Compounds and uses thereof for the treatment of neurodegenerative, degenerative and metabolic disorders - Patents.com

Abstract

In particular, compounds having the structure of formula (X), (XI), (XII) or (XIII), or substructures thereof, compositions containing same and methods of use are provided. JPEG2024505256000250.jpg58170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 142,634, filed January 28, 2021, which is incorporated herein by reference in its entirety for all purposes.

[0002] Statement of government support This invention was made with government support under Grant No. 5R01NS103195 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] Many fatal neurodegenerative diseases, including prion diseases such as Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), are characterized by toxicity due to protein misfolding and are termed protein misfolding neurodegenerative diseases (PMNDs). Proteins involved in these diseases misfold to form aggregates of various sizes. Some of these aggregates are highly toxic to neurons, a phenomenon also known as proteotoxicity. Protein aggregates can also exhibit "prion-like" properties in that they can propagate from cell to cell and act as seeds to amplify the misfolding and aggregation process within cells. Such toxic misfolded proteins include the prion protein PrP in CJD, Aβ and tau in AD, α-synuclein and tau in PD, tau, TDP-43, and C9ORF72 in FTD, and SOD1, TDP43, FUS, and C9ORF72 in ALS. PD belongs to a broad group of disorders called synucleinopathies, characterized by the accumulation of misfolded α-synuclein aggregates. Dementia with Lewy bodies and multiple system atrophy are also synucleinopathies. FTD belongs to another group of PMNDs called tauopathies, a group that also includes chronic traumatic encephalopathy (CTE) and progressive supranuclear palsy (PSP). Non-neurological diseases involving protein misfolding also exist, such as diabetes, in which the proteins IAPP and proinsulin form toxic protein aggregates in pancreatic beta cells, and cardiomyopathy caused by transthyretin (TTR) amyloidosis (ATTR). TTR amyloid is primarily deposited in peripheral nerves, causing polyneuropathy.

[0004] The development of effective treatments for PMND has been hindered by limited knowledge of the mechanisms of neurotoxicity. To study these mechanisms, models using the toxic misfolded prion protein (TPrP) have been developed; in particular, TPrP reproducibly induces neuronal death in cell culture and after intracerebral injection. 1At nanomolar concentrations, TPrP induces the death of over 60% of cultured neurons, whereas NTPrP, the naturally folded counterpart of the prion protein, does not. Therefore, this model provides a highly efficient system for studying mechanisms of proteotoxicity-associated neuronal cell death, with broad applicability to protein misfolding diseases. Thus, as shown herein, TPrP-based research has prompted the development of novel neuroprotective approaches for treating devastating neurodegenerative diseases and other disorders involving the death of specific cell types. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Patent Publication WO2020 / 232255 [Patent Document 2] U.S. Patent No. 4,911,920 [Patent Document 3] U.S. Patent No. 5,403,841 [Patent Document 4] U.S. Patent No. 5,212,162 [Patent Document 5] U.S. Patent No. 4,861,760 [Patent Document 6] WO96 / 05309 [Non-patent literature]

[0006] [Non-Patent Document 1] Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19. [Non-patent document 2] Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992) [Non-patent document 3] Lloyd, The Art, Science and Technology of Pharmaceutical Compounding(1999) [Non-patent document 4] Pickar, Dosage Calculations (1999) [Non-patent document 5] Remington: The Science and Practice of Pharmacy, 20th ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins [Non-patent document 6] Fingl et al. in THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch.1, pl, 1975 [Non-Patent Document 7] Pharmaceutical Sciences (17th edition, Mack Pub. Co., Easton, PA) [Non-patent document 8] Zhou et al., Proc Natl Acad Sci USA 109, 3113–3118 (2012) Summary of the Invention [Problem to be solved by the invention]

[0007] Provided herein are, inter alia, novel compounds that can inhibit NAD consumption and / or increase NAD synthesis. [Means for solving the problem]

[0008] In one embodiment, the structure of formula (X)

[0009] [ka]

[0010] or a pharmaceutically acceptable salt or isomer thereof (In the formula, R10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, R 20 Ha-L 1 -R 21 and L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R 21 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10 and R 20 are optionally linked to form a substituted or unsubstituted bicyclic heterocycloalkyl; R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is hydrogen, D, halogen, -CX 33. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -OR 3F , -SR 3F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 30 are independently halogen, -CX 30 3. -CHX 30 2. -CH2X 30 , -OCX 30 3. -OCH2X 30 , -OCHX 30 2, -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, z is an integer from 0 to 4, each X 1 , X 2 , X 3 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F , R 3F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; However, R 10 is hydrogen and L 1 If is a bond, R 21 is not unsubstituted phenyl or phenyl substituted with halogen, —C(O)CH3, —S(O)2—NH2, or substituted or unsubstituted alkyl, and L 1 is methylene, R 21 is not unsubstituted tetrahydropyranyl) is provided.

[0011] In one embodiment, the structure of formula (XII)

[0012] [ka]

[0013] or a pharmaceutically acceptable salt or isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, D, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -OR 3F , -SR 3F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 and R 3 are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; Each R 6 and R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, or R 6 and R 7 are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 8 is a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R 30 are independently halogen, -CX 30 3. -CHX 30 2. -CH2X 30 , -OCX 30 3. -OCH2X 30 , -OCHX 30 2, -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, z is an integer from 0 to 4, each X 1 , X 2 , X 3 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F , R 3F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; However, n is 0 and L 1 is a bond and R 6 and R 7 is hydrogen, R 8 is not unsubstituted tetrahydropyranyl) is provided.

[0014] In an embodiment, in formula (XII), R 2 and R 3 At least one of these is not hydrogen.

[0015] In one embodiment, the structure of formula (XIII):

[0016] [ka]

[0017] or a pharmaceutically acceptable salt or isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2 -C(=O)-, -C(=CR 9A R 9B )-, -CR 10A R 10B - or -C(=NR 11 )- and R 1are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9A and R 9B are independently hydrogen, -CX 9 3. -CHX 9 2. -CH2X 9 , -OCX 9 3. -OCH2X 9 , -OCHX 9 2, -CN, -OR 9F , -SR 9F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 10A and R 10B are independently hydrogen, D, halogen, -CX 10 3. -CHX 10 2. -CH2X 10 , -OCX 10 3. -OCH2X 10 , -OCHX 10 2, -CN, -OR 10F , -SR 10F , -C(O)OR 10F , -C(O)NHR 10F , -C(O)N(R 10F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10A and R 10B are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 11 -R 11F , -OR 11F , -S(O2)-R 11F , or -C(O)-R 11F and R 30 are independently halogen, -CX 30 3. -CHX 30 2. -CH2X 30 , -OCX 30 3. -OCH2X 30 , -OCHX 30 2, -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 1 to 4, z is an integer from 0 to 4, each X 1 , X 8 , X 9 , X 10 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 8F , R 9F , R 10F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl) is provided.

[0018] In an embodiment, in formula (XIII), R 10A and R 10B At least one of these is not hydrogen.

[0019] In one aspect, a pharmaceutical composition is provided that includes a compound described herein, a pharmaceutically acceptable salt form thereof, an isomer thereof, or a crystalline form thereof.

[0020] In one aspect, a method of inhibiting NAD consumption and / or increasing NAD synthesis in a patient is provided. The method can include administering to the patient an effective dose of a compound described herein.

[0021] In one aspect, a method of preventing or inhibiting NAD depletion in a patient or ameliorating a condition associated with altered NAD metabolism in a patient is provided, which can include administering to the patient an effective dose of a compound described herein.

[0022] In one aspect, a method is provided for providing protection from misfolded protein toxicity in a patient, the method may comprise administering to the patient an effective dose of a compound described herein.

[0023] In one aspect, a method of preventing or treating a protein misfolding neurodegenerative disease in a patient is provided, which can include administering to the patient an effective dose of a compound described herein.

[0024] In one aspect, a method of preventing or treating mitochondrial dysfunction in a patient is provided. The method can include administering to the patient an effective dose of a compound described herein.

[0025] In one aspect, a method of preventing or treating a retinal disease in a patient is provided. The method can include administering to the patient an effective dose of a compound described herein.

[0026] In one aspect, methods for preventing or treating diabetes, non-alcoholic fatty liver disease, or other metabolic disorders in a patient are provided. The methods can include administering to the patient an effective dose of a compound described herein.

[0027] In one aspect, a method of preventing or treating renal disease or renal failure in a patient is provided. The method can include administering to the patient an effective dose of a compound described herein.

[0028] In one aspect, a method for reducing the health effects of aging is provided. The method can include administering to a patient an effective dose of a compound described herein.

[0029] In one aspect, methods are provided for preventing or treating neuronal degeneration associated with multiple sclerosis, axonopathy, optic neuropathy, cardiomyopathy, cerebral or cardiac ischemia, traumatic brain injury, hearing loss, or retinal damage in a patient, which may comprise administering to the patient an effective dose of a compound described herein.

[0030] Other aspects of the invention are disclosed below. [Brief explanation of the drawings]

[0031] [Figure 1A-D] 1A-D show the dose-response curves of compounds in the TPrP neuroprotection assay. [Figure 2A-F] 2A-F show the effect of compounds on the activation rate of the enzyme nicotinamide phosphoribosyltransferase (NAMPT). DETAILED DESCRIPTION OF THE INVENTION

[0032] The misfolded, toxic prion protein TPrP induces a severe depletion of neuronal NAD, leading to cell death, as NAD replacement results in complete recovery of cells exposed to TPrP insult in vitro and in vivo despite continued exposure to TPrP. 2Intranasal administration of NAD improved motor function and activity in mice with prion disease. Furthermore, it was discovered that NAD depletion in neurons exposed to TPrP may be due, at least in part, to excessive consumption of intracellular NAD in a metabolic reaction called mono-ADP-ribosylation. 2 Inhibitors of poly(ADP-ribosylation), called PARP inhibitors, have been previously developed as anticancer drugs. Available selective PARP inhibitors did not reduce NAD depletion and neuronal cell death caused by TPrP, highlighting the need to identify new compounds that can interfere with mechanisms affecting misfolded protein-induced toxicity or prevent NAD depletion, regardless of the underlying mechanism of NAD imbalance. Imbalances in NAD metabolism, as described herein, are a pathogenic mechanism for many human conditions.

[0033] As used herein, NAD refers to both the oxidized (NAD+) and reduced (NADH) forms of the cofactor. NAD is important as a coenzyme for regulating energy metabolic pathways such as glycolysis, the TCA cycle, and oxidative phosphorylation, which leads to ATP production, among others. Additionally, NAD functions in signal transduction and as a substrate for a post-translational protein modification called ADP-ribosylation.

[0034] Because physiological cellular NAD levels result from a balance between the activities of NAD synthesizing and NAD consuming enzymes, it can be inferred that NAD imbalance induced by misfolded proteins (and assessed by the TPrP assay) could result from either impaired NAD biosynthesis or increased NAD consumption.

[0035] In mammalian cells, NAD is primarily synthesized via the salvage pathway using the precursor nicotinamide (NAM). The rate-limiting enzyme for NAD synthesis in the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT), which converts NAM to nicotinamide mononucleotide (NMN). Nicotinamide riboside (NR) is an alternative NAD precursor that is converted to NMN by nicotinamide riboside kinase. Other NAD synthesis pathways are the de novo pathway, which utilizes the precursor tryptophan, and the Preiss-Handler pathway, which utilizes the precursor nicotinic acid (NA).

[0036] Meanwhile, NAD is consumed in the following cellular reactions: 1) generation of the calcium-releasing second messengers cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from NAD by enzymes called NAD hydrolases or ADP-ribosyl cyclases (CD38 and CD157), 2) protein deacetylation via sirtuins, and 3) protein ADP-ribosylation, in which one or more ADP-ribose moieties from NAD are transferred to proteins by mono / oligo ADP-ribose transferases (mARTs) or poly ADP-ribose transferases (called PARPs).

[0037] NAD deficiency is a cause of prion disease 2 and PD 3、4 , A.D. 5~8 and ALS 9、10 are characteristic of other PMNDs.

[0038] Dysregulation of NAD is currently a major concern in aging. 11~13 , multiple sclerosis 14 , traumatic brain injury 15 , hearing loss 16 , axonopathy and axon degeneration 17、18 It is also recognized that NAD is involved in neuronal degeneration associated with cerebral ischemia. NAD enhancement, such as increasing NAD synthesis by administration of NAD or overexpression of the enzyme, can be effective in treating cerebral ischemia. 19 and cardiac ischemia / reperfusion injury 20、21 has been shown to reduce

[0039] Age-related retinal / macular degeneration (AMD) is associated with the death of photoreceptor cells and retinal pigment epithelial (RPE) cells in the eye's retina, leading to progressive vision loss. RPE cells isolated from AMD patients have reduced NAD levels. 22 Healthy NAD levels are necessary for vision in mice 23 Increasing NAD levels by overexpressing cytosolic nicotinamide mononucleotide adenyltransferase-1 (cytNMNATl) in mice or by NAM-supplemented diets in rats reduces Zn after light-induced retinal damage (LIRD). 2+ staining, loss of NAD+ and decreased cell death were observed. 24 Similarly, treatment with the NAD precursor NR maintained retinal NAD levels and protected retinal morphology and function in a mouse model of LIRD. 25 .

[0040] NAD metabolism has also been shown to be altered in mouse models of type 2 diabetes (T2D) 26、27 The alterations in NAD metabolism in diabetes can be explained, at least in part, by our finding that misfolded proteins induce NAD dysregulation. Indeed, diabetes has been shown to be a protein misfolding disease characterized by pancreatic beta cell dysfunction and death accompanied by the deposition of aggregated islet amyloid polypeptide (IAPP), a protein co-expressed and secreted with insulin by pancreatic beta cells. 28、29 Like proteins involved in other protein misfolding diseases, IAPP forms toxic oligomers. 28 Furthermore, proinsulin, the precursor to insulin, also tends to misfold in beta cells. Proinsulin misfolding has been linked to the development of type 2, type 1, and some monogenic forms of diabetes. 28、30、31 NR supplementation attenuates type 2 diabetes in mice 27 .

[0041] NAD supplementation can help treat metabolic disorders 32 , senile amyloidosis33 Protects against mitochondrial dysfunction in the brain and prevents mitochondrial damage and fragmentation after ischemia 34 Overexpression of the NAD synthase NAMPT suppresses mitochondrial fragmentation, loss of mitochondrial DNA content, and reduced expression of PGC-1 and NRF-1, key regulators of mitochondrial biogenesis, in cultured primary neurons subjected to glutamate-induced excitotoxicity or oxygen-glucose deprivation. 35 .

[0042] NAD levels are significantly reduced in degenerative renal conditions, and NAD enhancement attenuates acute kidney injury induced by ischemia-reperfusion, toxic injury, and systemic inflammation. 36 .

[0043] Using TPrP as a prototypical amyloidogenic misfolded protein exhibiting high neurotoxicity, a high-throughput screening (HTS) assay was developed to identify compounds effective in a) preventing cell death and b) preventing TPrP-induced NAD depletion.

[0044] An HTS campaign was conducted at Scripps Florida using a subset of the Scripps Drug Discovery Library (SDDL). Several potent, novel, and chemically tractable small molecules were identified that can provide complete neuroprotection and preserve NAD levels when used at doses ranging from low nanomolar to low micromolar levels, as detailed in International Patent Publication WO2020 / 232255, the entire contents of which are incorporated herein by reference for all purposes.

[0045] Members of each series of compounds described herein are highly potent in neuroprotective assays designed to reflect the likelihood of successful treatment of some of the neurodegenerative diseases described herein. Furthermore, many possess advantageous drug-like properties (e.g., they are PAlNS-free). 37and Lipinski and Weber's law of drug-likeness 38、39 These compounds prevent the depletion of cellular NAD levels or increase NAD levels, and are therefore useful for the prevention or treatment of diseases in which an imbalance in NAD metabolism occurs, such as protein misfolding neurodegenerative diseases, amyloidosis, mitochondrial diseases, aging, retinal degeneration, ischemic conditions, traumatic brain injury, renal failure, and metabolic diseases including diabetes and non-alcoholic fatty liver disease.

