the second agent are administered concurrently.

[00153] In other embodiments, the compound provided herein and the second agent are administered at about 2 to 3 days apart, 2 to 4 days apart, at about 4 to 6 days apart, at about 1 week part, at about 1 to 2 weeks apart, or more than 2 weeks apart.

[00154] In some or any embodiments, administration of the same agent may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[00155] In some or any embodiments, a compound provided herein and a second agent are administered to a patient, in some or any embodiments, a mammal, such as a human, in a sequence and within a time interval such that the compound provided herein can act together with the other agent to provide an increased benefit than if they were administered otherwise. In some or any embodiments, the second active agent can be administered at the same time or sequentially in any order at different points in time; however, if not administered at the same time, they should be administered sufficiently close in time so as to provide the desired therapeutic or prophylactic effect. In some or any embodiments, the compound provided herein and the second active agent exert their effect at times which overlap. Each second active agent can be administered separately, in any appropriate form and by any suitable route. In other embodiments, the compound provided herein is administered before, concurrently or after administration of the second active agent.

[00156] In some or any embodiments, the compound provided herein and the second agent are cyclically administered to a patient. Cycling therapy involves the administration of a first agent (e.g., a first prophylactic or therapeutic agent) for a period of time, followed by the administration of a second agent and/or third agent (e.g., a second and/or third prophylactic or therapeutic agent) for a period of time and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and/or improve the efficacy of the treatment.

[00157] In some or any embodiments, the compound provided herein and the second active agent are administered in a cycle of less than about 3 weeks, about once every two weeks, about once every 10 days or about once every week. One cycle can comprise the administration of a compound provided herein and the second agent by infusion over about 90 minutes every cycle, about 1 hour every cycle, about 45 minutes every cycle. Each cycle can comprise at least 1 week of rest, at least 2 weeks of rest, at least 3 weeks of rest. The number of cycles administered is from about 1 to about 12 cycles, more typically from about 2 to about 10 cycles, and more typically from about 2 to about 8 cycles.

[00158] In other embodiments, courses of treatment are administered concurrently to a patient, z.e., individual doses of the second agent are administered separately yet within a time interval such that the compound provided herein can work together with the second active agent. In some or any embodiments, one component can be administered once per week in combination with the other components that can be administered once every two weeks or once every three weeks. In other words, the dosing regimens are carried out concurrently even if the therapeutics are not administered simultaneously or during the same day.

[00159] The second agent can act additively or synergistically with the compound provided herein. In some or any embodiments, the compound provided herein is administered concurrently with one or more second agents in the same pharmaceutical composition. In another embodiment, a compound provided herein is administered concurrently with one or more second agents in separate pharmaceutical compositions. In still another embodiment, a compound provided herein is administered prior to or subsequent to administration of a second agent. Also contemplated are administration of a compound provided herein and a second agent by the same or different routes of administration, e.g., oral and parenteral. In some or any embodiments, when the compound provided herein is administered concurrently with a second agent that potentially produces adverse side effects including, but not limited to, toxicity, the second active agent can advantageously be administered at a dose that falls below the threshold that the adverse side effect is elicited.

Kits

[00160] Also provided are kits for use in methods of treatment of disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity. The kits can include a compound or composition provided herein, a second agent or composition, and instructions providing information to a health care provider regarding usage for treating the disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity. Instructions may be provided in printed form or in the form of an electronic medium such as a floppy disc, CD, or DVD, or in the form of a website address where such instructions may be obtained. A unit dose of a compound or composition provided herein, or a second agent or composition, can include a dosage such that when administered to a mammal, a therapeutically or prophylactically effective plasma level of the compound or composition can be maintained in the mammal for at least 1 day. In some or any embodiments, a compound or composition can be included as a sterile aqueous pharmaceutical composition or dry powder (e.g., lyophilized) composition.

[00161] In some or any embodiments, suitable packaging is provided. As used herein, “packaging” includes a solid matrix or material customarily used in a system and capable of holding within fixed limits a compound provided herein and/or a second agent suitable for administration to a mammal. Such materials include glass and plastic (e.g., polyethylene, polypropylene, and polycarbonate) bottles, vials, paper, plastic, and plastic-foil laminated envelopes and the like. If e-beam sterilization techniques are employed, the packaging should have sufficiently low density to permit sterilization of the contents.

Methods of Use

[00162] Provided herein is a method for inhibiting PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a mammal, which comprises the administration of an effective amount of a compound of Formula (I), (la), (la-1), (lb), or (Ic), including a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof.

[00163] Provided herein is a method for the treatment of a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a mammal, comprising the administration of a therapeutically or prophylactically effective amount of a compound of Formula (I), (la), (la-1), (lb), or (Ic) described herein (or any embodiments thereof), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof or a pharmaceutical composition described herein. In one or more embodiments, the method is for treating a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity, comprising administering a compound of Formula (I), (la), (la-1), (lb), or (Ic) (or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition according to one or more embodiments to a mammal in need thereof.

[00164] In a group of embodiments, the disease, disorder, or condition is cancer or a proliferative disease, disorder, or condition. In one embodiment, the cancer is selected from the group consisting of colorectal cancer, gastric cancer, lung cancer, small cell lung cancer, bladder cancer, breast cancer, ovarian cancer, fallopian tube carcinoma, cervical cancer, peritoneal carcinoma, prostate cancer, castration-resistant prostate, bile duct cancer, gastric/gastro-esophageal junction cancer, urothelial cancer, pancreatic cancer, peripheral nerve sheath cancer, uterine cancer, melanoma, a sarcoma, and lymphoma.

[00165] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is HER2-negative breast cancer. In some embodiments, the cancer is triple negative breast cancer. In some embodiments, the breast cancer is BRACA1/2 mutated cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is anti-androgen prostate cancer. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is a sarcoma, for example, angiosarcoma, osteosarcoma, Ewing’s sarcoma, chondrosarcoma, gastrointestinal stromal tumor, liposarcoma, fibrosarcoma, and hemangioendothelioma. In some embodiments, the cancer is a sarcoma and the sarcoma is fibrosarcoma. In some embodiments, the cancer is lymphoma. In some embodiments, the cancer is B-cell lymphoma.

[00166] In a group of embodiments, the disease, disorder, or condition is an inflammatory dermatitis disease. In one embodiment, the inflammatory dermatitis disease is selected from the group consisting of acne, psoriasis, rosacea, and scleroderma. In one embodiment, the inflammatory dermatitis disease is psoriasis.

[00167] In some or any embodiments, provided herein are methods for treating a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a mammal in need thereof. In some or any embodiments, the methods encompass the step of administering to the subject in need thereof a therapeutically or prophylactically effective amount of a compound effective for the treatment of a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in combination with a second agent effective for the treatment of a condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity. The compound can be any compound as described herein, and the second agent can be any second agent described in the art or herein. In some or any embodiments, the compound is in the form of a pharmaceutical composition or dosage form, as described elsewhere herein.

[00168] In some or any embodiments, provided herein is a method of inhibiting PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity comprising contacting Wnt with a compound of Formula (I), (la), (la- 1), (lb), or (Ic) (or any embodiments thereof), or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof or a compound selected from Compounds 1-7 or any pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof.

Assay Methods

[00169] Compounds can be assayed for efficacy in treating a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity according to any assay known to those of skill in the art. Exemplary assay methods are provided elsewhere herein. Second Therapeutic Agents

[00170] In some or any embodiments, the compounds and compositions provided herein are useful in methods of treatment of a condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity, that comprise further administration of a second agent effective for the treatment of a condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity. The second agent used in the method of treatment can be any agent known to those of skill in the art to be effective for the treatment of a condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity, including those currently approved by the United States Food and Drug Administration, or other similar body of a country foreign to the United States. Second medications (second agents) are previously described herein and can be used in the methods of treatment. In some or any embodiments, a compound provided herein is administered in combination with one second agent. In further embodiments, a compound provided herein is administered in combination with two second agents. In still further embodiments, a compound provided herein is administered in combination with two or more second agents.

[00171] In some or any embodiments, the second agent is a chemotherapeutic agent. Examples of suitable chemotherapeutic agents include, but are not limited to 1- dehydrotestosterone, 5 -fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HC1, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HC1, dronabinol, E. coli L-asparaginase, emetine, epoetin-a, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HC1, glucocorticoids, goserelin acetate, gramicidin D, granisetron HC1, hydroxyurea, idarubicin HC1, ifosfamide, interferon a-2b, irinotecan HC1, letrozole, leucovorin calcium, leuprolide acetate, levamisole HC1, lidocaine, lomustine, maytansinoid, mechlorethamine HC1, medroxyprogesterone acetate, megestrol acetate, melphalan HC1, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HC1, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HC1, plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HC1, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HC1, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[00172] In some or any embodiments, the second agent an immune modulator, for example, a checkpoint inhibitor, including but not limited to, a PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, small molecule, peptide, nucleotide, or other inhibitor. PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and Medlmmune), PF-06801591 (Pfizer), MED 10680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-LN/VISTA inhibitor CA-170 (Curis Inc.). PD- L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and Medlmmune), KN035 (Alphamab), and BMS-936559 (Bristol- Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and Medlmmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors, include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).