[0046] definition Abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are to be construed in accordance with standard rules of chemical valency known in the chemical arts.

[0047] Where substituents are designated by a conventional chemical formula written from left to right, they equally encompass the chemically identical substituents that would occur if the structure were written from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0048] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and which may include monovalent, divalent, and polyvalent groups. An alkyl may contain the specified number of carbon atoms (e.g., C1-C6). 10means 1 to 10 carbon atoms). Alkyl is a non-cyclized chain. Examples of saturated hydrocarbon groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), n-propyl ("Pr"), isopropyl ("iPr"), n-butyl ("Bu"), t-butyl ("t-Bu"), isobutyl, sec-butyl, methyl, and their homologs and isomers, such as n-pentyl, n-hexyl, n-heptyl, and n-octyl. Unsaturated alkyl groups are those containing one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers. Alkoxy is an alkyl attached to the rest of the molecule via an oxygen linker (-O-). The alkyl moiety may be an alkenyl moiety. The alkyl moiety may be an alkynyl moiety. The alkyl moiety may be fully saturated. An alkenyl may contain more than one double bond and / or one or more triple bonds in addition to one or more double bonds. An alkynyl may contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0049] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from alkyl, exemplified, but not limited to, by -CHCHCHCH-. Typically, an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being preferred herein. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms. The term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.

[0050] The term "heteroalkyl," by itself or in combination with other terms, means, unless otherwise stated, stable linear or branched chains, or combinations thereof, containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), where the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom (e.g., O, N, S, Si, or P) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is a non-cyclizing chain. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain two, optionally different, heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain three, optionally different, heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain four, optionally different, heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain five, optionally different, heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may contain up to eight, optionally different, heteroatoms (e.g., O, N, S, Si, or P). The term "heteroalkenyl," by itself or in combination with other terms, means, unless otherwise specified, a heteroalkyl containing at least one double bond. A heteroalkenyl can optionally contain more than one double bond and / or one or more triple bonds in addition to one or more double bonds.The term "heteroalkynyl," by itself or in combination with other terms, means, unless otherwise stated, a heteroalkyl containing at least one triple bond. A heteroalkynyl can optionally contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0051] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- represents both -C(O)R'- and -R'C(O)-. As noted above, heteroalkyl groups as used herein include groups attached to the remainder of the molecule via a heteroatom, such as -C(O)R', -C(O)NR', ​​-NR'R'', -OR', -SR', and / or -SOR'. Where "heteroalkyl" is recited followed by a specific heteroalkyl group, such as -NR'R'', it is understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is recited to add clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R''.

[0052] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Furthermore, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. A "cycloalkylene" and a "heterocycloalkylene," alone or as part of another substituent, mean a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0053] In embodiments, heterocycloalkyl is heterocyclyl. As used herein, the term "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6-, or 7-membered ring in which the ring is saturated or unsaturated, but not aromatic, and contains at least one heteroatom independently selected from the group consisting of O, N, and S. A 3- or 4-membered ring contains one heteroatom selected from the group consisting of O, N, and S. A 5-membered ring can contain zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A 6- or 7-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A heterocyclyl monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocyclyl monocyclic heterocycle. Representative examples of heterocyclyl monocyclic heterocycles include azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, and oxazolinyl. Heterocyclyl bicyclic heterocycles include, but are not limited to, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidethiomorpholinyl (thiomorpholinesulfone), thiopyranyl, and trithianyl. Heterocyclyl bicyclic heterocycles are monocyclic heterocycles fused to either phenyl, monocyclic cycloalkyl, monocyclic cycloalkenyl, monocyclic heterocycle, or monocyclic heteroaryl. Heterocyclyl bicyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained in the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocycles include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-IH-indolyl, and octahydrobenzofuranyl. In embodiments, the heterocyclyl group is optionally substituted with one or two groups, independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5- or 6-membered monocyclic cycloalkyl, a 5- or 6-membered monocyclic cycloalkenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- or 6-membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted with one or two groups that are independently oxo or thia. A polycyclic heterocyclyl ring system is a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) two other ring systems independently selected from the group consisting of phenyl, bicyclic aryl, monocyclic or bicyclic heteroaryl, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic cycloalkenyl, and monocyclic or bicyclic heterocyclyl. The polycyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, the polycyclic heterocyclyl ring system is (i) one ring system selected from the group consisting of bicyclic aryl, bicyclic heteroaryl, bicyclic cycloalkyl, bicyclic cycloalkenyl, and bicyclic heterocyclyl, or (ii) a monocyclic heterocyclyl ring (base ring) fused to either two other ring systems independently selected from the group consisting of phenyl, monocyclic heteroaryl, monocyclic cycloalkyl, monocyclic cycloalkenyl, and monocyclic heterocyclyl.Examples of polycyclic heterocyclyl groups include, but are not limited to, 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 1OH-phenoxazin-10-yl, 10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl, 1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl, 12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

[0054] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1-C4)alkyl" includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0055] The term "aryl," unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1 to 3 rings) fused together (i.e., fused-ring aryl) or covalently linked. Fused-ring aryl refers to multiple rings fused together, where at least one of the fused rings is an aryl ring. The term "heteroaryl" refers to an aryl group (or ring) containing at least one heteroatom, such as N, O, or S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Thus, the term "heteroaryl" includes fused-ring heteroaryl groups (i.e., multiple rings fused together, where at least one of the fused rings is a heteroaromatic ring). 5,6-fused-ring heteroarylene refers to two rings fused together, where one ring has five members and the other has six members, and at least one ring is a heteroaryl ring. Similarly, a 6,6-fused ring heteroarylene refers to two rings fused together, where one ring has 6 members and the other ring has 6 members, and at least one ring is a heteroaryl ring. Also, a 6,5-fused ring heteroarylene refers to two rings fused together, where one ring has 6 members and the other ring has 5 members, and at least one ring is a heteroaryl ring. The heteroaryl group can be attached to the rest of the molecule through a carbon or heteroatom.Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, and the like. aryl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An "arylene" and a "heteroarylene," alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O-bonded to a ring heteroatom nitrogen.

[0056] A fused-ring heterocycloalkyl-aryl is an aryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-heteroaryl is a heteroaryl fused to a heterocycloalkyl. A fused-ring heterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl. A fused-ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkyl fused to another heterocycloalkyl. Each fused-ring heterocycloalkyl-aryl, fused-ring heterocycloalkyl-heteroaryl, fused-ring heterocycloalkyl-cycloalkyl, or fused-ring heterocycloalkyl-heterocycloalkyl can independently be unsubstituted or substituted with one or more of the substituents described herein.

[0057] Spirocyclic rings are two or more rings in which adjacent rings are connected through a single atom. The individual rings within a spirocyclic ring can be the same or different. The individual rings within a spirocyclic ring can be substituted or unsubstituted and can have different substituents than the other individual rings within a set of spirocyclic rings. The possible substituents for the individual rings within a spirocyclic ring are the possible substituents for the same ring when not part of a spirocyclic ring (e.g., substituents for a cycloalkyl or heterocycloalkyl ring). The spirocyclic ring can be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings within a spirocyclic ring group can be any of the preceding lists, including having all rings of one type (e.g., all rings are substituted heterocycloalkylene, where each ring can be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, a heterocyclic spirocyclic ring means a spirocyclic ring in which at least one ring is heterocyclic and each ring can be a different ring. When referring to a spirocyclic ring system, a substituted spirocyclic ring means that at least one ring is substituted and each substituent can optionally be different.

[0058] symbol

[0059] [ka]

[0060] indicates the point of attachment of the chemical moiety to the rest of the molecule or chemical formula.

[0061] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0062] As used herein, the term "alkylsulfonyl" refers to a moiety having the formula -S(O2)-R', where R' is a substituted or unsubstituted alkyl group as defined above. R' may have a specific number of carbons (e.g., "C 1~ C4 alkylsulfonyl).

[0063] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," "heterocycloalkyl," "aryl," and "heteroaryl") includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0064] Substituents for alkyl and heteroalkyl groups (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) include, but are not limited to, -OR', ═0, ═NR', ═N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', - It can be one or more of a variety of groups selected from: -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(0)2R', -NR-C(NR'R''R'')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(0)2R', -S(0)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', -NR'OR''. R, R', R'', R''', and R'''' each preferably independently represent hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 to 3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy group, or arylalkyl group. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected, as are each R', R'', R''', and R'''' group when more than one of these groups is present. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the discussion of the above substituents, one of skill in the art will understand that the term "alkyl" is intended to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF and -CHCF) and acyl (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0065] Similar to the substituents described for the alkyl group, the substituents for the aryl and heteroaryl groups are varied and include, for example: OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)R', -NR-C(NR'R''R'')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)R', -S(O)NR'R'', -NRSOR', - and R', R''', R''', and R''', preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compounds described herein include more than one R group, for example, each of the R groups is independently selected, as are each R', R'', R''', and R''' groups when more than one of these groups is present.

[0066] Substituents for a ring (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be drawn as substituents on the ring rather than on a specific atom of the ring (commonly referred to as floating substituents). In such cases, the substituent may be attached to any of the ring atoms (subject to the rules of chemical valence), and in the case of a fused or spirocyclic ring, a substituent drawn as associated with one member of the fused or spirocyclic ring (floating substituent on a single ring) may be a substituent on any of the fused or spirocyclic rings (floating substituent on multiple rings). When a substituent is attached to a ring rather than to a specific atom (floating substituent), and the substituent subscript is an integer greater than 1, the multiple substituents may be on the same atom, the same ring, different atoms, different fused rings, or different spirocyclic rings, and each substituent may optionally be different. When the point of attachment of a ring to the rest of the molecule is not limited to a single atom (a floating substituent), the point of attachment may be any atom of the ring, or, in the case of a fused or spirocyclic ring, any atom of the fused or spirocyclic ring, subject to the rules of chemical valence. When a ring, fused ring, or spirocyclic ring contains one or more ring heteroatoms and the ring, fused ring, or spirocyclic ring is shown with one or more floating substituents (including, but not limited to, the point of attachment to the rest of the molecule), the floating substituents may be bonded to the heteroatoms. When a ring heteroatom is shown bonded to one or more hydrogens in a structure or formula with floating substituents (e.g., a ring nitrogen with two bonds to a ring atom and a third bond to a hydrogen), it is understood that when the heteroatom is bonded to the floating substituent, the substituent replaces the hydrogen, subject to the rules of chemical valence.

[0067] Two or more substituents may optionally be linked to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic ring structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0068] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be of the formula -TC(O)-(CRR') q -U-, where T and U are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r A and B may be optionally replaced with a substituent of the formula -B-, where A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, or a single bond, and r is an integer from 1 to 4. One of the single bonds in the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'-(C''R''R'') d-, where s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-. The substituents R, R', R" and R'" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0069] As used herein, the term "heteroatom" or "ring heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). As used herein, a "substituent" means a group selected from the following moieties: (A) Oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI 2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C 10aryl or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), which are substituted with at least one substituent selected from the following: (i) Oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI 2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C10 aryl or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), which are substituted with at least one substituent selected from the following: (a) Oxo, halogen, -CCl3, -CBr3, -CF3, -Cl3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -S O4H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI 2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10Aryl, C 10 aryl or phenyl), or unsubstituted heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), aryl (e.g., C6-C 10 Aryl, C 10 aryl or phenyl), heteroaryl (e.g., 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl), which are substituted with at least one substituent selected from the following: oxo, halogen, —CCl3, —CBr3, —CF3, —Cl3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —S03H, —S04H, —SON2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHS02H, —NHC(O)H, —NHC(O)OH, —NHOH, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -N3, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2-8 membered heteroalkyl, 2-6 membered heteroalkyl, or 2-4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3-8 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, or 5-6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C 10 Aryl, C10 aryl or phenyl), or unsubstituted heteroaryl (eg, 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, or 5- to 6-membered heteroaryl).

[0070] In embodiments, a substituted moiety (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent, and when a substituted moiety is substituted with multiple substituents, each substituent can optionally be different. In embodiments, when a substituted moiety is substituted with multiple substituents, each substituent is different.

[0071] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers, which can be defined in terms of absolute stereochemistry as (R)- or (S)- for amino acids, or as (D)- or (L)-, are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When a compound described herein contains an olefinic bond or other center of geometric asymmetry, and unless otherwise specified, the compound is intended to include both E and Z geometric isomers.

[0072] As used herein, the term "isomers" refers to compounds that have the same number and kind of atoms, and hence the same molecular weight, but differ with respect to the structural arrangement or configuration of the atoms.

[0073] The term "tautomer," as used herein, refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0074] It will be apparent to one skilled in the art that certain compounds of the present disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the present disclosure.

[0075] Unless otherwise specified, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0076] It should be noted that throughout this application, options are written in Markush groups, e.g., each amino acid position contains more than one possible amino acid. It is specifically contemplated that each member of a Markush group should be considered separately and thereby include alternative embodiments, and that a Markush group should not be read as a single unit.

[0077] As used herein, the terms "a" or "an" mean one or more. Additionally, as used herein, the phrase "substituted with a[n]" means that the specified group may be substituted with one or more of any or all of the specified substituents. For example, when a group such as an alkyl or heteroaryl group is "substituted with an unsubstituted C1-C 20 When "substituted with alkyl, or unsubstituted 2-20 membered heteroalkyl," the group is substituted with one or more unsubstituted C1-C 20 It may contain alkyl, and / or one or more unsubstituted 2- to 20-membered heteroalkyl.

[0078] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of a large number of substituents, such substitutions are selected to conform to the principles of chemical bonding and to provide a compound that is not inherently unstable and / or is known to those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0079] Those of skill in the art will understand that when a variable (e.g., a moiety or linker) of a compound or compound genus (e.g., a genus described herein) is described by the name or formula of an independent compound in which all valences are satisfied, the unsatisfied valences of the variable will be determined by the context in which the variable is used. For example, when a variable of a compound described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, the variable will be understood to represent the monovalent form of the independent compound (i.e., the unsatisfied valences allow for the formation of a single bond) (e.g., if an embodiment specifies a variable as "methane," but the variable is known to be attached to the remainder of the compound through a single bond, one of skill in the art will understand that the variable is actually the monovalent form of methane, i.e., methyl or -CH3). Similarly, linker variables (e.g., L as described herein) will be understood to represent the monovalent form of methane, i.e., methyl or -CH3). 1 , L 2 or L 3 ), one of skill in the art would understand that the variable is a divalent form of the independent compound (e.g., if an embodiment assigns a variable to "PEG" or "polyethylene glycol," but the variable is connected to the remainder of the compound by two separate bonds, one of skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds via two unsatisfied valences) form of PEG instead of the independent compound PEG).

[0080] The term "salt" as used herein refers to an acid or base salt of a compound used in the method of the present invention. Examples of acceptable salts include mineral acid salts (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acid salts (acetic acid, propionic acid, glutamic acid, citric acid, etc.), and quaternary ammonium salts (methyl iodide, ethyl iodide, etc.).

[0081] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric, monohydrogensulfuric, hydroiodic, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, etc. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain detailed compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0082] Therefore, the compounds of the present disclosure may exist as salts with pharmaceutically acceptable acids, etc. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochloride, hydrobromide, phosphate, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, propionate, tartrate (e.g., (+)-tartrate, (-)-tartrate, or a mixture thereof, including a racemic mixture), succinate, benzoate, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, etc.). These salts can be prepared by methods known to those skilled in the art.

[0083] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0084] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein can be converted in vivo after administration. Furthermore, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as when contacted with a suitable enzyme or chemical reagent.

[0085] Certain compounds of the present disclosure can exist in unsolvated forms and solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure. Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0086] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of an active agent by a subject and can be included in the compositions of the present disclosure without causing significant adverse toxicological effects to the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, can be mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with the compounds of the present disclosure. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.

[0087] The term "preparation" is intended to include formulations of the active compound with an encapsulating material as a carrier, with or without other carriers, providing a capsule in which the active ingredient is surrounded by the carrier. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0088] As used herein, the term "about" refers to a range of values ​​that includes the specified value and that one of ordinary skill in the art would consider to be reasonably similar to the specified value. In embodiments, about refers to within a standard deviation using measurements generally accepted in the art. In embodiments, about refers to a range that covers + / - 10% of the specified value. In embodiments, about includes the specified value.