[00173] In some or any embodiments, the second agent is an inihibtor of the PI3K/AKT/mTOR pathway. In one embodiment, the second agent is a PI3K inhibitor, including, but not limited to, Idelalisib (Zydelig), Copanlisib (Aliqopa), Duvelisib (Copiktra), Alpelisib (Piqray or Pivikto), Umbralisib (Ukoniq), and Leniolisib (Joenja). Other examples of PI3K inhibitors include Wortmannin, demethoxyviridin, perifosine, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC- 0032 (Taselisib), BYL-719 ((2S) — Nl-[4-methyl-5-[2-(2,2,2-trifluoro-l,l-dimethylethyl)-4- pyridinyl]-2-thiazolyl]-l,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-difluoro-N-{2- (methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide)

(omipalisib), TGX-221 ((+)-7-methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[l,2- a]-pyrimidin-4-one), GSK2636771 (2-methyl-l-(2-methyl-3-(trifluoromethyl)benzyl)-6- morpholino-lH-benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l- (7-methyl-2-morpholino-4-oxo-4H-pyrido[l,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR-1202/RP5264, GS-9820 ((S)-l-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- mohydroxypropan-l-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-l-[9H-purin-6-ylamino]- propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4 methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[l,2- c]quinaz), AS 252424 (5-[l-[5-(4-fluoro-2 -hydroxy -phenyl)-furan-2 -yl]-meth-(Z)-ylidene]- thiazolidine-2, 4-dione), CZ 24832 (5-(2-amino-8-fluoro-[l,2,4]triazolo[l,5-a]pyridin-6-yl)-N- tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6-di(4-morpholinyl)-4-pyrimidinyl]-4- (trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH-Indazol-4-yl)-6-[[4-(methylsulfonyl)-l- piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine), GDC-0980 ((S)-l-(4-((2-(2- aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6 yl)methyl)piperazin- l-yl)-2-hydroxypropan-l-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14- (carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-l-(4-(4- oxo-8-phenyl-4H-chromen-2-yl)morpholi no-4-ium)-2-oxa-7, 10,13,16-tetraazaoctadecan- 18- oate), PF-05212384 (N-[4-[[4-(Dimethylamino)-l-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6- di-4-morpholinyl-l,3,5-triazin-2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2- methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-lH-imidazo[4,5-c]quinolin-l- yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5- dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,l laS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl)-9a, 11 a-dimethyl- 1 ,4,7-trioxo-2,3 ,3 a, 9, 10, 11 -he xahydroindeno[4,5h]isochromen- 10-yl] acetate (also known as sonolisib)) LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3 -methyladenine), AS-252424, AS-604850, and apitolisib (GDC-0980; RG7422).

[00174] In one embodiment, the second agent is a mTOR inhibitor, including, but not limited to, everolimus (Afinitor), sirolimus (Rapamune), temsirolimus (Torisel), ridaforolimus, and deforolimus.

[00175] In one embodiment, the second agent is an AKT inhibitor, including, but not limited to, Truqap (capivasertib), Perifosine, Triciribine, Honokiol, and Miltefosine.

[00176] In one embodiment, the second agent is corticosteroid, a cytotoxic drug, an antibiotic, an antiseptic, nicotine, an anti-platelet drug, an NSAID, colchicine, an anticoagulant, a vasoconstricting drug or an immunosuppressive, a growth factor, an antibody, a protease, a protease inhibitor, an antibacterial peptide, an adhesive peptide, a hemostatic agent, living cells, honey, or nitric oxide.

[00177] As used herein, the term “in combination” includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a mammal with a disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a mammal with a disorder.

[00178] As used herein, the term “synergistic” includes a combination of a compound provided herein and another therapy (e.g., a prophylactic or therapeutic agent) which has been or is currently being used to prevent, manage or treat a disorder, which is more effective than the additive effects of the therapies. A synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a mammal with a disorder. The ability to utilize lower dosages of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a mammal without reducing the efficacy of said therapy in the prevention or treatment of a disorder). In addition, a synergistic effect can result in improved efficacy of agents in the prevention or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

[00179] The active compounds provided herein can be administered in combination or alternation with another therapeutic agent, in particular an agent effective in the treatment of a condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity. In combination therapy, effective dosages of two or more agents are administered together, whereas in alternation or sequent! al -step therapy, an effective dosage of each agent is administered serially or sequentially. The dosages given will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the wound or Wnt- transcription-related disorder to be alleviated. It is to be further understood that for any particular mammal, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

EXAMPLES

[00180] The following examples are provided for purpose of illustration of certain aspects of the description herein and should not be deemed to limit the disclosure in any way.

[00181] As used herein, the symbols and conventions used in these processes, schemes and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); pL (microliters); mM (millimolar); pM (micromolar); Hz (Hertz); MHz (megahertz); M (molar); M+l (MS peak, presence of carbon- 13 isotope in molecular ion + 1 peak); mmol (millimoles); m/z (mass per charge); h, hr, or hrs (hours); min (minutes); eq (equivalent(s)); RT, R.T., or rt (room temperature); Rt or Rt (retention time); Rf or Rf (retention factor); v (V) or vol (volume); E (cis); Z (trans); MS (mass spectrometry); ESI (electrospray ionization); TLC (thin layer chromatography); HPLC (high pressure liquid chromatography); LC-MS (liquid chromatography-mass spectrometry); ¹ H NMR (proton nuclear magnetic resonance); ACN or CH3CN (acetonitrile); AC2O (acetic anhydride); AcOH (acetic acid); BPin (bis(pinacolato)); BBrs (boron tribromide); CDCI3 (deuterated chloroform); CH2Q2 or DCM (di chloromethane); CuBr2 (copper (II) bromide); CN (cyanide or cyano); CS2CO3 (cesium carbonate); DCM (dichloromethane); DMF (dimethylformamide); DMSO (dimethylsulfoxide); DMSO-cf (deuterated dimethylsulfoxide); EtOAc (ethyl acetate); FA (formic acid); H2 (hydrogen gas); HC1 (hydrochloride or hydrochloric acid); I2 (iodine); K2CO3 (potassium carbonate); KO Ac (potassium acetate); LDA (lithium diisopropylamide); LAH (lithium aluminum hydride); LHMDS or LiHMDS (lithium bis(trimethylsilyl)amide); MeOH (methanol); MeOD (methanol-D); MeMgBr (methyl magnesium bromide); N2 (nitrogen); NaH (sodium hydride); NH2OH (hydroxylamine); Na2SO4 (sodium sulfate); NaHCOs (sodium bicarbonate); NaHMDS (sodium bis(trimethylsilyl)amide); NaOMe (sodium methoxide); NH3 (ammonia); NH4CI (ammonium chloride); NH4HCO3 (ammonium bicarbonate); NMP (n-methyl-2-pyrrolidone); OMe (methoxy); Pd/C (palladium on carbon); PE (petroleum ether); Ph (phenyl); -Si(/c/7-Bu)(Ph)2 and -Si^tBuPh2 (tert-butyl-diphenylsilyl); SiO2 (silicon dioxide); THF (tetrahydrofuran); TFA (trifluoroacetic acid); tBuONO (t-butyl nitrite); dppf (diphenylphosphino); TMS (trimethylsilyl); GO-HA (graphene oxide/hyaluronic acid); MWCO (molecular weight cutoff); RPM or rpm (revolutions per minute); N (normality) or N (newton); and CFU (colony -forming unit).

Synthetic Examples

Compound 1

Methyl (2-((2-(4-(8-(hydroxymethyl)-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propan-

2-yl)oxy)ethyl)carbamate

[00182] Synthesis of Methyl (2-((2-(4-vinylphenyl)propan-2-yl)oxy)ethyl)carbamate (1-2)

C₂H₃BF₃K (1.1 eq)

Pd(dppf)2Cl2 (0.05 eq)

1-2

[00183] To a solution of methyl (2-((2-(4-bromophenyl)propan-2-yl)oxy)ethyl)carbamate (1-1, 5 g, 15.81 mmol, 1.0 eq) and C2H3BF3K (2.33 g, 17.39 mmol, 1.1 eq) in dioxane (50 mL) and H2O (10 mL) was added Na2CO3 (3.35 g, 31.63 mmol, 2 eq) and Pd(dppf)C12 (578 mg, 790.5 pmol, 0.05 eq) at 25 °C. The reaction mixture was degassed with N2 three (3) times and stirred at 90 °C for 16 h. LCMS (ET69532-55-P1A1) indicated compound 1-1 was consumed completely and -40% methyl (2-((2-(4-vinylphenyl)propan-2- yl)oxy)ethyl)carbamate (1-2) was detected. The reaction mixture was quenched with H2O (20 mL) and extracted by EtOAc (50 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. Compound 1-2 (4 g, crude) was obtained as a colorless oil and used immediately in the next step. LCMS: 266.2 (M+l).

[00184] Synthesis of Methyl (2-((2-(4-formylphenyl)propan-2-yl)oxy)ethyl)carbamate

(1-3)

[00185] To a solution of 1-2 (200 mg, 759.50 pmol, 1.0 eq) in dioxane (5 mL) and H2O (1 mL) was added NalCh (649.80 mg, 3.04 mmol, 168.34 pL, 4.0 eq) and tetraoxoosmium (3.98 mg, 15.19 pmol, 8.13e^-1 pL, 0.02 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 4 h. TLC (petroleum ether/ethyl acetate = 3/1, Rf = 0.2) indicated compound 1-2 was consumed completely and one main spot was formed. The reaction mixture was quenched with H2O (4 mL) and extracted with DCM (5 mL x 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, that was purified by pre-TLC (SiCL, petroleum ether/ethyl acetate = 3/1). Methyl (2-((2-(4-formylphenyl)propan-2-yl)oxy)ethyl)carbamate (1-3, 150 mg, crude) was obtained as a colorless oil. 'HNMR (400 MHz, CDCI3): 8 = 9.94 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 5.11 - 4.97 (m, 1H), 3.60 (s, 3H), 3.26 (br s, 2H), 3.19 (br d, J = 4.5 Hz, 2H), 1.48 (s, 6H).