[0089] As used herein, "EC 50The term "median effective concentration" or "half maximal effective concentration" refers to the concentration of a molecule (e.g., a small molecule, drug, antibody, chimeric antigen receptor, or bispecific antibody) that can induce a response halfway between the baseline response and the maximal response after a specific exposure time. In embodiments, the EC 50 is the concentration of a molecule (e.g., a small molecule, drug, antibody, chimeric antigen receptor, or bispecific antibody) that produces 50% of the molecule's maximum possible effect.

[0090] As used herein, the term "neurodegenerative disorder" refers to a disease or condition in which the function of a subject's nervous system is impaired. Examples of neurodegenerative disorders that may be treated with the compounds, pharmaceutical compositions, or methods described herein include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, telangiectasia, Batten disease (also known as Spillmeyer-Voigt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, chronic traumatic encephalopathy, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krauss disease, and others. These include: Beyer's disease, kuru, dementia with Lewy bodies, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple system atrophy, myalgic encephalomyelitis, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined spinal degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various forms with varying features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, tabes dorsalis, or traumatic brain injury.

[0091] The term "retinal degeneration" as used herein refers to a disease or condition in which the visual acuity of a subject is impaired due to dysfunction and / or damage of the retina of the eye. Examples of retinal degeneration include age-related macular degeneration (AMD). Early AMD includes abnormalities of the retinal pigment epithelium and drusen. Late AMD can include dry (non-neovascular, atrophic) macular degeneration, wet (neovascular) macular degeneration, proliferative diabetic retinopathy (PDR), and diabetic macular edema (DME).

[0092] As used herein, the term "axonopathy" refers to functional or structural damage to nerve cells or peripheral nerves.

[0093] As used herein, the term "peripheral" refers to the anatomical parts of the body located outside the central nervous system.

[0094] The term "amyloidosis" as used herein refers to conditions associated with the deposition of protein amyloid. Amyloidosis can occur in the central nervous system and is also referred to as a protein misfolding neurodegenerative disease (e.g., prion diseases, AD, PD and other synucleinopathies, ALS, tauopathies). Amyloidosis can also occur outside the central nervous system and can be widespread, i.e., systemic, or present in various organ systems. When amyloid deposits occur in multiple organs, it is referred to as "multisystemic." Examples of amyloidosis are cardiomyopathy or polyneuritis, which are caused by deposition of the protein TTR in the heart or peripheral nerves, respectively. Other examples of peripheral amyloidosis are AL (primary) amyloidosis or AA (secondary) amyloidosis.

[0095] As used herein, the term "metabolic disorder" refers to a disease or condition that disrupts the body's metabolism, i.e., the process by which the body obtains, makes, and stores energy from food. Some metabolic disorders affect the breakdown of amino acids, carbohydrates, or lipids. Other metabolic disorders are known as mitochondrial diseases and affect mitochondria, the organelles that produce energy. Examples of metabolic disorders are diabetes (glucose metabolism), hypercholesterolemia, Gaucher disease (lipid metabolism), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (dyslipidemia, abdominal obesity, insulin resistance, and a pro-inflammatory state).

[0096] The term "mitochondrial disease" as used herein refers to a group of disorders affecting mitochondria, a cell organelle whose main function is to produce energy. Primary mitochondrial disorders are caused by mutations in mitochondrial DNA or nuclear DNA. They can affect various organ systems, causing myopathy, diabetes, and hearing loss, blindness, neuropathy, or encephalopathy. Alternatively, mitochondrial dysfunction is associated with aging and diseases such as diabetes, cancer, Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, and ischemic conditions.

[0097] As used herein, the terms "kidney disease," "kidney failure," "renal disease," or "renal failure" refer to a disease or condition in which a subject loses kidney function. The condition can have various etiologies, such as infectious, inflammatory, ischemic, or traumatic. Renal failure can be acute, which rapidly results in a rapid loss of kidney function, or chronic, which rapidly results in a gradual loss of kidney function. The condition ultimately leads to the accumulation of dangerous levels of fluid, electrolytes, and waste products in the body. End-stage renal failure is fatal without artificial filtration of the blood (dialysis) or a kidney transplant.

[0098] As used herein, the term "ischemic condition" or "ischemia" refers to a condition in which blood flow is restricted or reduced in a part of the body, such as the heart or brain.

[0099] The term "treating" or "treatment" refers to an indicator of success in treating or ameliorating an injury, disease, pathology, or condition, including objective or subjective parameters such as attenuation, remission, or reduction of symptoms, or making the injury, pathology, or condition more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, or improving the patient's physical or mental well-being. The treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treating" and its conjugations can include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.

[0100] As used herein (and as is well understood in the art), "treating" or "treatment" broadly includes any approach to obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, reduction or amelioration of one or more symptoms or conditions, reduction in the extent of disease, stabilization (i.e., not worsening) of the disease state, prevention of the spread or progression of disease, delay or slowing of disease progression, improvement or palliation of the disease state, reduction in disease recurrence, and remission, whether partial or total, and whether detectable or undetectable. In other words, "treatment" as used herein includes cure, amelioration, or prevention of disease. Treatment can prevent the onset of disease, inhibit the spread of disease, alleviate symptoms of disease, completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination thereof.

[0101] The term "preventing" refers to a reduction in the occurrence of disease symptoms in a patient. As indicated above, prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur in the absence of treatment.

[0102] "Patient" or "subject in need thereof" refers to a living organism suffering from or susceptible to developing a disease or condition that can be treated by administration of the pharmaceutical compositions provided herein. Non-limiting examples include humans, other mammals, cows, rats, mice, dogs, monkeys, goats, sheep, bovine, deer, and other non-mammals. In some embodiments, the patient is a human.

[0103] An "effective amount" is an amount sufficient for a compound to achieve a stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signal transduction pathway, or reduce one or more symptoms of a disease or condition) compared to the absence of the compound. An example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." A "reduction" of one or more symptoms (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of the symptoms, or the elimination of the symptoms. A "prophylactically effective amount" of a drug is an amount of drug that, when administered to a subject, exerts the intended prophylactic effect, for example, preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur with the administration of a single dose, but may occur only after the administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce the activity of an enzyme relative to the absence of the antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amount will depend on the purpose of the treatment and can be ascertained by one of skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0104] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. The target concentration is the concentration of active compound that can be measured using methods described herein or known in the art to achieve the methods described herein.

[0105] As is well known in the art, the therapeutically effective amount for use in humans can also be determined from animal models.For example, the dose for humans can be formulated to achieve a concentration found to be effective in animals.The dose for humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dose upward or downward, as described above.Based on the above and other methods, it is well within the ability of a person skilled in the art to adjust the dose to achieve maximum efficacy in humans.

[0106] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent sufficient to ameliorate a disorder as described above. For example, for a given parameter, a therapeutically effective amount may exhibit an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy may also be expressed as a "-fold" increase or decrease. For example, a therapeutically effective amount may have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or greater effect relative to a control.

[0107] Dosage can vary depending on the patient's needs and the compound being utilized. In the context of the present disclosure, the dosage administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of a physician. Generally, treatment is initiated with a dosage lower than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. Dosage amount and interval can be individually adjusted to provide an administered compound level effective for the particular clinical indication being treated. This provides a treatment regimen commensurate with the severity of the individual condition.

[0108] As used herein, the term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intranasal administration, or subcutaneous administration, or implantation of a sustained-release device, e.g., a mini-osmotic pump, into a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like. In embodiments, administering does not include administration of active agents other than the active agent(s) described.

[0109] As used herein, "cell" refers to a cell that has sufficient metabolic or other functions to store or replicate genomic DNA. Cells can be identified by methods well known in the art, including, for example, the presence of an intact membrane, staining with certain dyes, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable offspring. Cells can include prokaryotic and eukaryotic cells. Prokaryotic cells include, but are not limited to, bacteria. Eukaryotic cells include, but are not limited to, yeast cells and cells from animals and plants, such as mammals, insects (e.g., Spodoptera), and human cells. Cells can be useful if they are naturally non-adherent or have been treated to prevent them from adhering to surfaces, for example, by trypsinization.

[0110] compound Embodiment 1 In one aspect, provided herein are compounds that can provide complete neuroprotection and protection of non-neuronal cell types, as well as maintaining NAD levels. The compounds can be highly potent in a) preventing neuronal cell and / or cell death and b) preventing TPrP-induced NAD depletion, as determined by neuroprotection assays, when used at doses ranging from low nanomolar to low micromolar levels.

[0111] In one embodiment, the structure of formula (I):

[0112] [ka]

[0113] or a pharmaceutically acceptable salt or isomer thereof (In the formula, Each R A , R B , R C and R D are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl; R A, R B , R C and R D two of which are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is hydrogen, D, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -CN, -OR 3F , -SR 3F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, each X 1 , X 2 and X 3 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F and R 3F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl is provided.

[0114] In embodiments, R A and R B are linked to form a substituted or unsubstituted C5-C6 cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. A and R B are linked to form a substituted or unsubstituted C5-C6 cycloalkyl. A and R B are linked to form a substituted or unsubstituted C5 cycloalkyl. In an embodiment, R A and R B are linked to form a substituted or unsubstituted C6 cycloalkyl. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. A and R B are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, R A and R B are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl. In embodiments, R A and R Bare linked to form a substituted or unsubstituted 5-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted phenyl. In embodiments, R A and R B are linked to form a substituted or unsubstituted 5-6 membered heteroaryl. A and R B are linked to form a substituted or unsubstituted 5-membered heteroaryl. In embodiments, R A and R B are linked to form a substituted or unsubstituted 6-membered heteroaryl. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5-6 membered heteroaryl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5-membered heteroaryl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 6-membered heteroaryl containing N, O, or S.

[0115] In embodiments, R B and R C are linked to form a substituted or unsubstituted C5-C6 cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. B and R C are linked to form a substituted or unsubstituted C5-C6 cycloalkyl. B and R Care linked to form a substituted or unsubstituted C5 cycloalkyl. In an embodiment, R B and R C are linked to form a substituted or unsubstituted C6 cycloalkyl. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. B and R C are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 5-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted phenyl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 5-6 membered heteroaryl. B and R C are linked to form a substituted or unsubstituted 5-membered heteroaryl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 6-membered heteroaryl. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5-6 membered heteroaryl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5-membered heteroaryl containing N, O, or S. In an embodiment, R Band R C are linked to form a substituted or unsubstituted 6-membered heteroaryl containing N, O, or S.

[0116] In embodiments, R C and R D are linked to form a substituted or unsubstituted C5-C6 cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. C and R D are linked to form a substituted or unsubstituted C5-C6 cycloalkyl. C and R D are linked to form a substituted or unsubstituted C5 cycloalkyl. In an embodiment, R C and R D are linked to form a substituted or unsubstituted C6 cycloalkyl. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. C and R D are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, R C and R D are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl. In embodiments, R C and R D are linked to form a substituted or unsubstituted 5-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted phenyl. In embodiments, R C and R Dare linked to form a substituted or unsubstituted 5-6 membered heteroaryl. C and R D are linked to form a substituted or unsubstituted 5-membered heteroaryl. In embodiments, R C and R D are linked to form a substituted or unsubstituted 6-membered heteroaryl. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5-6 membered heteroaryl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5-membered heteroaryl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 6-membered heteroaryl containing N, O, or S.

[0117] In embodiments, the compound has the structure of formula (Ia), (Ib), or (Ic):

[0118] [ka]

[0119] It has.

[0120] In formula (Ia), (Ib) or (Ic), each W, X, Y, and Z is independently =N- or -CH=; Each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 5 are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -OCX 5 3. -OCH2X 5 , -OCHX 5 2, -CN, -OR 5F , -SR 5F , -C(O)OR 5F , -C(O)NHR 5F , -C(O)N(R 5F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 2, m is an integer from 0 to 4, each X 4 and X 5 are independently -F, -Br, -Cl, or -I; Each R 4F and R 5F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0121] In an embodiment, W, X, Y and Z are -CH=.

[0122] In embodiments, the compound has the structure (Ia-1), (Ib-1), or (Ic-1):

[0123] [ka]

[0124] R 1 , R 2 , R3 , R 4 , R 5 , k, m, and n are as defined above.

[0125] In embodiments, the compound has the structure of formula (Id), (Ie), (If), (I-d'), (I-e'), or (I-f'):

[0126] [ka]

[0127] R 1 , R 2 , R 3 , R 4 , R 5 , k, m, and n are as defined above.

[0128] In formula (Id), (Ie), (If), (I-d'), (I-e') or (I-f'), X' is -O-, -NH-, or -CH2-; Y' is -NH= or -CH=; k is an integer from 0 to 2, m is an integer from 0 to 3, Each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen, halogen, -CX 53. -CHX 5 2. -CH2X 5 , -OCX 5 3. -OCH2X 5 , -OCHX 5 2, -CN, -OR 5F , -SR 5F , -C(O)OR 5F , -C(O)NHR 5F , -C(O)N(R 5F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 2, m is an integer from 0 to 3, each X 4 and X 5 are independently -F, -Br, -Cl, or -I; Each R 4F and R 5F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0129] In embodiments, R 2 is H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 2 3, OR 2F and R 3 is H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 3 3, OR 3F In embodiments, each R 2F and R 3F is independently hydrogen or unsubstituted C1-C4 alkyl. 2F and R 3F are independently hydrogen or unsubstituted methyl. 2F is hydrogen or unsubstituted methyl. In an embodiment, R 3F is hydrogen or unsubstituted methyl.

[0130] In embodiments, R2 is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 2 3, OR 2F In an embodiment, R 2 is —H. In an embodiment, R 2 is -D. In an embodiment, R 2 is -F. In an embodiment, R 2 is —Cl. In an embodiment, R 2 is -Br. In an embodiment, R 2 is -I. In an embodiment, R 2 is a substituted C1-C4 alkyl. In an embodiment, R 2 is unsubstituted C1-C4 alkyl. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl. In an embodiment, R 2 is —CN. In an embodiment, R 2 is —CF. In an embodiment, R 2 is —OH. In an embodiment, R 2 is -OCH3.

[0131] In embodiments, R 3 is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 3 3, OR 3F In an embodiment, R 3 is —H. In an embodiment, R 3 is -D. In an embodiment, R 3 is -F. In an embodiment, R 3 is —Cl. In an embodiment, R 3 is -Br. In an embodiment, R 3 is -I. In an embodiment, R 3 is a substituted C1-C4 alkyl. In an embodiment, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is methyl. In an embodiment, R 3is ethyl. In an embodiment, R 3 is —CN. In an embodiment, R 3 is —CF. In an embodiment, R 3 is —OH. In an embodiment, R 3 is -OCH3.

[0132] In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2. In an embodiment, m is 0. In an embodiment, m is 1. In an embodiment, m is 2.

[0133] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4F In an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl.4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 -C(O)OR 4F In an embodiment, R 4 -C(O)NHR 4F In an embodiment, R 4 is -C(O)N(R 4F )2. In an embodiment, R 4 is -C(O)NH2.

[0134] In embodiments, R 4F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl. 4F is hydrogen. In embodiments, R 4F is substituted or unsubstituted alkyl. In embodiments, R 4F is a substituted or unsubstituted C1-C4 alkyl. 4F is unsubstituted C1-C4 alkyl. In embodiments, R 4F is methyl. In an embodiment, R 4F is ethyl. In an embodiment, R 4F is a substituted or unsubstituted 2-6 membered heteroalkyl. 4F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 6-membered heteroalkyl.

[0135] In embodiments, each R 5 are independently halogen, -CX 5 3. -OCX 5 3, -CN, -OR 5F, -C(O)OR 5F , -C(O)NHR 5F , -C(O)N(R 5F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 5 is halogen. In embodiments, R 5 is -F. In an embodiment, R 5 is —Cl. In an embodiment, R 5 is -Br. In an embodiment, R 5 is -I. In an embodiment, R 5 Ha-CX 5 3. In an embodiment, R 5 is —CF. In an embodiment, R 5 -OCX 5 3. In an embodiment, R 5 is -OCF3. In an embodiment, R 5 is —CN. In an embodiment, R 5 HA-OR 5F In an embodiment, R 5 is —OH. In an embodiment, R 5 is —OCH. In an embodiment, R 5 is a substituted or unsubstituted C1-C5 alkyl. 5 is unsubstituted C1-C5 alkyl. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 -C(O)OR 5F In an embodiment, R 5 -C(O)NHR 5F In an embodiment, R 5 is -C(O)N(R 5F )2. In an embodiment, R 5 is -C(O)NH2.