[00186] Synthesis of Methyl 2-amino-3-carbamoylbenzoate (1-5)

1-4 1-5

[00187] To a solution of 2-amino-3-(methoxycarbonyl)benzoic acid (1-4, 1 g, 5.12 mmol, 1 eq) and NH4CI (685.18 mg, 12.81 mmol, 2.5 eq) in DMF (10 mL) was added EDCI (1.47 g, 7.69 mmol, 1.5 eq), DIEA (1.99 g, 15.37 mmol, 2.68 mL, 3.0 eq), and HOBt (1.04 g, 7.69 mmol, 1.5 eq) at 25 °C. The reaction mixture was stirred at 25 °C for 16 h. LCMS indicated the reaction was completed. The reaction mixture was quenched with H2O (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed by brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was triturated with MTBE (5 mL) at 25 °C for 30 min. Methyl 2-amino-3- carbamoylbenzoate (1-5, 1.0 g, crude) was obtained as a white solid and used immediately in the next step. LCMS: 195.07 (M+l) [00188] Synthesis of 2-Amino-3-(hydroxymethyl)benzamide (1-6)

[00189] To a solution of compound 1-5 (1 g, 5.15 mmol, 1 eq) in THF (5 mL), was added dropwise, LAH (2 M, 6.44 mL, 2.5 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 4 h. TLC (petroleum ether/ethyl acetate =1/1, Rf =0.19) indicated the reaction was complete. The reaction mixture was quenched with aq. NH4CI (5 ml) at 0 °C, then filtered; the filtrate was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (5 mL x2), dried over ISfeSCU, filtered, and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters X bridge BEH C18 100 x 30 mm x 10 pm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: l%-20% B over 8.0 min). 2-Amino-3-(hydroxymethyl)benzamide (1-6, 0.9 g, 4.60 mmol, 87% purity) was obtained as a colorless oil. LCMS: 167.07 (M+l)

[00190] Synthesis of Compound 1

[00191] To a solution of compound 1-6 (100 mg, 601.77 pmol, 1 eq) and 1-3 (159.65 mg, 601.77 pmol, 1.0 eq) in DMSO (2 mL) was added CuCL (80.91 mg, 601.77 pmol, 1.0 eq) at 25 °C. The reaction was stirred at 80°C for 2 h. LCMS indicated that 1-6 was consumed completely and -58% of the desired compound was detected. The reaction mixture was filtered, and the filtrate was diluted with H2O (5 mL) and extracted by EtOAc (5 mL x 2). The combined organic layers were washed by brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Phenomenex Luna C18 80 x 30 mm x 3 pm; mobile phase: [H2O (0.1%TFA)- ACN]; gradient: 10%-40% B over 8.0 m). Compound 1 (25.03 mg, 56.58 pmol, 93% purity) was obtained as a white solid. 'H NMR (400 MHz, CD3OD): 5 = 8.20 - 8.12 (m, 3H), 7.99 - 7.93 (m, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 5.20 (s, 2H), 3.65 (s, 3H), 3.30 - 3.25 (m, 4H), 1.60 (s, 6H). LCMS: 412.5 (M+l).

Compound 2

(2-(4-(2-(2-((Methoxycarbonyl)amino)ethoxy)propan-2-yl)phenyl)-4-oxo-3,4- dihydroquinazolin-8-yl)boronic acid

[00192] Synthesis of Methyl 4-(8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate

(2-2)

[00193] To a mixture of 2-amino-3 -bromobenzamide (2-la, 3 g, 13.95 mmol, 1.0 eq) in DMSO (60 mL) was added methyl 4-formylbenzoate (2-1) (2.29 g, 13.95 mmol, 1.0 eq) at 20 °C. The reaction mixture was stirred at 100 °C for 14 h. TLC (DCM/MeOH = 10/1, Rf = 0.3) indicated the reactant 2-la was consumed completely. The reaction was cooled to 25 °C and then filtered. The filter caked was washed with H2O (15 ml x 2) and dried under reduced pressure to provide a residue that was triturated with MeOH (15 ml) at 25 °C for 0.5 h. Methyl 4-(8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)benzoate (2-2, 4 g, crude) was obtained as a white solid. ^XH NMR (400 MHz, DMSO-d₆): 8 = 13.06 - 12.82 (m, 1H), 8.45 - 8.31 (m, 2H), 8.23 - 8.08 (m, 4H), 7.51 - 7.42 (m, 1H), 3.92 (s, 2H). [00194] Synthesis of 8-Bromo-2-(4-(2-hydroxypropan-2-yl)phenyl)quinazolin-4(3H)- one (2-3)

[00195] To a solution of compound 2-2 (3 g, 8.35 mmol, 1 eq) in THF (60 mL) was added MeMgBr (3 M, 6.96 mL, 2.5 eq) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. TLC (DCM/MeOH = 10/1, Rf = 0.27) indicated compound 2-2 was consumed completely. The reaction mixture was quenched with aq. NH4CI (30 ml) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was used in the next step without further purification. 8-Bromo-2-(4-(2-hydroxypropan-2- yl)phenyl)quinazolin-4(3H)-one (2-3, 2.5 g, crude) was obtained as a white solid. LCMS: 361, 359 (bromine isomers, M+l).

[00196] Synthesis of 8-Bromo-2-(4-(2-(2-nitroethoxy)propan-2-yl)phenyl)quinazolin-

4(3H)-one (2-4)

[00197] To a solution of 2-3 (1 g, 2.78 mmol, 1 eq) in DCM (20 mL) was added 2- nitroethanol (5 mL) and TFA (31.74 mg, 278.38 pmol, 20.68 pL, 0.1 eq) at 20 °C. The reaction mixture was stirred at 20 °C for 4 hrs. The reaction mixture was quenched with H2O (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (15 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by prep-TLC (SiCL, petroleum ether/ethyl acetate = 1/1). 8-Bromo-2-(4-(2-(2 -nitroethoxy )propan-2-yl)phenyl)quinazolin-4(3H)-one (2-4, 0.3 g, crude) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO-d6): 5 = 12.80 - 12.73 (m, 1H), 8.28 - 8.24 (m, 2H), 8.19 - 8.16 (m, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.43 (t, J = 7.8 Hz, 1H), 4.75 - 4.70 (m, 2H), 3.71 - 3.66 (m, 2H), 1.53 (s, 6H).

[00198] Synthesis of 2-(4-(2-(2-Aminoethoxy)propan-2-yl)phenyl)-8- bromoquinazolin-4(3H)-one (2-5)

[00199] To a solution of compound 2-4 (800 mg, 1.85 mmol, 1 eq) in EtOH (5 mL) and H2O (1 mL) was added Fe (516.81 mg, 9.25 mmol, 5 eq) and NH4CI (494.97 mg, 9.25 mmol, 5 eq) at 25 °C. The reaction mixture was stirred at 80 °C for 16 hrs. LCMS indicated the reaction was complete. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to remove most of the EtOH. The resulting mixture was diluted with water (8 mL) and then extracted with EtOAc (5 mL x 5). The combined organic layers were washed in brine (5 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a residue that was used in the next step without further purification. 2-(4- (2-(2-Aminoethoxy)propan-2-yl)phenyl)-8-bromoquinazolin-4(3H)-one (2-5, 0.8 g, crude) was obtained as a white solid that was used in the next step without further purification. LCMS: 404, 402 (Bromine isomers; M+l). [00200] Synthesis of Methyl (2-((2-(4-(8-bromo-4-oxo-3,4-dihydroquinazolin-2- yl)phenyl)propan-2-yl)oxy)ethyl)carbamate (2-6)

[00201] To a solution of compound 2-5 (800 mg, 1.99 mmol, 1 eq) in DCM (8.0 mL) was added TEA (302 mg, 2.98 mmol, 415.2 pL, 1.5 eq) at 25 °C. Methyl carbonochloridate (206.7 mg, 2.19 mmol, 1.1 eq) was added to the reaction mixture at 0 °C and the mixture stirred at 25 °C for 4 hrs. LCMS indicated 2-5 was consumed completely and one main peak with the desired MS detected. The reaction mixture was quenched with sat.NELCl (15 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed in brine (10 mL x 2), dried over by ISfeSCU, filtered, and concentrated under reduced pressure to give a residue that was purified by prep-TLC (SiCL, petroleum ether/ethyl acetate = 1/1). Methyl (2-((2-(4-(8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propan-2- yl)oxy)ethyl)carbamate (2-6, 250 mg, 543.08 pmol) was obtained as a white solid. LCMS: 462, 460 (Bromine isomers; M+l).

[00202] Synthesis of Compound 2

Compound 2

[00203] To a solution of B2Pin2 (44.13 mg, 173.79 pmol, 2.0 eq) and compound 2-6 (40 mg, 86.90 pmol, 1 eq) in dioxane (2 mL) was added KOAc (25.58 mg, 260.69 pmol, 3.0 eq) and Pd(dppf)C12 (6.36 mg, 8.69 pmol, 0.1 eq) at 25 °C. The reaction mixture was degassed three (3) times with N2 and the reaction mixture stirred at 100 °C for 16 hrs. LCMS indicated that 2-6 was consumed completely and the desired product detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 pm; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient: 20%-55% B over 8.0 m). Compound 2 (10 mg, 23.52 pmol) was obtained as a white solid. ^JH NMR (400 MHz, DMSO-de): 8 = 13.03 - 12.32 (m, 1H), 9.37 - 9.26 (m, 2H), 8.31 - 8.21 (m, 2H), 8.04 (d, J= 8.6 Hz, 2H), 7.65 (d, J= 8.5 Hz, 2H), 7.55 (t, J= 7.5 Hz, 1H), 7.20 (br t, J= 4.7 Hz, 1H), 3.52 (s, 3H), 3.23 - 3.10 (m, 4H), 1.52 (s, 6H). LCMS: 426.2 (M+l).