[0136] In embodiments, R 5F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl.5F is hydrogen. In embodiments, R 5F is substituted or unsubstituted alkyl. In embodiments, R 5F is a substituted or unsubstituted C1-C4 alkyl. 5F is unsubstituted C1-C4 alkyl. In embodiments, R 5F is methyl. In an embodiment, R 5F is ethyl. In an embodiment, R 5F is a substituted or unsubstituted 2-6 membered heteroalkyl. 5F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 6-membered heteroalkyl.

[0137] In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2.

[0138] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In embodiments, each R 1F is independently hydrogen or unsubstituted C1-C4 alkyl. 1F are independently hydrogen or unsubstituted methyl.

[0139] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 1 is -F. In an embodiment, R 1 is —Cl. In an embodiment, R 1is -Br. In an embodiment, R 1 is -I. In an embodiment, R 1 is a substituted C1-C4 alkyl. In an embodiment, R 1 is unsubstituted C1-C4 alkyl. In embodiments, R 1 is methyl. In an embodiment, R 1 is ethyl. In an embodiment, R 1 is —CN. In an embodiment, R 1 is —CF. In an embodiment, R 1 is —OH. In an embodiment, R 1 is -OCH3.

[0140] In one embodiment, the structure of formula (X)

[0141] [ka]

[0142] or a pharmaceutically acceptable salt or isomer thereof (In the formula, R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, R 20 Ha-L 1 -R 21 and L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R 21 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10 and R 20 are optionally linked to form a substituted or unsubstituted bicyclic heterocycloalkyl; R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is hydrogen, D, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -OR 3F , -SR 3F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 30 are independently halogen, -CX 30 3. -CHX 30 2. -CH2X 30 , -OCX 30 3. -OCH2X 30 , -OCHX 30 2, -CN, -OR 30F , -SR 30F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, z is an integer from 0 to 4, each X 1 , X 2 , X 3 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F , R 3F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; However, R 10 is hydrogen and L 1 If is a bond, R 21 is not unsubstituted phenyl or phenyl substituted with halogen, —C(O)CH 3 , —S(O) 2 —NH 2 , or substituted or unsubstituted alkyl, and L 1 is methylene and R 2 and R 3 is hydrogen, R 21 is not unsubstituted tetrahydro-pyranyl) is provided.

[0143] In embodiments, R 10 is hydrogen and L 1 is a bond, and R 21 is not unsubstituted phenyl. In embodiments, R 10 is hydrogen and L 1 is a bond, and R 21 is not a phenyl substituted with a halogen. 10 is hydrogen and L 1 is a bond, and R 21 is not phenyl substituted with -C(O)CH. 10 is hydrogen and L 1 is a bond, and R 21is not phenyl substituted with -S(O)-NH. 10 is hydrogen and L 1 is a bond, and R 21 is not a phenyl substituted with substituted or unsubstituted alkyl.

[0144] In an embodiment, L 1 is a bond, substituted or unsubstituted C1-C4 alkylene, or substituted or unsubstituted 2-4 membered heteroalkylene. 1 is a bond. In embodiments, L 1 is a substituted or unsubstituted C1-C4 alkylene. 1 is unsubstituted C1-C4 alkylene. 1 is unsubstituted methylene. 1 is a substituted methylene. 1 is a substituted or unsubstituted 2-4 membered heteroalkylene. 1 is unsubstituted 2-4 membered heteroalkylene. 1 is —O—CH—. In an embodiment, L 1 is -O-CH2-CH2-.

[0145] In embodiments, R 21 is substituted or unsubstituted

[0146] [ka]

[0147] is.

[0148] In embodiments, R 21 teeth,

[0149] [ka]

[0150] and Each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , -S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 5, X 4 are independently -F, -Br, -Cl, or -I; Each R 4F is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0151] In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2. In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2.

[0152] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)R 4F , -C(O)OR 4F , -S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F)2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4F In an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 is —C(O)CH. In embodiments, R 4 teeth

[0153] [ka]

[0154] In an embodiment, R 4 is a 4- to 6-membered heterocycloalkyl.

[0155] In embodiments, n is 0 and R 2 and R 3 is hydrogen and R 21 teeth

[0156] [ka]

[0157] is.

[0158] In embodiments, n is 0 and R 2 and R 3 In an embodiment, n is 0 and at least one of R 2 and R 3 In an embodiment, n is 0 and at least one of R 2 and R 3 At least one of R is methyl; 4 is -C(O)CH3.

[0159] In an embodiment, L 1 is methylene and R 2 and R 3 is hydrogen and R 10 is hydrogen, R 21 is not unsubstituted tetrahydro-pyranyl.

[0160] In embodiments, R 10 and R 20 are linked to form substituted or unsubstituted

[0161] [ka]

[0162] Form.

[0163] In embodiments, the compound has the structure of formula (XI):

[0164] [ka]

[0165] or a pharmaceutically acceptable salt thereof or an isomer thereof (In the formula, Each R A , R B , R C and R D are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R A , R B , R C and R D two of which are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl L 1 , R 1 , R 2 , R 3 , R 30 , n and z are as defined in formula (X).

[0166] In embodiments, R A and R B are linked to form a substituted or unsubstituted C5-C6 cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. A and R B are linked to form a substituted or unsubstituted C5-C6 cycloalkyl. A and R B are linked to form a substituted or unsubstituted C5 cycloalkyl. In an embodiment, R A and R B are linked to form a substituted or unsubstituted C6 cycloalkyl. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. A and R B are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, R A and R B are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl. In embodiments, R A and RB are linked to form a substituted or unsubstituted 5-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted phenyl. In embodiments, R A and R B are linked to form a substituted or unsubstituted 5-6 membered heteroaryl. A and R B are linked to form a substituted or unsubstituted 5-membered heteroaryl. In embodiments, R A and R B are linked to form a substituted or unsubstituted 6-membered heteroaryl. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5-6 membered heteroaryl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 5-membered heteroaryl containing N, O, or S. In an embodiment, R A and R B are linked to form a substituted or unsubstituted 6-membered heteroaryl containing N, O, or S.

[0167] In embodiments, R B and R C are linked to form a substituted or unsubstituted C5-C6 cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. B and R C are linked to form a substituted or unsubstituted C5-C6 cycloalkyl. B and RC are linked to form a substituted or unsubstituted C5 cycloalkyl. In an embodiment, R B and R C are linked to form a substituted or unsubstituted C6 cycloalkyl. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. B and R C are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 5-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted phenyl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 5-6 membered heteroaryl. B and R C are linked to form a substituted or unsubstituted 5-membered heteroaryl. In embodiments, R B and R C are linked to form a substituted or unsubstituted 6-membered heteroaryl. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5-6 membered heteroaryl containing N, O, or S. In an embodiment, R B and R C are linked to form a substituted or unsubstituted 5-membered heteroaryl containing N, O, or S. In an embodiment, RB and R C are linked to form a substituted or unsubstituted 6-membered heteroaryl containing N, O, or S.

[0168] In embodiments, R C and R D are linked to form a substituted or unsubstituted C5-C6 cycloalkyl, a substituted or unsubstituted 5- to 6-membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5- to 6-membered heteroaryl. C and R D are linked to form a substituted or unsubstituted C5-C6 cycloalkyl. C and R D are linked to form a substituted or unsubstituted C5 cycloalkyl. In an embodiment, R C and R D are linked to form a substituted or unsubstituted C6 cycloalkyl. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5- to 6-membered heterocycloalkyl. C and R D are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl. In embodiments, R C and R D are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl. In embodiments, R C and R D are linked to form a substituted or unsubstituted 5-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted phenyl. In embodiments, R C and R Dare linked to form a substituted or unsubstituted 5-6 membered heteroaryl. C and R D are linked to form a substituted or unsubstituted 5-membered heteroaryl. In embodiments, R C and R D are linked to form a substituted or unsubstituted 6-membered heteroaryl. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5-6 membered heteroaryl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 5-membered heteroaryl containing N, O, or S. In an embodiment, R C and R D are linked to form a substituted or unsubstituted 6-membered heteroaryl containing N, O, or S.

[0169] In embodiments, the compound has the structure of formula (XI-a), (XI-b) or (XI-c)

[0170] [ka]

[0171] or a pharmaceutically acceptable salt thereof or an isomer thereof (In the formula, each W, X, Y, and Z is independently =N- or -CH=; Each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 5 are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -OCX 5 3. -OCH2X 5 , -OCHX 5 2, -CN, -OR 5F , -SR 5F , -C(O)OR 5F , -S(O)2R 5F , -C(O)NHR 5F , -C(O)N(R 5F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 2, m is an integer from 0 to 4, each X 4 and X 5 are independently -F, -Br, -Cl, or -I; Each R 4F and R 5F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl R 1 , R 2 , R 3 , R 30 and n are as described in formula (X).

[0172] In embodiments, the compound has the structure (XI-a-1), (XI-ba), or (XI-c-1):

[0173] [ka]

[0174] or a pharmaceutically acceptable salt thereof or an isomer thereof. 1 , R 2 , R 3 , R 4 , R 5 , R 30 , n, k and m are as described in (XI-a), (XI-b) or (XI-c).

[0175] In embodiments, the compound has the structure of formula (XI-d), (XI-e), (XI-f), (XI-d'), (XI-e'), or (XI-f'):

[0176] [ka]

[0177] or a pharmaceutically acceptable salt thereof or an isomer thereof (In the formula, X' is -O-, -NH-, or -CH2-; Y' is -NH= or -CH=; k is an integer from 0 to 2, m is an integer from 0 to 3, Each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 5are independently halogen, -CX 5 3. -CHX 5 2. -CH2X 5 , -OCX 5 3. -OCH2X 5 , -OCHX 5 2, -CN, -OR 5F , -SR 5F , -C(O)OR 5F , -S(O)2R 5F , -C(O)NHR 5F , -C(O)N(R 5F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each X 4 and X 5 are independently -F, -Br, -Cl, or -I; Each R 4F and R 5F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl R 1 , R 2 , R 3 , R 4 , R 5 , R 30 , n, k and m are as described in (XI-a), (XI-b) or (XI-c).

[0178] In embodiments, R 2 is H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CX 2 3, OR 2F and R 3 is H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CX 3 3, OR 3F In embodiments, each R 2F and R 3F is independently hydrogen or unsubstituted C1-C4 alkyl. 2F and R 3Fare independently hydrogen or unsubstituted methyl. 2F is hydrogen or unsubstituted methyl. In an embodiment, R 3F is hydrogen or unsubstituted methyl.

[0179] In embodiments, R 2 is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CX 2 3, OR 2F In an embodiment, R 2 is —H. In an embodiment, R 2 is -D. In an embodiment, R 2 is -F. In an embodiment, R 2 is —Cl. In an embodiment, R 2 is -Br. In an embodiment, R 2 is -I. In an embodiment, R 2 is a substituted C1-C4 alkyl. In an embodiment, R 2 is unsubstituted C1-C4 alkyl. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl. In an embodiment, R 2 is —CF. In an embodiment, R 2 is —OH. In an embodiment, R 2 is -OCH3.

[0180] In embodiments, R 3 is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CX 3 3 OR 3F In an embodiment, R 3 is —H. In an embodiment, R 3 is -D. In an embodiment, R 3 is -F. In an embodiment, R 3 is —Cl. In an embodiment, R 3 is -Br. In an embodiment, R 3 is -I. In an embodiment, R 3is a substituted C1-C4 alkyl. In an embodiment, R 3 is unsubstituted C1-C4 alkyl. In embodiments, R 3 is methyl. In an embodiment, R 3 is ethyl. In an embodiment, R 3 is —CF. In an embodiment, R 3 is —OH. In an embodiment, R 3 is -OCH3.

[0181] In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2. In an embodiment, m is 0. In an embodiment, m is 1. In an embodiment, m is 2.

[0182] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)R 4F , -C(O)OR 4F , -S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4FIn an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 -C(O)OR 4F In an embodiment, R 4 -S(O)2R 4F In an embodiment, R 4 -C(O)NHR 4F In an embodiment, R 4 is -C(O)N(R 4F )2. In an embodiment, R 4 is -C(O)NH2.

[0183] In embodiments, R 4F are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4F is hydrogen. In embodiments, R 4F is substituted or unsubstituted alkyl. In embodiments, R 4F is a substituted or unsubstituted C1-C4 alkyl. 4F is unsubstituted C1-C4 alkyl. In embodiments, R 4F is methyl. In an embodiment, R 4F is ethyl. In an embodiment, R 4F is a substituted or unsubstituted 2-6 membered heteroalkyl. 4F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4Fis a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 4F is substituted or unsubstituted cycloalkyl. In embodiments, R 4F is a substituted or unsubstituted C3-C6 cycloalkyl. 4F is a substituted or unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is an unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is a substituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is substituted or unsubstituted phenyl. In embodiments, R 4F is unsubstituted phenyl. In embodiments, R 4F is substituted phenyl. In embodiments, R 4F is a substituted or unsubstituted 5-6 membered heteroaryl. 4F is a substituted 5-6 membered heteroaryl. In embodiments, R 4F is an unsubstituted 5- to 6-membered heteroaryl.

[0184] In embodiments, each R 5 are independently halogen, -CX 5 3. -OCX 5 3, -CN, -OR 5F , -C(O)OR 5F , -S(O)2R 5F , -C(O)NHR 5F , -C(O)N(R 5F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 5 is halogen. In embodiments, R 5 is -F. In an embodiment, R 5 is —Cl. In an embodiment, R 5 is -Br. In an embodiment, R 5is -I. In an embodiment, R 5 Ha-CX 5 3. In an embodiment, R 5 is —CF. In an embodiment, R 5 -OCX 5 3. In an embodiment, R 5 is -OCF3. In an embodiment, R 5 is —CN. In an embodiment, R 5 HA-OR 5F In an embodiment, R 5 is —OH. In an embodiment, R 5 is —OCH. In an embodiment, R 5 is a substituted or unsubstituted C1-C5 alkyl. 5 is unsubstituted C1-C5 alkyl. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 -C(O)OR 5F In an embodiment, R 5 -S(O)2R 5F In an embodiment, R 5 -C(O)NHR 5F In an embodiment, R 5 is -C(O)N(R 5F )2. In an embodiment, R 5 is -C(O)NH2.

[0185] In embodiments, R 5F are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 5F is hydrogen. In embodiments, R 5F is substituted or unsubstituted alkyl. In embodiments, R 5F is a substituted or unsubstituted C1-C4 alkyl. 5Fis unsubstituted C1-C4 alkyl. In embodiments, R 5F is methyl. In an embodiment, R 5F is ethyl. In an embodiment, R 5F is a substituted or unsubstituted 2-6 membered heteroalkyl. 5F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 5F is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 5F is substituted or unsubstituted cycloalkyl. In embodiments, R 5F is a substituted or unsubstituted C3-C6 cycloalkyl. 5F is a substituted or unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 5F is an unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 5F is a substituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 5F is substituted or unsubstituted phenyl. In an embodiment, R 5F is unsubstituted phenyl. In embodiments, R 5F is substituted phenyl. In embodiments, R 5F is a substituted or unsubstituted 5-6 membered heteroaryl. 5F is a substituted 5-6 membered heteroaryl. In embodiments, R 5F is an unsubstituted 5-6 membered heteroaryl.

[0186] In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2.

[0187] In embodiments, R 1is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In embodiments, each R 1F is independently hydrogen or unsubstituted C1-C4 alkyl. 1F are independently hydrogen or unsubstituted methyl.

[0188] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 1 is -F. In an embodiment, R 1 is —Cl. In an embodiment, R 1 is -Br. In an embodiment, R 1 is -I. In an embodiment, R 1 is a substituted C1-C4 alkyl. In an embodiment, R 1 is unsubstituted C1-C4 alkyl. In embodiments, R 1 is methyl. In an embodiment, R 1 is ethyl. In an embodiment, R 1 is —CN. In an embodiment, R 1 is —CF. In an embodiment, R 1 is —OH. In an embodiment, R 1 is -OCH3.

[0189] In embodiments, R 30 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 30 3, OR 30F In embodiments, each R 30F is independently hydrogen or unsubstituted C1-C4 alkyl. 30F are independently hydrogen or unsubstituted methyl.

[0190] In embodiments, R 30is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 30 is -F. In an embodiment, R 30 is —Cl. In an embodiment, R 30 is -Br. In an embodiment, R 30 is -I. In an embodiment, R 30 is a substituted C1-C4 alkyl. In an embodiment, R 30 is unsubstituted C1-C4 alkyl. In embodiments, R 30 is methyl. In an embodiment, R 30 is ethyl. In an embodiment, R 30 is —CN. In an embodiment, R 30 is —CF. In an embodiment, R 30 is —OH. In an embodiment, R 30 is -OCH3.

[0191] Compounds of formula (X) and (XI) are shown in Table 1 below.

[0192] [Table 1]

[0193] In one embodiment, the compound has the structure of formula (II)

[0194] [ka]

[0195] or a pharmaceutically acceptable salt thereof or an isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -CN, -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is hydrogen, D, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -CN, -OR 3F , -SR 3F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 6 and R 7 are linked together to form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocycloalkyl; R8 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, each X 1 , X 2 and X 3 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F and R 3F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl It has.

[0196] In embodiments, R 8 teeth,

[0197] [ka]

[0198] is.

[0199] In embodiments, each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4 is independently -F, -Br, -Cl, or -I, and each R 4Fis independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In an embodiment, k is an integer from 0 to 5.

[0200] In an embodiment, k is an integer of 0 to 5. In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2.

[0201] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4F In an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4is ethyl. In an embodiment, R 4 -C(O)OR 4F In an embodiment, R 4 -C(O)NHR 4F In an embodiment, R 4 is -C(O)N(R 4F )2. In an embodiment, R 4 is -C(O)NH2.

[0202] In embodiments, R 4F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl. 4F is hydrogen. In embodiments, R 4F is substituted or unsubstituted alkyl. In embodiments, R 4F is a substituted or unsubstituted C1-C4 alkyl. 4F is unsubstituted C1-C4 alkyl. In embodiments, R 4F is methyl. In an embodiment, R 4F is ethyl. In an embodiment, R 4F is a substituted or unsubstituted 2-6 membered heteroalkyl. 4F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 6-membered heteroalkyl.

[0203] In embodiments, R 6 and R 7 are linked together to form a substituted or unsubstituted C3-C6 cycloalkyl, or a substituted or unsubstituted 4-6 membered heterocycloalkyl. 6 and R 7are linked together to form a substituted or unsubstituted C3-C6 cycloalkyl. In an embodiment, R 6 and R 7 are linked together to form a substituted or unsubstituted cyclopropyl. 6 and R 7 are linked together to form a substituted or unsubstituted cyclobutyl. 6 and R 7 are linked together to form a substituted or unsubstituted cyclopentyl. 6 and R 7 are linked together to form a substituted or unsubstituted cyclohexyl. 6 and R 7 are linked together to form a substituted or unsubstituted 4- to 6-membered heterocycloalkyl. 6 and R 7 are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl. In embodiments, R 6 and R 7 are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl. In an embodiment, R 6 and R 7 are linked together to form a substituted or unsubstituted 6-membered heterocycloalkyl.

[0204] In embodiments, R 6 and R 7 are linked together to form a substituted or unsubstituted 4-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R 6 and R 7 are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 6 and R 7 are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 6 and R 7 are linked together to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 6and R 7 are linked together to form a substituted or unsubstituted 4-6 membered heterocycloalkyl containing O. In an embodiment, R 6 and R 7 are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl containing O. In an embodiment, R 6 and R 7 are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl containing O. In an embodiment, R 6 and R 7 are linked together to form an O-containing substituted or unsubstituted 6-membered heterocycloalkyl.

[0205] In embodiments, the compound has the structure of formula (II-a) or (II-a′):

[0206] [ka]

[0207] R 1 , L 1 , R 4 , n and k are as described above.

[0208] In an embodiment, L 1 is a bond or C1-C4 alkylene.

[0209] In embodiments, each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X 4 is independently -F, -Br, -Cl, or -I, and each R 4F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0210] In embodiments, R 2 is hydrogen. In embodiments, R 3 is hydrogen.

[0211] In an embodiment, k is an integer of 0 to 5, and in an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2.

[0212] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4HA-OR 4F In an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 -C(O)OR 4F In an embodiment, R 4 -C(O)NHR 4F In an embodiment, R 4 is -C(O)N(R 4F )2. In an embodiment, R 4 is -C(O)NH2.

[0213] In embodiments, R 4F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl. 4F is hydrogen. In embodiments, R 4F is substituted or unsubstituted alkyl. In embodiments, R 4F is a substituted or unsubstituted C1-C4 alkyl. 4F is unsubstituted C1-C4 alkyl. In embodiments, R 4F is methyl. In an embodiment, R 4F is ethyl. In an embodiment, R 4F is a substituted or unsubstituted 2-6 membered heteroalkyl. 4F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4Fis a substituted or unsubstituted 6-membered heteroalkyl.

[0214] In one embodiment, the structure of formula (XII)

[0215] [ka]

[0216] or a pharmaceutically acceptable salt or isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3. -CHX 2 2. -CH2X 2 , -OCX 2 3. -OCH2X 2 , -OCHX 2 2, -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, D, halogen, -CX 3 3. -CHX 3 2. -CH2X 3 , -OCX 3 3. -OCH2X 3 , -OCHX 3 2, -OR 3F , -SR 3F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 and R 3 are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; Each R 6 and R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, or R 6 and R 7 are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 8 is a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R 30 are independently halogen, -CX 30 3. -CHX 30 2. -CH2X 30 , -OCX 30 3. -OCH2X 30 , -OCHX 30 2, -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, z is an integer from 0 to 4, each X 1 , X 2 , X 3 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F , R 3F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; However, n is 0 and L 1 is a bond and R 6 and R 7 is hydrogen, R 8 is not unsubstituted tetrahydropyranyl) is provided.

[0217] In embodiments, R 2 or R 3 At least one of R is not hydrogen. 2 is not hydrogen. In embodiments, R 3 is not hydrogen. In embodiments, R 1 is not hydrogen, but R 2 is not hydrogen. In embodiments, R 1 is not hydrogen, but R 3 is not hydrogen.

[0218] In embodiments, R 8 is substituted or unsubstituted

[0219] [ka]

[0220] is.

[0221] In embodiments, R 8 teeth,

[0222] [ka]

[0223] and Each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 5, X 4 are independently -F, -Br, -Cl, or -I; Each R 4F is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0224] In embodiments, the compound has the structure of formula (XII-a):

[0225] [ka]

[0226] (In the formula, W 1 is —O— or CH2—, L 1 is a bond or C1-C4 alkylene, Each R 4 are independently halogen, -CX 4 3. -CHX4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 5, X 4 are independently -F, -Br, -Cl, or -I; Each R 4F are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. L 1 , R 1 , R 30 , n and z are as described in (XII).

[0227] In embodiments, R 8 teeth

[0228] [ka]

[0229] In an embodiment, R 8 teeth

[0230] [ka]

[0231] In an embodiment, R 8 teeth

[0232] [ka]

[0233] In an embodiment, R 8 teeth

[0234] [ka]

[0235] is.

[0236] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)R 4F , -C(O)OR 4F , -S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4F In an embodiment, R 4is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 HA-C(O)R 4F In an embodiment, R 4 -C(O)OR 4F In an embodiment, R 4 -S(O)2R 4F In an embodiment, R 4 -C(O)NHR 4F In an embodiment, R 4 is -C(O)N(R 4F )2. In an embodiment, R 4 is -C(O)NH2.

[0237] In embodiments, R 4F are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4F is hydrogen. In embodiments, R 4F is substituted or unsubstituted alkyl. In embodiments, R 4F is a substituted or unsubstituted C1-C4 alkyl. 4F is unsubstituted C1-C4 alkyl. In embodiments, R 4F is methyl. In an embodiment, R 4F is ethyl. In an embodiment, R 4F is a substituted or unsubstituted 2-6 membered heteroalkyl. 4F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R4F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 4F is substituted or unsubstituted cycloalkyl. In embodiments, R 4F is a substituted or unsubstituted C3-C6 cycloalkyl. 4F is a substituted or unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is an unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is a substituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is substituted or unsubstituted phenyl. In embodiments, R 4F is unsubstituted phenyl. In embodiments, R 4F is substituted phenyl. In embodiments, R 4F is a substituted or unsubstituted 5-6 membered heteroaryl. 4F is a substituted 5-6 membered heteroaryl. 4F is an unsubstituted 5- to 6-membered heteroaryl.

[0238] In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2.

[0239] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In embodiments, each R 1F is independently hydrogen or unsubstituted C1-C4 alkyl. 1F are independently hydrogen or unsubstituted methyl.

[0240] In embodiments, R 1is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 1 is -F. In an embodiment, R 1 is —Cl. In an embodiment, R 1 is -Br. In an embodiment, R 1 is -I. In an embodiment, R 1 is a substituted C1-C4 alkyl. In an embodiment, R 1 is unsubstituted C1-C4 alkyl. In embodiments, R 1 is methyl. In an embodiment, R 1 is ethyl. In an embodiment, R 1 is —CN. In an embodiment, R 1 is —CF. In an embodiment, R 1 is —OH. In an embodiment, R 1 is -OCH3.

[0241] In embodiments, R 30 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 30 3, OR 30F In embodiments, each R 30F is independently hydrogen or unsubstituted C1-C4 alkyl. 30F are independently hydrogen or unsubstituted methyl.

[0242] In embodiments, R 30 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 30 is -F. In an embodiment, R 30 is —Cl. In an embodiment, R 30 is -Br. In an embodiment, R 30 is -I. In an embodiment, R 30 is a substituted C1-C4 alkyl. In an embodiment, R 30is unsubstituted C1-C4 alkyl. In embodiments, R 30 is methyl. In an embodiment, R 30 is ethyl. In an embodiment, R 30 is —CN. In an embodiment, R 30 is —CF. In an embodiment, R 30 is —OH. In an embodiment, R 30 is -OCH3.

[0243] In an embodiment, n is not 0. In an embodiment, n is 0. In an embodiment, R 1 is a substituted or unsubstituted C1-C4 alkyl, and R 2 is a substituted or unsubstituted C1-C4 alkyl. 1 is methyl and R 2 is methyl. In an embodiment, R 1 is a substituted or unsubstituted C1-C4 alkyl, and R 3 is a substituted or unsubstituted C1-C4 alkyl. 1 is methyl and R 3 is methyl.

[0244] Compounds of formula (XII) are shown in Table 2 below.

[0245] [Table 2]

[0246] In one embodiment, the compound has the structure of formula (III):

[0247] [ka]

[0248] or a pharmaceutically acceptable salt thereof or an isomer thereof (In the formula, L 1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2 -C(=O)-, -C(=CR 9A R 9B )-, -CR 10A R 10B - or -C(=NR 11 )- and R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; Each R 9A and R 9B are independently hydrogen, -CX 9 3. -CHX 9 2. -CH2X 9 , -OCX 9 3. -OCH2X 9 , -OCHX 9 2, -CN, -OR 9F , -SR 9F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 10A and R 10B are independently hydrogen, D, halogen, -CX 10 3. -CHX10 2. -CH2X 10 , -OCX 10 3. -OCH2X 10 , -OCHX 10 2, -CN, -OR 10F , -SR 10F , -C(O)OR 10F , -C(O)NHR 10F , -C(O)N(R 10F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10A and R 10B are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 11 -R 11F , -OR 11F , -S(O2)-R 11F , or -C(O)-R 11F and n is an integer from 0 to 4, each X 1 , X 8 , X 9 and X 10 are independently -F, -Br, -Cl, or -I; Each R 1F , R 8F , R 9F and R 10F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl) It has.

[0249] In an embodiment, L 2 is -C(=O)-.

[0250] In embodiments, the compound has the structure of formula (III-a)

[0251] [ka]

[0252] or a pharmaceutically acceptable salt thereof or an isomer thereof. 1 , L 1 , R 8 and n are as described above.

[0253] In an embodiment, L 2 is -C(=CR 9A R 9B )-.

[0254] In embodiments, the compound has the structure of formula (III-b)

[0255] [ka]

[0256] or a pharmaceutically acceptable salt thereof or an isomer thereof. 1 , L 1 , R 8 , R 9A , R 9B and n are as described above.

[0257] In an embodiment, L 2 -CR 10A R 10B -It is.

[0258] In embodiments, the compound has the structure of formula (III-c)

[0259] [ka]

[0260] or a pharmaceutically acceptable salt thereof or an isomer thereof. 1 , L 1 , R 8 , R 10A , R10B and n are as described above.

[0261] In an embodiment, n is 1 to 4. In an embodiment, n is not 0.

[0262] In embodiments, R 10A and R 10B are linked to form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 4-6 membered heterocycloalkyl. 10A and R 10B are linked to form a substituted or unsubstituted C3-C6 cycloalkyl. 10A and R 10B are linked to form a substituted or unsubstituted C3-C6 cycloalkyl.

[0263] In embodiments, R 10A and R 10B are linked together to form a substituted or unsubstituted C3-C6 cycloalkyl, or a substituted or unsubstituted 4-6 membered heterocycloalkyl. 10A and R 10B are linked together to form a substituted or unsubstituted C3-C6 cycloalkyl. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted cyclopropyl. 10A and R 10B are linked together to form a substituted or unsubstituted cyclobutyl. 10A and R 10B are linked together to form a substituted or unsubstituted cyclopentyl. 10A and R 10B are linked together to form a substituted or unsubstituted cyclohexyl. 10A and R 10B are linked together to form a substituted or unsubstituted 4- to 6-membered heterocycloalkyl. 10A and R 10Bare linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl. In embodiments, R 10A and R 10B are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 6-membered heterocycloalkyl.

[0264] In embodiments, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-6 membered heterocycloalkyl containing O. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl containing O. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl containing O. In an embodiment, R 10A and R 10B are linked together to form an O-containing substituted or unsubstituted 6-membered heterocycloalkyl.

[0265] In embodiments, the compound has the structure of formula (III-c-1) or (III-c-2)

[0266] [ka]

[0267] or a pharmaceutically acceptable salt thereof or an isomer thereof. 1 , L 1 , R 8 and n are as described above.

[0268] In an embodiment, n is an integer of 0 to 4. In an embodiment, n is 0. In an embodiment, n is 1. In an embodiment, n is 2.

[0269] In embodiments, each R 12 are independently halogen, -CX 12 3. -CHX 12 2. -CH2X 12 , -OCX 12 3. -OCH2X 12 , -OCHX 12 2, -CN, -OR 12F , -SR 12F , -C(O)OR 12F , -C(O)NHR 12F , -C(O)N(R 12F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and X 12 are independently -F, -Br, -Cl, or -I, and R 12F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

[0270] In an embodiment, p is an integer of 0 to 4. In an embodiment, p is 0. In an embodiment, p is 1. In an embodiment, p is 2.

[0271] In embodiments, each R 12 are independently halogen, -CX 12 3. -OCX 123, -CN, -OR 12F , -C(O)OR 12F , -C(O)NHR 12F , -C(O)N(R 12F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 12 is halogen. In embodiments, R 12 is -F. In an embodiment, R 12 is —Cl. In an embodiment, R 12 is -Br. In an embodiment, R 12 is -I. In an embodiment, R 12 Ha-CX 12 3. In an embodiment, R 12 is —CF. In an embodiment, R 12 -OCX 12 3. In an embodiment, R 12 is -OCF3. In an embodiment, R 12 is —CN. In an embodiment, R 12 HA-OR 12F In an embodiment, R 12 is —OH. In an embodiment, R 12 is —OCH. In an embodiment, R 12 is substituted or unsubstituted C1-C 12 In embodiments, R 12 is unsubstituted C1~C 12 In embodiments, R 12 is methyl. In an embodiment, R 12 is ethyl. In an embodiment, R 12 -C(O)OR 12F In an embodiment, R 12 -C(O)NHR 12F In an embodiment, R 12 is -C(O)N(R 12F )2. In an embodiment, R 12 is —C(O)NH. In an embodiment, R 12 is substituted or unsubstituted phenyl. In embodiments, R 12 is unsubstituted phenyl. In each occurrence, R12 may be the same or different.