Compound 3

Methyl (2-((2-(4-(6-hydroxy-4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propan-2- yl)oxy)ethyl)carbamate [00204] Synthesis of 2-Amino-5-((tert-butyldimethylsilyl)oxy)benzamide (3-3)

3-3

[00205] A mixture of 2-amino-5-hydroxybenzoic acid (3-1, 5.0 g, 32.6 mmol, 1.0 eq.), TBDMSC1 (19.7 g, 130 mmol, 4.0 eq.), and imidazole (8.9 g, 130 mmol, 4.0 eq.) in DMF (200 mL) was stirred at room temperature for 16 hrs. The mixture was quenched with water (IL) and extracted with EtOAc (IL). The organic layer was dried over ISfeSCh and concentrated to obtain 2-amino-5-((tert-butyldimethylsilyl)oxy)benzoic acid (3-2) as a brown oil (9.0 g), which was used in the next step without further purification.

[00206] The mixture of compound 3-2 (2.0 g, 7.47 mmol, 1.0 eq.), (NH^CCh (2.15 g, 22.43 mmol, 3.0 eq.), EDCI (2.15 g, 11.21 mmol, 1.5 eq.), HOBt (1.37 g, 8.97 mmol, 1.2 eq.), and TEA (2.64 g, 26.17 mmol, 3.5 eq.) in THF (70 mL) was stirred at room temperature for 5 hrs. Then the mixture was diluted with water (100 mL), extracted with EtOAc (200 mL), dried over Na2SO4, and concentrated. The crude mixture was purified by column chromatography on silica gel and eluted with 50% EtOAc/DCM to afford 2-amino-5-((tert- butyldimethylsilyl)oxy)benzamide (3-3, 0.78 g, 39 % yield) as a yellow solid. LCMS: 267.5 (M+l).

[00207] Synthesis of Methyl (2-((2-(4-(6-((tert-butyldimethylsilyl)oxy)-4-oxo-3,4- dihydroquinazolin-2-yl)phenyl)propan-2-yl)oxy)ethyl)carbamate (3-5)

[00208] The mixture of methyl (2-((2-(4-formylphenyl)propan-2-yl)oxy)ethyl)carbamate (3-4, 99.0 mg, 0.367 mmol, 1.0 eq.) and compound 3-3 (140 mg, 0.525 mmol, 1.4 eq.) in DMSO (4.0 mL) was stirred at 120 °C for 2 hrs. Then the mixture was cooled to room temperature, quenched with water (50 mL), extracted with EtOAc (100 mL), dried over Na2SO4, and concentrated. The crude mixture was passed through a silica pad to afford methyl (2-((2-(4-(6-((tert-butyl dimethyl silyl)oxy)-4-oxo-3, 4-dihy droquinazolin-2- yl)phenyl)propan-2-yl)oxy)ethyl)carbamate (3-5, 100 mg, 53% yield) as an off-white solid. LCMS: 512.3 (M+l).

[00209] Synthesis of Compound 3

Compound 3

[00210] To the solution of compound 3-5 (100 mg, 0.195 mmol, 1.0 eq.) in THF (2.0 mL) was slowly added TBAF (IM in THF, 0.4 mL, 0.390 mmol, 2.0 eq). The mixture was stirred at room temperature for 2 hrs. Then the mixture was extracted with EtOAc (2 x 50 mL), washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated. The crude was purified by column chromatography on silica gel and eluted with 50% EtOAc/DCM to afford Compound 3; 42 mg, 54% yield) as a white solid. 1H NMR (400MHz, d6-DMSO) 5: 12.31 (brs, 1H), 10.08 (s, 1H), 8.1 (m, 2H), 7.58 (m, 3H), 7.28 (m, 2H), 3.30 (s, 3H), 3.13 (m, 4H), 1.48 (6H); LCMS: 398.3 (M+l).

Compound 4

Methyl (2-((2-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)phenyl)propan-2- yl)oxy)ethyl)carbamate

[00211] Synthesis of 4-(2-(2-Nitroethoxy)propan-2-yl)benzaldehyde (4-2)

[00212] To the solution of 4-(2-(2 -nitroethoxy )propan-2-yl)benzonitrile (4-1, 0.50 g, 2.13 mmol, 1.0 eq.) in DCM (20 mL) was added the solution of DIBAL (IM in hexanes, 2.32 mL, 2.34 mmol, 1.10 eq) at -78 °C. The mixture was stirred for 2 hrs, warmed up to 0 °C, quenched with silica gel (3.0 g) and H2O (1.8 mL), and then stirred for one more hour. Crude 4-(2-(2-nitroethoxy)propan-2-yl)benzaldehyde (4-2, 0.48 g, 95% yield) was obtained as colorless liquid. LCMS: 238.1 (M+l).

[00213] Synthesis of 2-(4-(2-(2-Nitroethoxy)propan-2-yl)phenyl)quinazolin-4(3H)-one (4-4) [00214] The mixture of compound 4-2 (0.42 g, 1.77 mmol, 1.0 eq.) and 2-aminobenzamide (4-3, 0.24 g, 1.77 mmol, 1.0 eq.) in DMSO (5.0 mL) was stirred at 120 °C for 16 hrs. Then the mixture was cooled to room temperature, quenched with water (50 mL), extracted with EtOAc (100 mL), dried over Na2SO4, and concentrated. The crude mixture was purified by column chromatography on silica gel and eluted with 10% EtOAc/DCM to afford 2-(4-(2-(2- nitroethoxy)propan-2-yl)phenyl)quinazolin-4(3H)-one (4-4, 0.16 g, 25% yield) as an off- white solid. LCMS: 354.2 (M+l).

[00215] Synthesis of 2-(4-(2-(2-Aminoethoxy)propan-2-yl)phenyl)quinazolin-4(3H)- one (4-5)

[00216] To a solution of compound 4-4 (0.15 g, 0.424 mmol, 1.0 eq.) in EtOH/FLO (1.5 mL/0.5 mL) was added Fe (powder; 0.237 g, 4.24 mmol, 10.0 eq.) and NH4CI (0.227 g, 4.24 mmol, 10.0 eq.). The resulting mixture was stirred for 1 hr at 70 °C. The reaction mixture was cooled to room temperature, diluted with EtOH (20 mL), and passed through a celite pad. Then mixture was then concentrated and diluted with EtOAc (100 mL), washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 2-(4-(2-(2- aminoethoxy)propan-2-yl)phenyl)quinazolin-4(3H)-one (4-5, 0.130 g, crude, 95% yield) as an off-white (waxy) solid. LCMS: 324.2 (M+l).

[00217] Synthesis of Compound 4

[00218] To solution of compound 4-5 (0.120 g, 0.371 mmol, 1.0 eq.) in DCM (2.0 mL) was added TEA (0.056 g, 0.55 mmol, 1.5 eq.), followed by the addition of 4-6 (0.031 g, 0.33 mmol, 0.9 eq.). The mixture was stirred at room temperature for 2 h. The reaction was then concentrated and the residue was purified by column chromatography on silica gel and eluted with 20% EtOAc/DCM to afford compound Compound 4 (26 mg, 19 % yield) as an off- white solid. 1H NMR (400MHz, CDC1₃) 5:10.70 (brs, 1H), 8.32 (d, J = 8Hz, 1H), 8.13 (d, J= 8Hz, 2H), 7.81 (m, 2H), 7.59 (d, J = 8.8Hz, 2H), 7.52 (t, J = 4.78Hz, 1H), 5.06 (brs, 1H), 3.68 (s, 3H), 3.36-3.29 (m, 4H), 1.59 (s, 6H); LCMS: 382.2.

Compound 5

Methyl (2-(2-hydroxy-4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazin-l-yl)phenyl)-2- methylpropyl)carbamate

[00219] Synthesis of 2-(4-Bromo-2-methoxyphenyl)-2-methylpropanenitrile (5-2)

[00220] 2-(4-Bromo-2-methoxyphenyl)acetonitrile (5-1, 4.50 g, 19.9 mmol, 1.00 eq) was added portion-wise at 0 °C to a solution of NaH (1.59 g, 39.8 mmol, 60.0% purity, 2.00 eq) in DMF (45 mL). The mixture was stirred at 25 °C for 30 min. Then Mel (7.06 g, 49.8 mmol, 3.10 mL, 2.50 eq) was added dropwise at 0 °C and the mixture stirred at 25 °C for 3 hrs. TLC (petroleum ether/ethyl acetate = 8/1, Rf (compound 5-1) = 0.61) indicated that compound 5-1 was consumed completely. The reaction mixture was poured into ice water (60.0 mL) at 0 °C and extracted with EtOAc 60.0 mL (20 mL x 3). The combined organic layers were washed with brine (90 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 100/1 to 0/1) to provide 2-(4-bromo-2-methoxyphenyl)-2- methylpropanenitrile (5-2, 4.3 g, 16.92 mmol, yield: 85.0%) was obtained as a white solid. 'HNMR (400 MHz, DMSO-t/e): d 7.14 - 7.11 (m, 1H), 7.05 - 6.99 (m, 2H), 3.85 (s, 3H), 1.67 (s, 6H). [00221] Synthesis of tert-Butyl 4-(4-(2-cyanopropan-2-yl)-3- methoxyphenyl)piperazine-l-carboxylate (5-3)

[00222] To a mixture of Pd2(dba)s (360 mg, 394 pmol, 0.1 eq) and BINAP (155 mg, 394 pmol, 0.1 eq) in toluene (10 mL) was added a solution of 2-(4-bromo-2-methoxyphenyl)-2- methylpropanenitrile (5-2, 1.00 g, 3.94 mmol, 1.00 eq) and tert-butyl piperazine-1- carboxylate (5-2A, 733 mg, 3.94 mmol, 1.00 eq) in toluene (10.0 mL) at 25 °C under N2. t- BuONa (529 mg, 5.51 mmol, 1.40 eq) was then added to the mixture at 25 °C under N2, and the mixture was stirred at 65 °C for 13 hrs under N2. TLC (petroleum ether/ethyl acetate = 5/1, Rf (compound 5-2) = 0.49) indicated that compound 5-2 was consumed completely and new spots formed. After cooling to 25 °C, the reaction mixture was poured into water (15 mL) and extracted with EtOAc 15.0 mL (5 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, petroleum ether/ethyl acetate = 100/1 to 0/1) to provide tert-butyl 4-(4-(2-cyanopropan-2-yl)- 3 -methoxyphenyl)piperazine-l -carboxylate (5-3, 1.00 g, 2.78 mmol, yield: 70.7%) as an off- white solid. 'H NMR (400 MHz, DMSO-t/e): d 7.12 (d, J= 8.7 Hz, 1H), 6.66 (d, J= 1.8 Hz, 1H), 6.51 (dd, J= 1.9, 8.6 Hz, 1H), 3.86 (s, 3H), 3.46 (br s, 4H), 3.15 (br d, J= 4.8 Hz, 4H), 1.64 (s, 6H), 1.43 (s, 9H).

[00223] Synthesis of 2-(2-Methoxy-4-(piperazin-l-yl)phenyl)-2-methylpropanenitrile (5-4)

[00224] To a solution of compound 5-3 (1.00 g, 2.78 mmol, 1.00 eq) in DCM (5.00 mL) was added HCl/dioxane (4 M, 5.00 mL, 7.19 eq) at 25 °C. The mixture was stirred at 25 °C for 13 hrs. LCMS showed 5-3 was consumed completely and one main peak with the desired mass detected. The reaction mixture was concentrated under reduced pressure to give crude 2-(2-methoxy-4-(piperazin-l-yl)phenyl)-2 -methylpropanenitrile (5-4, 823 mg, HC1) as a white solid. 'HNMR (400 MHz, DMSO-t/e): d 9.46 - 9.30 (m, 2H), 7.09 (d, J= 8.7 Hz, 1H), 6.63 (d, J= 2.4 Hz, 1H), 6.48 (dd, J= 2.4, 8.7 Hz, 1H), 3.80 (s, 3H), 3.42 - 3.33 (m, 4H), 3.12 (br s, 4H), 1.57 (s, 6H). LCMS: 260.17 (M+l)

[00225] Synthesis of 2-(2-Methoxy-4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazin- l-yl)phenyl)-2-methylpropanenitrile (5-6)

[00226] To a solution of compound 5-4 (823 mg, 2.78 mmol, 1.00 eq, HC1) and 2- chloroquinazolin-4(3H)-one (5-5, 502 mg, 2.78 mmol, 1.00 eq) in DMF (10.0 mL) was added DIEA (1.08 g, 8.35 mmol, 1.45 mL, 3.00 eq) at 25 °C. The mixture was stirred at 110 °C for 13 hrs. TLC (petroleum ether/ethyl acetate = 3/1, Rf (compound 5-5) = 0.53) indicated compound 5-5 was consumed completely and one major new spot with larger polarity was detected. After cooling to 25 °C, the reaction mixture was poured into water (30 mL). The mixture was stirred at 25 °C for 10 min, and then the mixture was filtered and the filter cake dried under reduced pressure to give 2-(2-methoxy-4-(4-(4-oxo-3,4-dihydroquinazolin-2- yl)piperazin-l-yl)phenyl)-2-m ethylpropanenitrile (5-6, 1.06 g, 2.63 mmol, yield: 94.4%) as a light brown solid. ¹ H NMR (400 MHz, DMSO-t/e): d 7.96 - 7.90 (m, 1H), 7.64 - 7.57 (m, 1H), 7.32 (d, J= 8.1 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.71 (d, = 2.2 Hz, 1H), 6.56 (dd, J= 2.2, 8.8 Hz, 1H), 3.89 (s, 3H), 3.83 - 3.76 (m, 4H), 3.31 - 3.25 (m, 4H), 1.65 (s, 6H). LCMS: 404.5 (M+l). [00227] Synthesis of 2-(4-(4-(l-amino-2-methylpropan-2-yl)-3- methoxyphenyl)piperazin-l-yl)quinazolin-4(3H)-one (5-7)

[00228] To a solution of compound 5-6 (860 mg, 2.13 mmol, 1.00 eq) in EtOH (10 mL) was added Raney-Ni (860 mg, 20.0% purity) and NH3.H2O (783 mg, 5.58 mmol, 860 pL, 25% purity, 2.62 eq) at 25 °C under N2. The suspension was degassed and purged with H2 three (3) times. The mixture was stirred under H2 (15 Psi) at 25 °C for 13 hrs. LCMS showed -57% of compound 5-6 remained. To the mixture was added additional Raney-Ni (500 mg, 20% purity) at 25 °C under N2. The suspension was degassed and purged with H2 three (3) times. The mixture was then stirred under H2 (15 Psi) at 25 °C for 13 hrs. LCMS showed 5-6 was consumed completely and one main peak with the desired mass was detected. The reaction mixture was then filtered through diatomite and concentrated under reduced pressure to provide 2-(4-(4-(l-amino-2-methylpropan-2-yl)-3-methoxyphenyl)piperazin-l- yl)quinazolin-4(3H)-one (5-7, 700 mg, crude) as a light yellow solid. 'H NMR (400 MHz, DMSO-t/e): d 7.94 (dd, J = 1.3, 7.9 Hz, 1H), 7.63 - 7.53 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.17 - 7.10 (m, 1H), 7.09 - 7.04 (m, 1H), 6.68 - 6.60 (m, 1H), 6.57 - 6.48 (m, 1H), 3.87 - 3.83 (m, 7H), 3.27 - 3.20 (m, 4H), 2.84 (s, 2H), 1.34 - 1.26 (m, 6H). LCMS: 408.5 (M+l).

[00229] Synthesis of Methyl (2-(2-methoxy-4-(4-(4-oxo-3,4-dihydroquinazolin-2- yl)piperazin-l-yl)phenyl)-2-methylpropyl)carbamate (5-8)

[00230] To a solution of compound 5-7 (200 mg, 491 pmol, 1.00 eq) in DCM (2 mL) was added TEA (149 mg, 1.47 mmol, 205 pL, 3.00 eq) at 25 °C. Then methyl carb onochl ori date (5-7^a, 186 mg, 1.96 mmol, 152 pL, 4.00 eq) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into water (5 mL) at 0 °C and extracted with DCM (2 mL x 3). The combined organic layers were washed with brine (10 mL), dried over ISfeSCh, filtered, and concentrated under reduced pressure to give a residue that was purified by prep-TLC (SiCL, petroleum ether/ethyl acetate = 0/1). Methyl (2-(2- methoxy-4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazin-l-yl)phenyl)-2- methylpropyl)carbamate (5-8, 80.0 mg, 172 pmol, yield: 35.0%) was obtained as a light yellow solid. 'H NMR (400 MHz, DMSO-t/e): d 7.96 - 7.91 (m, 1H), 7.65 - 7.58 (m, 1H), 7.33 (br d, J = 8.3 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.78 - 6.69 (m, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.51 - 6.44 (m, 1H), 3.84 - 3.76 (m, 7H), 3.48 (s, 3H), 3.36 (br s, 2H), 3.22 (br d, J = 4.9 Hz, 4H), 1.22 (s, 6H). LCMS: 466.5 (M+l). [00231] Synthesis of Compound 5

[00232] To a solution of compound 5-8 (80.0 mg, 172 pmol, 1.00 eq) in DCM (1 mL) was added BB (215 mg, 859 pmol, 82.8 pL, 5.00 eq) at -70 °C. The mixture was stirred at 25 °C for 13 hrs. The reaction mixture was quenched by dropwise addition of H2O (3.00 mL) at 25 °C and extracted with DCM (1 mL x 3). The combined organic layers were washed with brine (5 mL) and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (neutral condition; column: Waters Xbridge BEH C18 100 x 30 mm x 10 pm; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 25% - 55% B over 8.0 min), to provide Compound 5 (26.18 mg, 58.0 pmol, yield: 33.7%, 100% purity) as a white solid. ^JH NMR (400 MHz, DMSO /p d 9.26 - 9.21 (m, 1H), 7.91 (d, J= 7.8 Hz, 1H), 7.58 (t, J= 8.0 Hz, 1H), 7.29 (d, J= 8.1 Hz, 1H), 7.14 (t, J= 7.5 Hz, 1H), 6.99 - 6.94 (m, 1H), 6.69 (br t, J= 6.5 Hz, 1H), 6.41 - 6.37 (m, 2H), 3.81 - 3.73 (m, 4H), 3.49 (s, 3H), 3.39 (br s, 2H), 3.16 - 3.09 (m, 4H), 1.22 (s, 6H); LCMS: 452.5 (M+l).

Compound 6

(2-Hydroxy-4-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)piperazin-l-yl)phenyl)boronic acid [00233] Synthesis of tert-Butyl 4-(4-bromo-3-methoxyphenyl)piperazine-l- carboxylate (6-3)

[00234] To a solution of BINAP (453 mg, 1.15 mmol, 0.1 eq) and Pd2(dba)s (1.05 g, 1.15 mmol, 0.1 eq) in toluene (20 mL) was added a solution of tert-butyl piperazine- 1 -carboxylate (6-2, 2.14 g, 11.5 mmol, 1.00 eq) and l-bromo-4-iodo-2-m ethoxybenzene (6-1, 3.60 g, 11.5 mmol, 1.00 eq) in toluene (50 mL) at 25 °C under N2. Then t-BuONa (1.55 g, 16.1 mmol, 1.40 eq) was added to the mixture in one portion at 25 °C under N2. The mixture was stirred at 50 °C for 13 hrs. TLC (petroleum ether/ethyl acetate = 5/1) indicated 6-1 was consumed completely and one major new spot formed. After cooling to 25 °C, the reaction mixture was filtered and the filtrate diluted with water (90 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue that was purifyied by column chromatography (SiO₂, petroleum ether/ethyl acetate = 100/1 to 0/1) to provide tert-butyl 4- (4-bromo-3-methoxyphenyl)piperazine-l -carboxylate (6-3, 1.35 g, 3.64 mmol, yield: 31.6%) as a light brown solid. 'H NMR (400 MHz, DMSO t/e): d 7.36 (d, J= 8.7 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 6.50 (dd, J= 2.6, 8.8 Hz, 1H), 3.85 (s, 3H), 3.53 - 3.44 (m, 4H), 3.21 - 3.12 (m, 4H), 1.45 (s, 9H).