[0272] In embodiments, R 12F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl. 12F is hydrogen. In embodiments, R 12F , substituted or unsubstituted alkyl. In embodiments, R 12F is a substituted or unsubstituted C1-C4 alkyl. 12F is unsubstituted C1-C4 alkyl. In embodiments, R 12F is methyl. In an embodiment, R 12F is ethyl. In an embodiment, R 12F is a substituted or unsubstituted 2-6 membered heteroalkyl. 12F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 6-membered heteroalkyl.

[0273] In embodiments, the compound has the structure of formula (III-c-3), (III-c-4), or (III-c-5):

[0274] [ka]

[0275] or a pharmaceutically acceptable salt thereof or an isomer thereof. 1 , R 10A , R 10B and n are as described above.

[0276] In embodiments, R 10Ais H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10 3, OR 10F and R 10B is H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10 3, OR 10F In embodiments, each R 10F is independently hydrogen or unsubstituted C1-C4 alkyl. 10F are independently hydrogen or unsubstituted methyl. 10F is hydrogen or unsubstituted methyl.

[0277] In embodiments, R 10A is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10 3, OR 10F In an embodiment, R 10A is —H. In an embodiment, R 10A is -D. In an embodiment, R 10A is -F. In an embodiment, R 10A is —Cl. In an embodiment, R 10A is -Br. In an embodiment, R 10A is -I. In an embodiment, R 10A is a substituted C1-C4 alkyl. In an embodiment, R 10A is unsubstituted C1-C4 alkyl. In embodiments, R 10A is methyl. In an embodiment, R 10A is ethyl. In an embodiment, R 10A is —CN. In an embodiment, R 10A is —CF. In an embodiment, R 10A is —OH. In an embodiment, R 10A is -OCH3.

[0278] In embodiments, R 10B is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10B10B OR 10BF In an embodiment, R 10B is —H. In an embodiment, R 10B is -D. In an embodiment, R 10B is -F. In an embodiment, R 10B is —Cl. In an embodiment, R 10B is -Br. In an embodiment, R 10B is -I. In an embodiment, R 10B is a substituted C1-C4 alkyl. In an embodiment, R 10B is unsubstituted C1-C4 alkyl. In embodiments, R 10B is methyl. In an embodiment, R 10B is ethyl. In an embodiment, R 10B is —CN. In an embodiment, R 10B Ha-CF 10B In an embodiment, R 10B is —OH. In an embodiment, R 10B is -OCH3.

[0279] In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2. In an embodiment, m is 0. In an embodiment, m is 1. In an embodiment, m is 2.

[0280] In an embodiment, L 2 is -C(=NR 11 In an embodiment, R 11 -R 11F , -OR 11F , -S(O2)-R 11F , or -C(O)-R 11F In an embodiment, R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0281] In embodiments, the compound has the structure of formula (III-d-1), (III-d-2), (III-d-3), or (III-d-4):

[0282] [ka]

[0283] R 1 or a pharmaceutically acceptable salt thereof or an isomer thereof. 1 , R 8 , R 11F and n are as described above.

[0284] In embodiments, R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 11F is hydrogen. In embodiments, R 11F is substituted or unsubstituted alkyl. In embodiments, R 11F is a substituted or unsubstituted C1-C4 alkyl. 11F is unsubstituted C1-C4 alkyl. In embodiments, R 11F is methyl. In an embodiment, R 11F is ethyl. In an embodiment, R 11F is substituted or unsubstituted phenyl. In embodiments, R 11F is unsubstituted phenyl. In embodiments, R 11F is a substituted or unsubstituted 5-8 membered heteroaryl. 11F is a substituted or unsubstituted 5-6 membered heteroaryl. 11F is a substituted or unsubstituted 5-membered heteroaryl. In an embodiment, R 11F is a substituted or unsubstituted 6-membered heteroaryl.

[0285] In an embodiment, L 1 is a bond or unsubstituted C1-C4 alkylene. 1is a bond. In embodiments, L 1 is unsubstituted C1-C4 alkylene. 1 is unsubstituted C1-C4 alkylene.

[0286] In embodiments, R 8 teeth

[0287] [ka]

[0288] In embodiments, each R 4 are independently halogen, -CX 4 3. -CHX 4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4 is independently -F, -Br, -Cl, or -I, and each R 4F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. In an embodiment, k is an integer from 0 to 5.

[0289] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)OR 4F , -C(O)NHR 4F , -C(O)N(R 4F)2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4F In an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 -C(O)OR 4F In an embodiment, R 4 -C(O)NHR 4F In an embodiment, R 4 is -C(O)N(R 4F )2. In an embodiment, R 4 is -C(O)NH2.

[0290] In embodiments, R 4F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl. 4F is hydrogen. In embodiments, R 4Fis substituted or unsubstituted alkyl. In embodiments, R 4F is a substituted or unsubstituted C1-C4 alkyl. 4F is unsubstituted C1-C4 alkyl. In embodiments, R 4F is methyl. In an embodiment, R 4F is ethyl. In an embodiment, R 4F is a substituted or unsubstituted 2-6 membered heteroalkyl. 4F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 6-membered heteroalkyl.

[0291] In embodiments, n is 0 or 1 and R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F and R 1F is hydrogen or unsubstituted C1-C4 alkyl.

[0292] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 1F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl. 1F is hydrogen. In embodiments, R 1F is substituted or unsubstituted alkyl. In embodiments, R 1F is a substituted or unsubstituted C1-C4 alkyl. 1F is unsubstituted C1-C4 alkyl. In embodiments, R 1Fis methyl. In an embodiment, R 1F is ethyl.

[0293] In embodiments, R 1 is -F. In an embodiment, R 1 is —Cl. In an embodiment, R 1 is -Br. In an embodiment, R 1 is -I. In an embodiment, R 1 is a substituted C1-C4 alkyl. In an embodiment, R 1 is unsubstituted C1-C4 alkyl. In embodiments, R 1 is methyl. In an embodiment, R 1 is ethyl. In an embodiment, R 1 is —CN. In an embodiment, R 1 is —CF. In an embodiment, R 1 is —OH. In an embodiment, R 1 is -OCH3.

[0294] In embodiments, exemplary compounds of formula (III) are

[0295] [ka]

[0296] Includes.

[0297] In one embodiment, the structure of formula (XIII):

[0298] [ka]

[0299] or a pharmaceutically acceptable salt or isomer thereof (In the formula, L 1is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2 -C(=O)-, -C(=CR 9A R 9B )-, -CR 10A R 10B - or -C(=NR 11 )- and R 1 are independently halogen, -CX 1 3. -CHX 1 2. -CH2X 1 , -OCX 1 3. -OCH2X 1 , -OCHX 1 2, -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9A and R 9B are independently hydrogen, -CX 9 3. -CHX 9 2. -CH2X 9 , -OCX 9 3. -OCH2X 9 , -OCHX 9 2, -CN, -OR 9F , -SR 9F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 10A and R 10Bare independently hydrogen, D, halogen, -CX 10 3. -CHX 10 2. -CH2X 10 , -OCX 10 3. -OCH2X 10 , -OCHX 10 2, -CN, -OR 10F , -SR 10F , -C(O)OR 10F , -C(O)NHR 10F , -C(O)N(R 10F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10A and R 10B are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 11 -R 11F , -OR 11F , -S(O2)-R 11F , or -C(O)-R 11F and R 30 are independently halogen, -CX 30 3. -CHX 30 2. -CH2X 30 , -OCX 30 3. -OCH2X 30 , -OCHX 30 2, -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 1 to 4, z is an integer from 0 to 4, each X 1 , X 8 , X 9 , X 10 and X 30are independently -F, -Br, -Cl, or -I; Each R 1F , R 8F , R 9F , R 10F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl) is provided.

[0300] In embodiments, R 10A or R 10B At least one of R is not hydrogen. 10A is not hydrogen. In embodiments, R 10B is not hydrogen. In embodiments, R 1 is not hydrogen, but R 10A is not hydrogen. In embodiments, R 1 is not hydrogen, but R 10B is not hydrogen.

[0301] In embodiments, R 8 is substituted or unsubstituted

[0302] [ka]

[0303] is.

[0304] In embodiments, R 8 teeth,

[0305] [ka]

[0306] and Each R 4 are independently halogen, -CX 4 3. -CHX4 2. -CH2X 4 , -OCX 4 3. -OCH2X 4 , -OCHX 4 2, -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 5, X 4 are independently -F, -Br, -Cl, or -I; Each R 4F is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0307] In embodiments, R 8 teeth

[0308] [ka]

[0309] In an embodiment, R 8 teeth

[0310] [ka]

[0311] In an embodiment, R 8 teeth

[0312] [ka]

[0313] In an embodiment, R 8 teeth

[0314] [ka]

[0315] is.

[0316] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)R 4F , -C(O)OR 4F , -S(O)2R 4F , -C(O)NHR 4F , -C(O)N(R 4F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4F In an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 -C(O)OR 4F In an embodiment, R 4 -S(O)2R 4F In an embodiment, R 4 -C(O)NHR 4F In an embodiment, R 4 is -C(O)N(R 4F )2. In an embodiment, R 4 is -C(O)NH2.

[0317] In embodiments, R 4F are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 4F is hydrogen. In embodiments, R 4F is substituted or unsubstituted alkyl. In embodiments, R 4F is a substituted or unsubstituted C1-C4 alkyl. 4F is unsubstituted C1-C4 alkyl. In embodiments, R 4F is methyl. In an embodiment, R 4F is ethyl. In an embodiment, R 4F is a substituted or unsubstituted 2-6 membered heteroalkyl. 4F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 4F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 4Fis a substituted or unsubstituted 6-membered heteroalkyl. In embodiments, R 4F is substituted or unsubstituted cycloalkyl. In embodiments, R 4F is a substituted or unsubstituted C3-C6 cycloalkyl. 4F is a substituted or unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is an unsubstituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is a substituted 5-12 membered monocyclic or bicyclic heterocycloalkyl. 4F is substituted or unsubstituted phenyl. In embodiments, R 4F is unsubstituted phenyl. In embodiments, R 4F is substituted phenyl. In embodiments, R 4F is a substituted or unsubstituted 5-6 membered heteroaryl. 4F is a substituted 5-6 membered heteroaryl. 4F is an unsubstituted 5- to 6-membered heteroaryl.

[0318] In embodiments, the compound has the structure of formula (XIII-a)

[0319] [ka]

[0320] or a pharmaceutically acceptable salt thereof or an isomer thereof (wherein n is an integer of 1 to 4). 1 , L 1 , R 8 , R 30 and n is defined in formula (XIII) and described above.

[0321] In embodiments, the compound has the structure of formula (XIII-b)

[0322] [ka]

[0323] or a pharmaceutically acceptable salt thereof or an isomer thereof (wherein n is an integer of 1 to 4). 1 , L 1 , R 8 , R 9A , R 9B , R 30 and n is defined in formula (XIII) and described above.

[0324] In embodiments, the compound has the structure of formula (XIII-c)

[0325] [ka]

[0326] or a pharmaceutically acceptable salt thereof or an isomer thereof (wherein n is an integer of 1 to 4). 1 , L 1 , R 8 , R 10A , R 10B , R 30 and n is defined in formula (XIII) and described above.

[0327] In an embodiment, L 1 is a bond or unsubstituted C1-C4 alkylene. 1 is a bond. In embodiments, L 1 is unsubstituted C1-C4 alkylene. 1 is unsubstituted C1-C4 alkylene.

[0328] In an embodiment, n is 1 to 4, and in an embodiment, n is not 0.

[0329] In embodiments, R 10A and R 10Bare linked to form a substituted or unsubstituted C3-C6 cycloalkyl or a substituted or unsubstituted 4-6 membered heterocycloalkyl. 10A and R 10B are linked to form a substituted or unsubstituted C3-C6 cycloalkyl. 10A and R 10B are linked to form a substituted or unsubstituted C3-C6 cycloalkyl.

[0330] In embodiments, R 10A and R 10B are linked together to form a substituted or unsubstituted C3-C6 cycloalkyl, or a substituted or unsubstituted 4-6 membered heterocycloalkyl. 10A and R 10B are linked together to form a substituted or unsubstituted C3-C6 cycloalkyl. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted cyclopropyl. 10A and R 10B are linked together to form a substituted or unsubstituted cyclobutyl. 10A and R 10B are linked together to form a substituted or unsubstituted cyclopentyl. 10A and R 10B are linked together to form a substituted or unsubstituted cyclohexyl. 10A and R 10B are linked together to form a substituted or unsubstituted 4- to 6-membered heterocycloalkyl. 10A and R 10B are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl. In embodiments, R 10A and R 10B are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 6-membered heterocycloalkyl.

[0331] In embodiments, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-6 membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 6-membered heterocycloalkyl containing N, O, or S. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-6 membered heterocycloalkyl containing O. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 4-membered heterocycloalkyl containing O. In an embodiment, R 10A and R 10B are linked together to form a substituted or unsubstituted 5-membered heterocycloalkyl containing O. In an embodiment, R 10A and R 10B are linked together to form an O-containing substituted or unsubstituted 6-membered heterocycloalkyl.

[0332] In embodiments, the compound has the structure of formula (XIII-c-1) or (XIII-c-2)

[0333] [ka]

[0334] or a pharmaceutically acceptable salt thereof or an isomer thereof (In the formula, Each R 12 are independently halogen, -CX 12 3. -CHX 122. -CH2X 12 , -OCX 12 3. -OCH2X 12 , -OCHX 12 2, -CN, -OR 12F , -SR 12F , -C(O)OR 12F , -C(O)NHR 12F , -C(O)N(R 12F )2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X 12 are independently -F, -Br, -Cl, or -I; Each R 12F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; p is an integer from 0 to 4 R 1 , L 1 , R 8 , R 30 and n is defined in formula (XIII) and described above.

[0335] In an embodiment, p is an integer of 0 to 4. In an embodiment, p is 0. In an embodiment, p is 1. In an embodiment, p is 2.

[0336] In embodiments, each R 12 are independently halogen, -CX 12 3. -OCX 12 3, -CN, -OR 12F , -C(O)OR 12F , -C(O)NHR 12F , -C(O)N(R 12F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 12 is halogen. In embodiments, R 12 is -F. In an embodiment, R 12 is —Cl. In an embodiment, R 12is -Br. In an embodiment, R 12 is -I. In an embodiment, R 12 Ha-CX 12 3. In an embodiment, R 12 is —CF. In an embodiment, R 12 -OCX 12 3. In an embodiment, R 12 is -OCF3. In an embodiment, R 12 is —CN. In an embodiment, R 12 HA-OR 12F In an embodiment, R 12 is —OH. In an embodiment, R 12 is —OCH. In an embodiment, R 12 is substituted or unsubstituted C1-C 12 In embodiments, R 12 is unsubstituted C1~C 12 In embodiments, R 12 is methyl. In an embodiment, R 12 is ethyl. In an embodiment, R 12 -C(O)OR 12F In an embodiment, R 12 -C(O)NHR 12F In an embodiment, R 12 is -C(O)N(R 12F )2. In an embodiment, R 12 is —C(O)NH. In an embodiment, R 12 is substituted or unsubstituted phenyl. In embodiments, R 12 is unsubstituted phenyl. In each occurrence, R 12 may be the same or different.

[0337] In embodiments, R 12F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroalkyl. 12F is hydrogen. In embodiments, R 12F is substituted or unsubstituted alkyl. In embodiments, R12F is a substituted or unsubstituted C1-C4 alkyl. 12F is unsubstituted C1-C4 alkyl. In embodiments, R 12F is methyl. In an embodiment, R 12F is ethyl. In an embodiment, R 12F is a substituted or unsubstituted 2-6 membered heteroalkyl. 12F is a substituted or unsubstituted 2-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 3-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 4-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 5-membered heteroalkyl. In embodiments, R 12F is a substituted or unsubstituted 6-membered heteroalkyl.