[00235] Synthesis of l-(4-Bromo-3-methoxyphenyl)piperazine (6-4)

[00236] To a solution of compound 6-3 (1.35 g, 3.64 mmol, 1.00 eq) in DCM (6 mL) was added HCl/di oxane (4M, 6 mL, 6.60 eq) at 25 °C. The mixture was stirred at 25 °C for 13 hrs.

The reaction mixture was concentrated under reduced pressure to give l-(4-bromo-3- methoxyphenyl)piperazine (6-4, 1.12 g, crude, HC1) as a white solid. ¹ H NMR (400 MHz, DMSO f): d 9.28 (br s, 2H), 7.30 (d, J= 8.7 Hz, 1H), 6.62 (d, J= 2.5 Hz, 1H), 6.44 (dd, J= 2.6, 8.8 Hz, 1H), 3.77 (s, 3H), 3.38 - 3.31 (m, 4H), 3.12 (br s, 4H).

[00237] Synthesis of 2-(4-(4-Bromo-3-methoxyphenyl)piperazin-l-yl)quinazolin- 4(3H)-one (6-5)

[00238] To a solution of compound 6-4 (1.12 g, 3.64 mmol, 1.00 eq, HC1) and 2- chloroquinazolin-4(3H)-one (6-4A, 658 mg, 3.64 mmol, 1.00 eq) in DMF (12 mL) was added DIEA (1.41 g, 10.9 mmol, 1.90 mL, 3.00 eq) at 25 °C. The mixture was stirred at 110 °C for 13 hrs. TLC (petroleum ether/ethyl acetate = 3/1, Rf (compound 6-4A) = 0.53) indicated 6-4A was consumed completely and one major new spot with larger polarity was detected. After cooling to 25 °C, the reaction mixture was poured into water (30 mL). The mixture was stirred at 25 °C for 10 min, then the mixture was filtered and the filter cake was dried under reduced pressure to give a residue. 2-(4-(4-Bromo-3-methoxyphenyl)piperazin-l- yl)quinazolin-4(3H)-one (6-5, 1.00 g, 2.41 mmol, yield: 66.1%) was obtained as a light brown solid. ^JH NMR (ET84814-23-P1 Al) confirmed the identity of the compound. ^JH NMR (400 MHz, DMSO4): 3 11.67 - 11.56 (m, 1H), 8.07 - 8.01 (m, 1H), 7.76 - 7.67 (m, 1H), 7.43 (br dd, J= 8.4, 15.0 Hz, 2H), 7.27 (br t, J= 7.5 Hz, 1H), 6.80 (d, J= 2.1 Hz, 1H), 6.61 (br dd, J= 2.0, 8.8 Hz, 1H), 3.95 (s, 3H), 3.88 (br s, 4H), 3.38 (br s, 4H).

[00239] Synthesis of 2-(4-(4-Bromo-3-hydroxyphenyl)piperazin-l-yl)quinazolin- 4(3H)-one (6-6) [00240] To a solution of compound 6-5 (200 mg, 482 pmol, 1.00 eq) in DCM (2 mL), BBr3 (603 mg, 2.41 mmol, 232 pL, 5 eq) was added dropwise at -70 °C. The mixture was stirred at 25 °C for 13 hrs. The reaction mixture was quenched by dropwise addition of saturated NaHCCL (5 mL) at 25 °C, and extracted with DCM (2 mL x 3). The combined organic layers were washed with brine (10 mL) and concentrated under reduced pressure to give 2-(4-(4-bromo-3-hydroxyphenyl)piperazin-l-yl)quinazolin-4(3H)-one (6-6, 160 mg, crude) as a light brown solid^H NMR (400 MHz, DMSO tL) d 7.96 - 7.90 (m, 1H), 7.64 - 7.57 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.71 (d, J= 2.2 Hz, 1H), 6.56 (dd, J= 2.2, 8.8 Hz, 1H), 3.89 (s, 3H), 3.83 - 3.76 (m, 4H), 3.31 - 3.25 (m, 4H), 1.65 (s, 6H).

[00241] Synthesis of Compound 6

[00242] To a solution of compound 6-6 (80.0 mg, 199 pmol, 1.00 eq) and B2(OH)4 (53.6 mg, 598 pmol, 3 eq) in EtOH (1 mL) was added XPhos (9.50 mg, 19.9 pmol, 0.1 eq), XPhos- Pd-G? (7.84 mg, 9.97 pmol, 0.05 eq), and K3PO4 (84.6 mg, 399 pmol, 2.00 eq) at 15 °C under N2. The mixture was stirred at 25 °C for 13 hrs under N2. After cooling to 25 °C, the reaction mixture was filtered and the filter cake dried under reduced pressure to give a residue that was purified by prep-HPLC (neutral condition; column: Waters Xbridge BEH C18 100 x 30 mm x 10 pm; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 5% - 50% B over 8.0 min) to provide Compound 6 (15.91 mg, 39.58 pmol, yield: 9.93%, 91.1% purity) as an off-white solid. 'H NMR (400 MHz, DMSO tL): <5 11.61 - 11.37 (m, 1H), 7.92 (br s, 1H), 7.61 (br s, 1H), 7.38 - 7.25 (m, 1H), 7.24 - 7.12 (m, 1H), 7.12 - 6.87 (m, 1H), 6.57 - 6.39 (m, 1H), 6.38 - 6.20 (m, 1H), 3.76 (br s, 4H), 3.29 - 3.06 (m, 4H). Compound 7 (6-(4-(4-Oxo-3,4-dihydroquinazolin-2-yl)piperazin-l-yl)pyridin-3-yl)boronic acid

[00243] Synthesis of l-(5-bromopyridin-2-yl)piperazine hydrochloride (7-2)

[00244] To a solution of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-l-carboxylate (7-1, 2.00 g, 5.84 mmol, 1.00 eq) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 10.00 mL, 6.84 eq) at 25 °C. The mixture was stirred at 25 °C for 13 hrs.. The reaction mixture was concentrated under reduced pressure to give l-(5-bromopyridin-2-yl)piperazine hydrochloride (7-2, 1.64 g, crude, HC1) as a white solid. ^JH NMR (400 MHz, DMSO cfj: d 9.55 (br s, 2H), 8.23 (d, J= 2.4 Hz, 1H), 7.80 (dd, J= 2.6, 9.1 Hz, 1H), 6.96 (d, J= 9.1 Hz, 1H), 3.82 - 3.72 (m, 4H), 3.14 (br s, 4H).

[00245] Synthesis of 2-(4-(5-bromopyridin-2-yl)piperazin-l-yl)quinazolin-4(3H)-one

[00246] To a solution of compound 7-2 (600 mg, 2.15 mmol, 1.00 eq, HC1) and 2- chloroquinazolin-4(3H)-one (7-2A, 389 mg, 2.15 mmol, 1.00 eq) in DMF (6.00 mL) was added DIEA (835 mg, 6.46 mmol, 1.13 mL, 3.00 eq) at 25 °C. The mixture was stirred at 110 °C for 13 hrs. TLC (petroleum ether/ethyl acetate = 5/1, Rf (compound 7-2A) = 0.59) indicated 7-2A was consumed completely and one major new spot formed on TLC. After cooling to 25 °C, the reaction mixture was poured into water (20 mL) and stirred at 25 °C for 10 min. Then the mixture was filtered, and the filter cake was dried under reduced pressure to give 2-(4-(5 -brom opyri din-2 -yl)piperazin-l-yl)quinazolin-4(3H)-one (7-3, 600 mg, 1.55 mmol, yield: 72.1%) as a light brown solid. 'H NMR (400 MHz, DMSO-t/e): 3 11.58 - 11.39 (m, 1H), 8.21 (d, J= 2.4 Hz, 1H), 7.93 (br d, J= 7.7 Hz, 1H), 7.73 (dd, J= 2.5, 9.1 Hz, 1H), 7.61 (t, .7= 7.0 Hz, 1H), 7.31 (br d, = 8.3 Hz, 1H), 7.17 (br t, J= 1A Hz, 1H), 6.91 (d, J= 9.2 Hz, 1H), 3.74 (br s, 4H), 3.60 (br s, 4H).

[00247] Synthesis of Compound 7

[00248] To a solution of compound 7-3 (100 mg, 259 pmol, 1.00 eq) and B2(OH)4 (69.6 mg, 777 pmol, 3.00 eq) in EtOH (1 mL) was added XPhos (12.3 mg, 25.9 pmol, 0.1 eq), XPhos-Pd-G? (10.2 mg, 13.0 pmol, 0.05 eq), and KOAc (76.2 mg, 777 pmol, 3.00 eq) at 25 °C under nitrogen. The mixture was stirred at 50 °C for 13 hrs under nitrogen. After cooling to 25 °C, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue that was purified by prep-HPLC (neutral condition; column: 3_Phenomenex Luna C18 75 x 30mm x 3pm; mobile phase: [H2O (0.04% HC1) - ACN]; gradient: 1-27% B over 8.0 m) to provide Compound 7 (30.67 mg, 87.3 pmol, yield: 33.7%, 100% purity) as a white solid. 'H NMR (400 MHz, DMSO 3 8.35 (d, J= 1.1 Hz, 1H), 8.30 - 8.22 (m, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.81 - 7.63 (m, 2H), 7.42 (br d, J= 9.1 Hz, 1H), 7.34 (br t, J= 13 Hz, 1H), 3.98 (br s, 8H).

Biological Example 1

HEK CELL Wnt Assay

[00249] In order to determine the effect of the compounds of Formula (I) on Wnt inhibition, an in vitro assay using HEK293 SuperTOPFlash reporter cells, with the Wnt promoter driving a luciferase reporter gene, were utilized. 40,000 HEK293 SuperTOPFlash reporter cells were seeded, per well, in a 48 well plate for 24 hours, prior to administration of serial dilutions of the compound of Formula (I) to individual wells. Serial dilutions ranging from 10 pm to 1 nM of the compound of Formula (I) were added with or without 50 ng/mL Wntsa (Time Biosciences) and allowed to incubate with the reporter cells for 18 hours. Reporter cells with no treatment were used as negative control. Following the 18-hour incubation, luciferase activity was measured using Steady-Gio® Luciferase Assay System (Promega) and a Luminometer; with luciferase activity correlated to Wnt activation, and 50% inhibition of the Wnt promoter (IC50) calculated. Results are shown in Table 2. NT indicates that the compound was not tested.

Biological Example 2 TNK-2 Binding Assay

[00250] Tankyrase 2 assay (n=3) was performed with the following steps: step 1, coating a 96-well plate with 50 pL/well of histone solution; step 2, conducting ribosylation reaction; and step 3, detection.

[00251] Step 1: Coating a 96-well plate with 50 pL/well of histone solution.

[00252] A 5x histone mixture was diluted 1 :5 with PBS to make a lx histone in PBS mixture. 50 pL of the histone mixture was added to each well and incubated at 4 °C overnight. The plate was washed three times using 200 pL PBST buffer (lx PBS containing 0.05% Tween®20 (polysorbate 20) per well. The plate was tapped onto a clean paper towel to remove the liquid. The wells were blocked by adding 200 pL of blocking buffer 3 to each well. The plate was incubated at room temperature for at least 90 minutes. The plate was washed three times with 200 pL PBST buffer. The plate was tapped onto a clean paper towel to remove the liquid. [00253] Step 2: Ribosylation reaction.

[00254] A fresh solution of 10 mM DTT in water was prepared.

[00255] A master mix was prepared and delivered to each well (25 pL/well). Master mix delivered to each well: (2.5 pL of lOx PARP assay buffer (purchased from BPS Bioscience) + 2.5 pL of PARP substrate mixture 2 + 17.5 pL of water + 2.5 pL of 10 mM fresh DTT). The concentration of DTT in the master mix was 1 mM. 25 pL of master mix was added to each well.

[00256] lx PARP buffer with DTT was prepared. lOx PARP assay buffer was diluted to lx PARP assay buffer containing DTT by adding 1 volume of lOx PARP assay buffer + 1 volume of 10 mM DTT + 8 volumes of water. The concentration of DTT in the lx PARP assay buffer was 1 mM.

[00257] Serial dilutions of each test inhibitor were made (in lx PARP assay buffer with DTT), starting from 10 pM to 0 pM (10 pM, 1 pM, 0.1 pM, 0.05 pM, 0.025 pM, 0.01 pM, 0.001 pM, 0 pM). 5 pL of a test inhibitor was added to each well labeled as “Test Inhibitor.” For the “Positive Control,” the PARP inhibitor, XAV939, was used. For the negative control, no inhibitor is added to the assay mix.

[00258] The Tankyrase 2 (TNKS2) enzyme on ice was thawed. The tube containing the enzyme was spun briefly to recover the full content of the tube. The amount of TNKS2 enzyme required for the assay was calculated and the enzyme was diluted to 0.5 ng/pL with lx PARP assay buffer with DTT. 16) The final concentration of TNKS2 enzyme in the assay was 2 nM. The reaction was initiated by adding 10 pL of diluted TNKS2 enzyme to each well designated “Positive Control” and “Test Inhibitor.” To each well designated as “Blank,” 10 pL of lx PARP assay buffer with DTT was added. The plate was incubated at room temperature for 1 hour. The plate was washed three times with 100 pL of PBST buffer and the plate was tapped onto a clean paper towel.

[00259] Step 3 : Detection.

[00260] 1) Streptavidin-HRP was diluted 1 :50 in Blocking buffer (purchased from BPS

Bioscience) 3. 50 pL of diluted Streptavidin-HRP was added to each well and incubated for 30 minutes at room temperature. The plate was washed three times with 100 pL of PBST buffer and tapped onto a clean paper towel. Just before use, 1 volume of ELISA ECL Substrate A and 1 volume of ELISA ECL Substrate B were mixed on ice; and 100 pL was added to each well. Immediately, the plate was read in a luminometer or microtiter-plate reader capable of reading chemiluminescence. The “Blank” value was subtracted from all other values. The results are shown in Table 2. NT indicates that the compound was not tested.

Biological Example 3

PARP-1 Assay

[00261] PARP1 assay was performed with the following steps: step 1, coating a 96-well plate with 50 pL/well of histone solution; step 2, conducting ribosylation reaction; and step 3, detection.

[00262] Step 1: Coating a 96-well plate with 50 pL/well of histone solution.

[00263] A 5x histone mixture was diluted 1 :5 with PBS to make a lx histone in PBS mixture. 50 pL of the histone mixture was added to each well and incubated at 4 °C overnight. The plate was washed three times using 200 pL PBST buffer (lx PBS containing 0.05% Tween®20 (polysorbate 20) per well. The plate was tapped onto a clean paper towel to remove the liquid. The wells were blocked by adding 200 pL of blocking buffer 3 to each well. The plate was incubated at room temperature for at least 90 minutes. The plate was washed three times with 200 pL PBST buffer. The plate was tapped onto a clean paper towel to remove the liquid.

[00264] Step 2: Ribosylation reaction.

[00265] Activated DNA was diluted 32-fold with PBS. DTT (0.5 M) was diluted 50-fold with distilled water to make a 10 mM DTT solution.

[00266] A Master Mix was prepared and delivered to each well (25 pl/well). Master Mix delivered to each well: (2.5 pl of lOx PARP Assay Buffer + 2.5 pl of PARP Substrate Mixture 1 + 5 pl of diluted Activated DNA + 12.5 pl of distilled water + 2.5 pl of 10 mM DTT solution). [00267] lx PARP Assay Buffer was prepared by adding 1 volume of lOx PARP Assay Buffer and 1 volume of 10 mM DTT solution to 8 volumes of distilled water.

[00268] Test Inhibitor was prepared and 5 pl/well was added. For a titration, serial dilutions were prepared at concentrations 10-fold higher than the desired final concentrations. The final volume of the reaction was 50 pl. The Test Inhibitor was prepared by dissolving Test Inhibitior in DMSO (10 mM) and then diluting 10-fold with lx PARP Assay Buffer (at this step the compound concentration was 10-fold higher than the desired final concentration). The concentration of DMSO in the dilution was 10%.

[00269] Serial dilutions of the Test Inhibitor at concentrations 10-fold higher than the desired final concentrations were prepared using 10% DMSO in lx PARP Assay Buffer to keep the concentration of DMSO constant. Serial dilutions were made from 10 pM-0.001 pM. [00270] After adding the Test Inhibitor (5 pl) to each well, 5 pl of Diluent Solution was added to the “Positive Control” and “Blank” wells.

[00271] PARP1 enzyme was thawed on ice and briefly spun to recover its full content. The PARP1 enzyme was diluted to 0.33 ng/pl with lx PARP Assay Buffer (20 pl/well).

[00272] The reaction was initiated by adding 20 pl of diluted PARP1 enzyme to the wells designated “Positive Control” and "Test Inhibitor." 20 pl of lx PARP Assay Buffer was added to the “Blank” wells. The wells were incubate at RT for 1 hour and the plate was washed three times with 200 pl of PBST Buffer per well and tapped onto clean paper towel.

[00273] Step 3 : Detection.

[00274] Streptavidin-HRP was diluted 50-fold in Blocking Buffer 3 and 50 pl/well of the diluted Streptavidin-HRP was added to every well. The plate was incubated for 30 minutes at room temperature. The plate was then washed three times with 200 pl of PBST Buffer per well and tapped onto clean paper towel. Just before use, 1 volume of ELISA ECL Substrate A and 1 volume of ELISA ECL Substrate B were mixed and added to each well (100 pl of mix/well). [00275] The plate was immediately read in a luminometer or microtiter-plate reader capable of reading chemiluminescence and the data was analyzed using GraphPad Prism 10 software. Results are shown in Table 2. NT indicates that the compound was not tested.

Biological Example 4

PARP-2 Assay

[00276] PARP2 assay was performed with the following steps: step 1, coating a 96-well plate with 50 pL/well of histone solution; step 2, conducting ribosylation reaction; and step 3, detection.

[00277] Step 1: Coating a 96-well plate with 50 pL/well of histone solution.

[00278] A 5x histone mixture was diluted 1 :5 with PBS to make a lx histone in PBS mixture. 50 pL of the histone mixture was added to each well and incubated at 4 °C overnight. The plate was washed three times using 200 pL PBST buffer (lx PBS containing 0.05% Tween®20 (polysorbate 20) per well. The plate was tapped onto a clean paper towel to remove the liquid. The wells were blocked by adding 200 pL of blocking buffer 3 to each well. The plate was incubated at room temperature for at least 90 minutes. The plate was washed three times with 200 pL PBST buffer. The plate was tapped onto a clean paper towel to remove the liquid.

[00279] Step 2: Ribosylation reaction.

[00280] Activated DNA was diluted 32-fold with PBS. DTT (0.5 M) was diluted 50-fold with distilled water to make a 10 mM DTT solution.

[00281] A Master Mix was prepared and delivered to each well (25 pl/well). Master Mix delivered to each well: (2.5 pl of lOx PARP Assay Buffer + 2.5 pl of PARP Substrate Mixture 1 + 5 pl of diluted Activated DNA + 12.5 pl of distilled water + 2.5 pl of 10 mM DTT solution). [00282] lx PARP Assay Buffer was prepared by adding 1 volume of lOx PARP Assay Buffer and 1 volume of 10 mM DTT solution to 8 volumes of distilled water.