[0338] In embodiments, the compound has the structure of formula (XIII-c-3), (XIII-c-4), or (XIII-c-5):

[0339] [ka]

[0340] or a pharmaceutically acceptable salt thereof or an isomer thereof.

[0341] In embodiments, R 10A is H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10 3, OR 10F and R 10B is H, D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10 3, OR 10F In embodiments, each R 10F is independently hydrogen or unsubstituted C1-C4 alkyl. 10F are independently hydrogen or unsubstituted methyl. 10Fis hydrogen or unsubstituted methyl.

[0342] In embodiments, R 10A is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10 3, OR 10F In an embodiment, R 10A is —H. In an embodiment, R 10A is -D. In an embodiment, R 10A is -F. In an embodiment, R 10A is —Cl. In an embodiment, R 10A is -Br. In an embodiment, R 10A is -I. In an embodiment, R 10A is a substituted C1-C4 alkyl. In an embodiment, R 10A is unsubstituted C1-C4 alkyl. In embodiments, R 10A is methyl. In an embodiment, R 10A is ethyl. In an embodiment, R 10A is —CN. In an embodiment, R 10A is —CF. In an embodiment, R 10A is —OH. In an embodiment, R 10A is -OCH3.

[0343] In embodiments, R 10B is -H, -D, halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 10B 10B OR 10BF In an embodiment, R 10B is —H. In an embodiment, R 10B is -D. In an embodiment, R 10B is -F. In an embodiment, R 10B is —Cl. In an embodiment, R 10B is -Br. In an embodiment, R 10B is -I. In an embodiment, R 10B is a substituted C1-C4 alkyl. In an embodiment, R 10Bis unsubstituted C1-C4 alkyl. In embodiments, R 10B is methyl. In an embodiment, R 10B is ethyl. In an embodiment, R 10B is —CN. In an embodiment, R 10B Ha-CF 10B In an embodiment, R 10B is —OH. In an embodiment, R 10B is -OCH3.

[0344] In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2. In an embodiment, m is 0. In an embodiment, m is 1. In an embodiment, m is 2.

[0345] In an embodiment, L 2 is -C(=NR 11 In an embodiment, R 11 -R 11F , -OR 11F , -S(O2)-R 11F , or -C(O)-R 11F In an embodiment, R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0346] In embodiments, the compound has the structure of formula (XIII-d-1), (XIII-d-2), (XIII-d-3), or (XIII-d-4):

[0347] [ka]

[0348] or a pharmaceutically acceptable salt thereof or an isomer thereof.

[0349] In embodiments, R 11Fis hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 11F is hydrogen. In embodiments, R 11F is substituted or unsubstituted alkyl. In embodiments, R 11F is a substituted or unsubstituted C1-C4 alkyl. 11F is unsubstituted C1-C4 alkyl. In embodiments, R 11F is methyl. In an embodiment, R 11F is ethyl. In an embodiment, R 11F is substituted or unsubstituted phenyl. In embodiments, R 11F is unsubstituted phenyl. In embodiments, R 11F is a substituted or unsubstituted 5-8 membered heteroaryl. 11F is a substituted or unsubstituted 5-6 membered heteroaryl. 11F is a substituted or unsubstituted 5-membered heteroaryl. In an embodiment, R 11F is a substituted or unsubstituted 6-membered heteroaryl.

[0350] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In embodiments, each R 1F is independently hydrogen or unsubstituted C1-C4 alkyl. 1F are independently hydrogen or unsubstituted methyl.

[0351] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 1 is -F. In an embodiment, R 1 is —Cl. In an embodiment, R 1 is -Br. In an embodiment, R 1is -I. In an embodiment, R 1 is a substituted C1-C4 alkyl. In an embodiment, R 1 is unsubstituted C1-C4 alkyl. In embodiments, R 1 is methyl. In an embodiment, R 1 is ethyl. In an embodiment, R 1 is —CN. In an embodiment, R 1 is —CF. In an embodiment, R 1 is —OH. In an embodiment, R 1 is -OCH3.

[0352] In embodiments, R 30 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 30 3, OR 30F In embodiments, each R 30F is independently hydrogen or unsubstituted C1-C4 alkyl. 30F are independently hydrogen or unsubstituted methyl.

[0353] In embodiments, R 30 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 30 is -F. In an embodiment, R 30 is —Cl. In an embodiment, R 30 is -Br. In an embodiment, R 30 is -I. In an embodiment, R 30 is a substituted C1-C4 alkyl. In an embodiment, R 30 is unsubstituted C1-C4 alkyl. In embodiments, R 30 is methyl. In an embodiment, R 30 is ethyl. In an embodiment, R 30 is —CN. In an embodiment, R 30 is —CF. In an embodiment, R 30 is —OH. In an embodiment, R30 is -OCH3.

[0354] In embodiments, the compound has the structure of formula (XIII-e)

[0355] [ka]

[0356] or a pharmaceutically acceptable salt thereof or an isomer thereof.

[0357] In embodiments, the compound has the structure of formula (XIII-f)

[0358] [ka]

[0359] or a pharmaceutically acceptable salt thereof or an isomer thereof.

[0360] In embodiments, the compound has the structure of formula (XIII-g)

[0361] [ka]

[0362] or a pharmaceutically acceptable salt thereof or an isomer thereof.

[0363] In an embodiment, k is 0. In an embodiment, k is 1. In an embodiment, k is 2, and in an embodiment, n is 1. In an embodiment, n is 2.

[0364] In embodiments, each R 4 are independently halogen, -CX 4 3. -OCX 4 3, -CN, -OR 4F , -C(O)R 4F , -C(O)OR 4F , -S(O)2R4F , -C(O)NHR 4F , -C(O)N(R 4F )2, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R 4 is halogen. In embodiments, R 4 is -F. In an embodiment, R 4 is —Cl. In an embodiment, R 4 is -Br. In an embodiment, R 4 is -I. In an embodiment, R 4 Ha-CX 4 3. In an embodiment, R 4 is —CF. In an embodiment, R 4 -OCX 4 3. In an embodiment, R 4 is -OCF3. In an embodiment, R 4 is —CN. In an embodiment, R 4 HA-OR 4F In an embodiment, R 4 is —OH. In an embodiment, R 4 is —OCH. In an embodiment, R 4 is a substituted or unsubstituted C1-C4 alkyl. 4 is unsubstituted C1-C4 alkyl. In embodiments, R 4 is methyl. In an embodiment, R 4 is ethyl. In an embodiment, R 4 is —C(O)CH. In embodiments, R 4 teeth

[0365] [ka]

[0366] is.

[0367] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1FIn embodiments, each R 1F is independently hydrogen or unsubstituted C1-C4 alkyl. 1F are independently hydrogen or unsubstituted methyl.

[0368] In embodiments, R 1 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 1 is -F. In an embodiment, R 1 is —Cl. In an embodiment, R 1 is -Br. In an embodiment, R 1 is -I. In an embodiment, R 1 is a substituted C1-C4 alkyl. In an embodiment, R 1 is unsubstituted C1-C4 alkyl. In embodiments, R 1 is methyl. In an embodiment, R 1 is ethyl. In an embodiment, R 1 is —CN. In an embodiment, R 1 is —CF. In an embodiment, R 1 is —OH. In an embodiment, R 1 is -OCH3.

[0369] In embodiments, R 30 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 30 3, OR 30F In embodiments, each R 30F is independently hydrogen or unsubstituted C1-C4 alkyl. 30F are independently hydrogen or unsubstituted methyl.

[0370] In embodiments, R 30 is halogen, substituted or unsubstituted C1-C4 alkyl, -CN, -CX 1 3, OR 1F In an embodiment, R 30is -F. In an embodiment, R 30 is —Cl. In an embodiment, R 30 is -Br. In an embodiment, R 30 is -I. In an embodiment, R 30 is a substituted C1-C4 alkyl. In an embodiment, R 30 is unsubstituted C1-C4 alkyl. In embodiments, R 30 is methyl. In an embodiment, R 30 is ethyl. In an embodiment, R 30 is —CN. In an embodiment, R 30 is —CF. In an embodiment, R 30 is —OH. In an embodiment, R 30 is -OCH3.

[0371] In embodiments, R 1 is a substituted or unsubstituted C1-C4 alkyl, and R 10A is a substituted or unsubstituted C1-C4 alkyl. 1 is methyl and R 10A is methyl. In an embodiment, R 1 is a substituted or unsubstituted C1-C4 alkyl, and R 10B is a substituted or unsubstituted C1-C4 alkyl. 1 is methyl and R 10B is methyl.

[0372] Exemplary compounds of formula (XIII) are shown in Table 3 below.

[0373] [Table 3A]

[0374] [Table 3B]

[0375] [Table 3C]

[0376] Pharmaceutical Composition In one aspect, provided are pharmaceutical compositions comprising a compound described herein, a pharmaceutically acceptable salt form thereof, an isomer thereof, or a crystalline form thereof. Also provided herein are pharmaceutical formulations. In embodiments, the pharmaceutical formulation comprises a compound (e.g., a compound of Formulas (X), (XI), (XII), and (XIII), including all embodiments and subformulas thereof, or a compound of Tables 1-3 above) and a pharmaceutically acceptable excipient.

[0377] The pharmaceutical composition can include a therapeutically effective amount of the compound administered.

[0378] In embodiments, the pharmaceutical composition comprises any of the compounds described above.

[0379] 1. Preparation The pharmaceutical compositions can be prepared and administered in a wide variety of dosage formulations. The described compounds can be administered orally, rectally, or by injection (e.g., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally).

[0380] For preparing pharmaceutical compositions from the compounds described herein, pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powder, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0381] In powders, the carrier may be a finely divided solid in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0382] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound and an encapsulating material as a carrier, with or without other carriers, providing a capsule in which the active ingredient is surrounded by the carrier. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0383] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein, as by stirring, etc. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.

[0384] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0385] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0386] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0387] Pharmaceutical preparations are preferably in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active ingredients.The unit dosage form may be a packaged preparation, the package containing discrete amounts of the preparation, such as individual tablets, capsules, and powders in vials or ampoules.The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0388] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg depending on the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0389] Some compounds may have limited solubility in water and therefore may require a surfactant or other suitable cosolvent in the composition. Such cosolvents include polysorbates 20, 60, and 80, Pluronic F-68, F-84, and P-103, cyclodextrin, and polyoxyl 35 castor oil. Such cosolvents are typically utilized at levels of about 0.01% to about 2% by weight. Viscosities greater than those of simple aqueous solutions may be desirable to reduce formulation dispensing variability, reduce physical separation of formulation suspension or emulsion components, and / or otherwise enhance formulation. Examples of such viscosity-enhancing agents include polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically utilized at levels of about 0.01% to about 2% by weight.

[0390] The pharmaceutical composition may further comprise ingredients to provide sustained release and / or comfort. Such ingredients include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and finely divided drug carrier matrices. These ingredients are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760, the entire contents of which are incorporated herein by reference in their entirety for all purposes.

[0391] The pharmaceutical composition may be intended for intravenous use. The pharmaceutically acceptable excipient may include a buffer to adjust the pH to a range desired for intravenous use. Many buffers are known, including salts of inorganic acids such as phosphates, borates, and sulfates.

[0392] 2. Effective dosage Pharmaceutical compositions may include compositions in which the active material is contained in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated.

[0393] The dosage and frequency (single or multiple doses) of the compound administered can vary depending on a variety of factors, including the route of administration, the size, age, sex, health, weight, body mass index, and diet of the recipient, the nature and extent of the symptoms of the disease being treated, the presence of other diseases or other health-related problems, the type of concomitant treatment, and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds disclosed herein.

[0394] The therapeutically effective amount for human use can be determined from animal models.For example, the dose for human can be formulated to achieve the concentration found to be effective in animals.The dose for human can be adjusted by monitoring the response of constipation or dry eye to treatment, and adjusting the dose upward or downward, as described above.

[0395] Dosage can vary depending on the needs of the subject and the compound used.The dosage administered to the subject should be sufficient to bring about a beneficial therapeutic response in the subject over time in the context of the pharmaceutical compositions presented herein.The size of the dosage will also be determined by the existence, nature and extent of adverse side effects.Generally, treatment is initiated with a smaller dosage that is less than the optimal dose of the compound.The dosage is then increased by small increments until the optimal effect under the circumstances is reached.

[0396] Dosage amount and interval can be adjusted individually to provide levels of the administered compound that are effective for the particular clinical indication being treated, thereby providing a therapeutic regimen commensurate with the severity of the individual disease state.

[0397] Utilizing the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that does not cause substantial toxicity, yet is fully effective in treating the clinical symptoms exhibited by a particular patient. This design should involve careful selection of an active compound by considering factors such as the compound's potency, relative bioavailability, the patient's weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent.

[0398] 3.Toxicity The ratio between the toxicity and therapeutic effect of a particular compound is its therapeutic index, LD 50 (the amount of compound that is lethal to 50% of the population) and ED 50 Therapeutic indices can be expressed as a ratio between the ED (the amount of compound effective in 50% of the population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds is preferably at an ED with little or no toxicity. 50 The plasma concentration range includes: (a) a concentration of 0.05% or more of the active ingredient in the compound of formula (I) or (II) above. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. See, for example, Fingl et al. in THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, 1975. The exact formulation, route of administration, and dosage may be chosen by the individual physician in view of the patient's condition and the particular method in which the compound is used.

[0399] When parenteral application is necessary or desired, particularly suitable admixtures for the compounds contained in the pharmaceutical composition may be injectable sterile solutions, oily or aqueous solutions, and suspensions, emulsions, or implants, including suppositories. Particularly, carriers for parenteral administration include aqueous solutions of dextrose, saline, purified water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, etc. Ampoules are convenient unit doses. Suitable pharmaceutical admixtures for use in the pharmaceutical compositions presented herein include, for example, those described in Pharmaceutical Sciences (17th Edition, Mack Pub. Co., Easton, PA) and WO96 / 05309, the teachings of both of which are incorporated herein by reference.

[0400] method In one aspect, a method is provided for inhibiting NAD consumption and / or increasing NAD synthesis in a patient, the method comprising administering to the patient an effective dose of a compound (e.g., a compound of Formulas (X), (XI), (XII), and (XIII), including all embodiments and subformulas thereof, or Tables 1-3 above) and a pharmaceutically acceptable excipient.

[0401] The compound can inhibit NAD-consuming reactions, such as protein ADP-ribosylation. The compound can inhibit NAD cleavage by protein deacetylase or NAD hydrolase. The compound can increase NAD synthesis. The compound can activate enzymes in the NAD synthesis pathway, such as the rate-limiting enzyme for NAD synthesis in the salvage pathway called NAMPT. The patient has or is at risk for a protein misfolding neurodegenerative disease, another protein misfolding disease, or another degenerative or metabolic disease.

[0402] Protein misfolding neurodegenerative diseases include prion diseases, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia or other tauopathies, chronic traumatic encephalopathy, and protein misfolding diseases include diabetes and amyloidosis.

[0403] In one embodiment, a method is provided for preventing or inhibiting NAD depletion in a patient. In another embodiment, a method is provided for increasing NAD levels to improve cellular function. In another embodiment, a method is provided for improving a condition associated with altered NAD metabolism in a patient. The method comprises administering to the patient an effective dose of a compound described herein.

[0404] Conditions include metabolic disorders, liver damage, aging, degenerative diseases, neurodegenerative diseases, neuronal degeneration associated with multiple sclerosis, hearing loss, retinal damage or multiple sclerosis, macular degeneration, cerebral or cardiac ischemia, renal failure, renal disease, traumatic brain injury or axonal damage.

[0405] In one aspect, a method is provided for providing protection from misfolded protein toxicity in a patient, the method comprising administering an effective dose of a compound described herein to the patient, the patient suffering from a prion disease, Parkinson's disease or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, tauopathy, amyloidosis, or diabetes.

[0406] In one aspect, a method is provided for preventing or treating a protein misfolding neurodegenerative disease in a patient, the method comprising administering to the patient an effective dose of a compound described herein.