[00283] Test Inhibitor was prepared and 5 pl/well was added. For a titration, serial dilutions were prepared at concentrations 10-fold higher than the desired final concentrations. The final volume of the reaction was 50 pl. The Test Inhibitor was prepared by dissolving Test Inhibitior in DMSO (10 mM) and then diluting 10-fold with lx PARP Assay Buffer (at this step the compound concentration was 10-fold higher than the desired final concentration). The concentration of DMSO in the dilution was 10%. [00284] Serial dilutions of the Test Inhibitor at concentrations 10-fold higher than the desired final concentrations were prepared using 10% DMSO in lx PARP Assay Buffer to keep the concentration of DMSO constant. Serial dilutions were made from 10 pM-0.001 pM. [00285] After adding the Test Inhibitor (5 pl) to each well, 5 pl of Diluent Solution was added to the “Positive Control” and “Blank” wells.

[00286] PARP2 enzyme was thawed on ice and briefly spun to recover its full content. The PARP2 enzyme was diluted to 0.23 ng/pl with lx PARP Assay Buffer (20 pl/well).

[00287] The reaction was initiated by adding 20 pl of diluted PARP2 enzyme to the wells designated “Positive Control” and "Test Inhibitor." 20 pl of lx PARP Assay Buffer was added to the “Blank” wells. The wells were incubate at RT for 1 hour and the plate was washed three times with 200 pl of PBST Buffer per well and tapped onto clean paper towel.

[00288] Step 3 : Detection.

[00289] Streptavidin-HRP was diluted 50-fold in Blocking Buffer 3 and 50 pl/well of the diluted Streptavidin-HRP was added to every well. The plate was incubated for 30 minutes at room temperature. The plate was then washed three times with 200 pl of PBST Buffer per well and tapped onto clean paper towel. Just before use, 1 volume of ELISA ECL Substrate A and 1 volume of ELISA ECL Substrate B were mixed and added to each well (100 pl of mix/well). [00290] The plate was immediately read in a luminometer or microtiter-plate reader capable of reading chemiluminescence and the data was analyzed using GraphPad Prism 10 software. Results are shown in Table 2. In Table 2, A is 250 nM or less; A' is greater than 250 nM but less than or equal to 500 nM; B is greater than 500 nM but less than or equal to 1,000 nM; C is greater than 1,000 nM but less than or equal to 5,000 nM; D is greater than 5,000 nM but less than or equal to 10,000 nM; and, E is greater than 10,000 nM. NT means not tested.

Table 2. Assay Results

[00291] All publications, patents, and patent applications cited in this specification are herein incorporated by reference as if each individual publication, patent, or patent application were specifically and individually indicated to be incorporated by reference. While the claimed subject matter has been described in terms of various embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the claimed subject matter is limited solely by the scope of the following claims, including equivalents thereof.

Claims

1. A compound of Formula (I): or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof: wherein

R¹ is selected from hydrogen; Ci-ealkyl optionally substituted with -OH, -OCi-ealkyl, -OC(O)R⁶, -C(O)OR⁶, -NR^4aR^4b, -NR^4aC(O)R^4b, or -C(O)NR^4aR^4b; -OH; -B(OH)₂; -OCi-₆alkyl; halo; -NR^4aR^4b; -NR^4aC(O)R^4b, and -C(O)NR^4aR^4b;

Cy is absent, cycloalkyl, or heterocycloalkyl;

X¹, X², X³, and X⁴ are independently N or CR² wherein at least 2 of X¹ to X⁴ are CR²; each R² is independently selected from hydrogen, Ci-ealkyl, -OH, -B(OH)₂, -OCi-ealkyl, halo, -NR^4aR^4b, -NR^4aC(O)R^4b, and -C(O)NR^4aR^4b;

R³ is -B(OH)₂, -(Co-6alkylene)-X⁵-R⁵, or -(Ci-3alkylene)-X⁵-R⁵ wherein the Ci-3alkylene is substituted with R^7a and R^7b;

R^4a and R^4b are independently selected from hydrogen and Ci-ealkyl;

R⁵ is Ci-ealkoxycarbonyl-NH-Ci-ealkyl-;

X⁵ is bond, O, or NR^4a;

R⁶ is hydrogen or Ci-ealkyl; and

R^7a and R^7b are joined together with the atom or atoms to which they are attached to form a Cs-scycloalkyl.

2. The compound of claim 1, of Formula (la):

(la); or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof.

3. The compound of claim 1, of Formula (la-1): or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof.

4. The compound of claim 1, of Formula (lb):

(lb); or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof.

5. The compound of claim 1, of Formula (Ic): or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R¹ is selected from hydrogen; Ci-ealkyl optionally substituted with -OH, -OCi-ealkyl, -OC(O)R⁶, -C(O)OR⁶, -NR^4aR^4b, -NR^4aC(O)R^4b, or -C(O)NR^4aR^4b; -OH; -B(OH)₂; and -OCi-₆alkyl.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R¹ is hydrogen, -OH, or -B(0H)2.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R¹ is hydrogen.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R¹ is -OH or -B(OH)2.

11. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R¹ is -OH.

12. The compound of any one of claims 1, 4, and 6-11, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein Cy is absent.

13. The compound of any one of claims 1, 4, and 6-11, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein Cy is heterocycloalkyl.

14. The compound of any one of claims 1, 4, 6-11, and 13, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein Cy is a 5- to 6-membered heterocycloalkyl comprising 1 or 2 nitrogen atoms wherein the remaining ring atoms are carbon.

15. The compound of claim any one of claims 1, 4, 6-11, 13, and 14, or a pharmaceutically indicates attachment to the rest of the formula.

16. The compound of any one of claims 1, 4, 6-11, and 13-15, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein Cy is

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein wherein R² is not hydrogen; and wherein indicates attachment to the rest of the formula and indicates attachment to the R³ group.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein

19. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein

R² ju ,

R³ ? and wherein R is not hydrogen.

20. The compound of any one of claims 1-17, and 19, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein one R² is -OH or -OCi-ealkyl.

21. The compound of any one of claims 1-17, 19, and 20, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein one R² is -OH.

22. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein

23. The compound of any one of claims 1 and 5-22, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R³ is -B(OH)2.

24. The compound of any one of claims 1 and 5-22, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R³ is -(Co-C6alkylene)-X⁵-R⁵.

25. The compound of any one of claims 1 and 5-22, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R³ is -(Co-Cealkylene)-O-R⁵ or -(Co- Cealkylene)-R⁵.

26. The compound of any one of claims 1 and 5-22, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein R³ is -C(CH3)2-X⁵-R⁵.

27. The compound of any one of claims 1-2 and 5-26, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein X⁵-R⁵ is -OCi-6alkyl-NHC(O)OCi-6alkyl.

28. The compound of any one of claims 1-2 and 5-27, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein X⁵-R⁵ is -OC2alkyl-NHC(O)OCi-6alkyl.

29. The compound of any one of claims 1-2 and 5-28, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein X⁵-R⁵ is -OC2alkyl-NHC(O)OCH3.

30. The compound of any one of claims 1-2 and 5-26, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein X⁵-R⁵ is -Ci-6alkyl-NHC(O)OCi-6alkyl.

31. The compound of any one of claims 1-2, 5-26, and 30, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein X⁵-R⁵ is -CH2-NHC(O)OCi-6alkyl.

32. The compound of any one of claims 1-2, 5-26, and 30-31, or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, wherein X⁵-R⁵ is -CH2-NHC(O)OCH₃.

33. The compound of claim 1 selected from:

or a pharmaceutically acceptable salt, stereoisomer, and/or tautomer thereof, A pharmaceutical composition comprising the compound of any one of claims 1-33, or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof; and comprising a pharmaceutically acceptable carrier. A method of inhibiting PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity in a subject comprising contacting an effective amount of a compound of any one of claims 1-33 or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34 with the subject.

36. A method of treating a disease, disorder, or condition associated with PARP-1, PARP-2, PARP-5A, and/or PARP-5B signaling pathway activity, comprising administering a compound of any one of claims 1-33, or a single stereoisomer or mixture of stereoisomers thereof, a single tautomer or mixture of tautomers thereof, and/or a pharmaceutically acceptable salt thereof; or administering a pharmaceutical composition of claim 34 to a mammal in need thereof.

37. The method of claim 36, wherein the disease, disorder, or condition is a cellular proliferative disease or cancer.

38. The method of claim 37, wherein the cancer is selected from the group consisting of colorectal cancer, gastric cancer, lung cancer, small cell lung cancer, bladder cancer, breast cancer, ovarian cancer, fallopian tube carcinoma, cervical cancer, peritoneal carcinoma, prostate cancer, castration-resistant prostate, bile duct cancer, gastric/gastro-esophageal junction cancer, urothelial cancer, pancreatic cancer, peripheral nerve sheath cancer, uterine cancer, melanoma, a sarcoma, and lymphoma.

39. The method of claim 38, wherein the cancer is breast cancer, ovarian cancer, prostate cancer, colorectal cancer, melanoma, a sarcoma, or lymphoma.

40. The method of claim 39, wherein the cancer is breast cancer and the breast cancer is triple negative breast cancer.

41. The method of any one of claims 38 to 40, wherein the breast cancer is BRACA1/2 mutated cancer.

42. The method of claim 38, wherein the cancer is prostate cancer and the prostate cancer is antiandrogen prostate cancer.

43. The method of claim 38, wherein the cancer is a sarcoma and the sarcoma is fibrosarcoma.

44. The method of claim 38, wherein the cancer is melanoma.

45. The method of claim 36, wherein the disease, disorder, or condition is an inflammatory dermatitis disease.

46. The method of claim 45, wherein the inflammatory dermatitis disease is acne, psoriasis, rosacea, or scleroderma.

47. The method of claim 45, wherein the inflammatory dermatitis disease is psoriasis.