[0407] In some embodiments, the protein misfolding neurodegenerative disease is a disorder associated with protein aggregate-induced neurodegeneration and NAD depletion. In some embodiments, the protein misfolding neurodegenerative disease includes prion disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia or other tauopathies, and chronic traumatic encephalopathy. In some embodiments, the neurodegenerative disease is multiple sclerosis, cerebral ischemia, or axonopathy.

[0408] In embodiments, the metabolic disorder comprises diabetes or liver damage.

[0409] In embodiments, the condition associated with an alteration in NAD metabolism comprises aging, a retinal disease, a mitochondrial disease, or a kidney disease.

[0410] In one aspect, a method of preventing or treating a retinal disease in a patient is provided, the method comprising administering to the patient an effective dose of a compound described herein.

[0411] In one aspect, there is provided a method of preventing or treating diabetes, non-alcoholic fatty liver disease, or other metabolic disease in a patient, comprising administering to the patient an effective dose of a compound described herein.

[0412] In one aspect, there is provided a method of preventing or treating kidney disease in a patient, comprising administering to the patient an effective dose of a compound described herein.

[0413] In one aspect, a method of reducing the health effects of aging is provided, comprising administering to a patient an effective dose of a compound described herein. [Example]

[0414] Example 1 Cell viability assay The following table shows the structures of specific examples of compounds useful in practicing the methods of the invention, associated with corresponding data such as compound identifiers and biological results.

[0415] The biological activity of test compounds was quantified using a cell viability assay (CellTiter-Glo®) to assess the ability of compounds to prevent neuronal cell death due to NAD depletion induced by the misfolded protein TPrP. A dose-response profile for each compound was established in the TPrP neuroprotection assay. PK1 neuroblastoma cells (approximately 1000 cells / well, 96-well plate) were exposed to 5 μg / ml of TPrP and doses of compound ranging from 1.67 nM to 405 nM or 900 nM for 4 days. TPrP was prepared as described in Zhou et al., Proc Natl Acad Sci USA 109, 3113-3118 (2012). 1 Compounds were added at the indicated doses in a final concentration of 0.5% DMSO. Cell viability was measured using CellTiter-Glo® (Promega). Effective concentrations (EC 50 The EC values ​​of TPrP for the compounds described herein were determined. 50 are shown in Table 4. The dose-response activity curve is shown in Figure 1.

[0416] Example 2 Microsome stability assay The metabolic stability of several test compounds was determined in human and mouse liver microsomes. Compounds were incubated with 1 mg / ml human or mouse liver microsomes at 37°C with continuous shaking. Aliquots were removed at various time points between 5 minutes and 2 hours, and acetonitrile was added to quench the reaction and precipitate the proteins. Samples were then centrifuged through a 0.45 μm filter plate, and half-lives were determined by LC-MS / MS. Microsomal stability of test compounds at ≥15 minutes is shown in Table 4.

[0417] Example 3 NAMPT activation assay The ability of several test compounds to activate human NAMPT was tested using a colorimetric NAMPT activity assay (AbCam ab221819). The assay was performed according to the manufacturer's instructions. The enzyme activity rate was calculated using the formula: ((A at T2)-(A at T1)) / (T2-T1), where A is the OD450 at each time point T (min). An example of an activation curve is shown in Figure 2. The activation ratio compared to baseline (CTRL, no compound) is also shown in Figure 2. The NAMPT activation of ≥10% at 1 μM compound of the test compounds is shown in Table 4.

[0418] [Table 4A]

[0419] [Table 4B]

[0420] [Table 4C]

[0421] [Table 4D]

[0422] [Table 4E]

[0423] [Table 4F]

[0424] [Table 4G]

[0425] [Table 4H]

[0426]

Table 4I

[0427] Table 4J

[0428] Table 4K

[0429] Table 4L

[0430] Table 4M

[0431] Table 4N

[0432]

Table 4O

[0433]

Table 4P

[0434]

Table 4Q

[0435]

Table 4R

[0436] [Table 4S]

[0437] Example 4 Synthesis I The following schemes illustrate the synthesis of example compounds useful in the practice of the present invention. These examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein. The starting materials and reagents used in the synthesis of the compounds described herein may be synthesized or obtained from commercial sources.

[0438] Scheme 1: Synthesis of compound SR-32077 Compound SR-32077 can be synthesized according to Scheme 1 by Buckwald-Hartwig coupling of 1-chloro-4-(pyridin-4-ylmethyl)phthalazine and 2-aminobenzoxazole.

[0439] [ka]

[0440] Compound 1 in Scheme 1 can be synthesized according to Scheme 1-1 and Scheme 1-2.

[0441] [ka]

[0442] Compound 2 in Scheme 1 can be synthesized according to Schemes 1-3.

[0443] [ka]

[0444] Scheme 2: Synthesis of compound SR-32073 Compound SR-32073 can be synthesized by Buckwald-Hartwig coupling of 1-chloro-4-(pyridin-4-ylmethyl)phthalazine and 2-aminobenzoxazole according to Scheme 2.

[0445] [ka]

[0446] Compound 1 in Scheme 2 can be synthesized according to the above-mentioned Schemes 1-1 and 1-2. Compound 3 can be synthesized according to Scheme 2-1.

[0447] [ka]

[0448] Scheme 3 The compounds of the present invention can be synthesized according to Scheme 3 by Buckwald-Hartwig coupling of 1-chloro-4-(pyridin-4-ylmethyl)phthalazine with (3-aryloxetan-3-yl)methanamine.

[0449] [ka]

[0450] Compound 1 in Scheme 3 can be synthesized according to the above-mentioned Scheme 1-1 and Scheme 1-2. Compound 4 can be synthesized according to Scheme 3-1.

[0451] [ka]

[0452] Scheme 4 The compounds of the present invention can be synthesized according to Scheme 4 by Buckwald-Hartwig coupling of 1-chloro-4-(pyridin-4-ylmethyl)phthalazine with 3-aryloxetan-3-amines.

[0453] [ka]

[0454] Compound 1 in Scheme 4 can be synthesized according to the above-mentioned Scheme 1-1 and Scheme 1-2. Compound 5 can be synthesized according to Scheme 4-1.

[0455] [ka]

[0456] Scheme 5 Compounds of the present invention can be synthesized by Buckwald-Hartwig coupling of N-(3-(oxetan-3-yl)phenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine according to Scheme 5.

[0457] [ka]

[0458] Compound 1 in Scheme 5 can be synthesized according to the above-mentioned Scheme 1-1 and Scheme 1-2. Compound 6 can be synthesized according to Scheme 5-1.

[0459] [ka]

[0460] Scheme 6: Alternative to Scheme 1-1 and Scheme 1-2 Compound 1 in Scheme 1-5 can be synthesized according to Scheme 6-1, or Schemes 6-2 and 6-3.

[0461] [ka]

[0462] Example 5 Synthesis II Synthesis of starting materials Starting material 1

[0463] [ka]

[0464] A solution of sodium methoxide (596 mmol, 32.2 g) in methanol (298 mL) in 1 L of RB was cooled to 0 °C in an ice bath. An addition funnel containing a solution of 1-isobenzofuranone (149 mmol, 20.0 g), 4-pyridinecarboxaldehyde (156 mmol, 14.7 mL), and ethyl propionate (80 mL) was attached, and the solution was added dropwise over 20 min. After complete addition, the ice bath was removed, and the reaction was stirred at rt for 1 h. The addition funnel was replaced with a reflux condenser, and the reaction was heated to reflux (100 °C) for 1.5 h. The cooled reaction mixture was concentrated to a thick slurry, diluted with water (approximately 700 mL), and transferred to a separatory funnel. The dark red solution was extracted with diethyl ether (3 × 200 mL). The aqueous layer in a 2 L Erlenmeyer flask was acidified with acetic acid and swirled to produce a yellow precipitate. The precipitated solid was filtered and rinsed with water, ethyl acetate, and diethyl ether. The collected solid was placed in a vacuum desiccator and dried under high vacuum overnight to give 22.8 g (69%) of 2-[4(1H)-pyridinylidene]indan-1,3-dione as a light yellow solid.

[0465] [ka]

[0466] A 10-20 mL microwave vial was charged with 2-[4(1H)-pyridinylidene]indan-1,3-dione (11.2 mmol, 2.5 g) and hydrazine monohydrate (11 mL), sealed with a crimp cap, and heated in a Biotage microwave reactor at 160 °C for 1 h. The vial was placed in an ice bath for 10 min, and the precipitated solid was filtered and rinsed with ethanol (20 mL) followed by diethyl ether (4 x 20 mL) to give 2.19 g (83%) of 4-(pyridin-4-ylmethyl)phthalazin-1(2H)-one as a light tan solid. 1 H NMR (400 MHz, d6-DMSO) δ 12.62 (bs, 1 H), 8.47 (dd, J = 1.6 & 6.0 Hz, 2H), 8.27 (m, 1H), 7.94-7.82 (m, 3H), 7.32 (dd, J = 1.6 & 6.0 Hz, 2H), 4.35 (s, 2H).

[0467] [ka]

[0468] A flame-dried 500 mL RB was charged with phthalazin-1-one (23.2 mmol, 5.53 g) and placed under an argon atmosphere. Freshly distilled dry acetonitrile (90 mL) and 4 M HCl in dioxane (46.6 mmol, 11.65 mL) were added, and the mixture was stirred for 10 min. To the semi-homogeneous solution was added phosphoryl chloride (58.3 mmol, 5.43 mL). The RB was placed in an oil bath and heated to 50 °C for 24 h. After the reaction was cooled to room temperature, the RB was placed in an ice bath. To the cooled pale orange slurry was carefully and slowly added 268 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 min, then filtered and rinsed with ether. The solid was dried under high vacuum overnight to give 4.95 g (83%) of 1-chloro-4-(pyridin-4-ylmethyl)phthalazine as a dark orange solid. 1H NMR (400 MHz, d6-DMSO) δ 8.46 (d, J = 5.0 Hz, 2H), 8.35 (m, 2H), 8.14 (m, 2H), 7.33 (d, J = 5.0 Hz, 2H), 4.77 (s, 2H).

[0469] Starting material 2

[0470] [ka]

[0471] A solution of sodium methoxide (28.16 mmol, 1.52 g) in 14 mL of methanol in 50 mL LRB was cooled to 0 °C in an ice bath. In a separate 20 mL scintillation vial, a solution of 1-isobenzofuranone (7.04 mmol, 0.944 g) and 2,6-dimethylpyridine-4-carboxaldehyde (7.39 mmol, 1.00 g) in 3.8 mL of ethyl propionate was prepared and transferred to the methoxide solution dropwise over 10 min via syringe. After complete addition, the reaction was stirred at rt for 1 h. A reflux condenser was attached and the reaction was heated to reflux (100 °C) for 1.5 h. The cooled reaction mixture was concentrated to a thick slurry, diluted with water (30 mL), and transferred to a separatory funnel. The dark red solution was extracted with diethyl ether (3 x 15 mL). The aqueous layer in a 250 mL Erlenmeyer flask was acidified with acetic acid to produce a yellow precipitate. The precipitated solid was filtered and rinsed with water, ethyl acetate, and diethyl ether. The collected solid was dried under high vacuum overnight to give 1.149 g (65%) of 2-(2,6-dimethylpyridin-4-yl)-3-hydroxy-1H-inden-1-one as a light yellow solid. 1 H NMR (400 MHz, d6-DMSO) δ 12.94 (bs, 1H), 8.45 (s, 2H), 7.51 (m, 2H), 7.45 (m, 2H), 2.46 (s, 6H)

[0472] [ka]

[0473] A 5 mL microwave vial was charged with 2-(2,6-dimethylpyridin-4-yl)-3-hydroxy-1H-inden-1-one (4.57 mmol, 1.149 g) and 4 mL of hydrazine monohydrate. The vial was sealed with a crimp cap and heated to 160 °C in a microwave reactor for 1 h. The cooled reaction mixture was placed in an ice bath and cooled for 1 h. The precipitated solid was filtered and rinsed with ethanol, then ether (×4) to give 0.751 g (61%) of 4-((2,6-dimethylpyridin-4-yl)methyl)phthalazin-1(2H)-one as a tan solid. The filtrate was extracted with EtOAc (×2) to give an additional 0.219 g (18%, 90% pure) of 4-((2,6-dimethylpyridin-4-yl)methyl)phthalazin-1(2H)-one as a yellow solid. 1 H NMR (400 MHz, d6-DMSO) δ 12.60 (bs, 1H), 8.27 (d, 1H), 7.89 (m, 2H), 7.87-7.81 (m, 1H), 6.97 (s, 2H), 4.24 (s, 2H), 2.36 (s, 6H)

[0474] [ka]

[0475] A flame-dried 50 mL RB was charged with 4-((2,6-dimethylpyridin-4-yl)methyl)phthalazin-1(2H)-one (3.66 mmol, 0.97 g) and placed under an argon atmosphere. Freshly distilled dry acetonitrile (14.6 mL) and HCl in dioxane (4 M, 7.32 mmol, 1.93 mL) were added. To the homogeneous solution was added phosphoryl chloride (9.14 mmol, 0.852 mL). The RB was placed in an oil bath and heated to 50 °C for 24 h. After the reaction was cooled to room temperature, the RB was placed in an ice bath. To the cooled pale orange slurry was added 45 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 min. The precipitated solid was filtered and rinsed with water. The solid was dried under vacuum to give 1.03 g (99%) of 1-chloro-4-((2,6-dimethylpyridin-4-yl)methyl)phthalazine as a tan solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.33 (m, 2H), 8.14 (m, 2H), 6.99 (s, 2H), 4.66 (s, 2H), 2.34 (s, 6H)

[0476] Starting material 3

[0477] [ka]

[0478] A flame-dried 200 mL flask was charged with DMP (12.6 mmol, 5.34 g) and placed under an argon atmosphere. 45 mL of dry DCM was poured into the RB. Once the DMP was dissolved, (2-(trifluoromethyl)pyridin-4-yl)methanol (9.0 mmol, 1.60 g) was added dropwise. The reaction was stirred at rt until completion. The reaction mixture was diluted with DCM and quenched with saturated NaHCO3(aq). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 100 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.636 g (40%) of 2-(trifluoromethyl)isonicotinaldehyde as a clear oil. 1 H NMR (400 MHz, d6-DMSO) δ 10.16 (s, 1H), 9.08 (d, J = 4.8 Hz, 1H), 8.29 (s, 1H), 8.14 (d, J = 4.8 Hz, 1H)

[0479] [ka]

[0480] A solution of sodium methoxide (13.84 mmol, 0.747 g) in 7 mL of methanol in 25 mL of L.B. was cooled to 0 °C in an ice bath. In a separate vial, a solution of 1-isobenzofuranone (3.46 mmol, 0.464 g), 2-(trifluoromethyl)isonicotinaldehyde (3.63 mmol, 0.635 g), and 5 mL of ethyl propionate was prepared and transferred to the methoxide solution dropwise over 10 min via a syringe attached to a reflux condenser. After complete addition, the reaction was stirred at rt for 1 h. The reaction was heated to reflux (100 °C) for 1.5 h. The cooled reaction mixture was concentrated to a thick slurry, diluted with water (100 mL), and transferred to a separatory funnel. The dark red solution was extracted with diethyl ether (3 × 50 mL). The aqueous layer in a 100 mL Erlenmeyer flask was acidified with acetic acid. A precipitate formed which was filtered and rinsed with water and a small amount of ether to give 0.241 g (24%) of 3-hydroxy-2-(2-(trifluoromethyl)pyridin-4-yl)-1H-inden-1-one as an orange solid. The aqueous filtrate was then extracted with EtOAc. The organic layer was washed twice with brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume to give 0.358 g (35%) of 3-hydroxy-2-(2-(trifluoromethyl)pyridin-4-yl)-1H-inden-1-one as a yellow solid. 1 H NMR (400 MHz, d6-DMSO) δ 13.22 (bs, 1H), 9.04 (d, J = 1.8 Hz, 1H), 8.69 (dd, J = 1.9 & 6.5 Hz, 1H), 8.30 (d, J = 6.7 Hz, 1H), 7.57-7.48 (m, 4H)

[0481] [ka]

[0482] A 2 mL vial was charged with 3-hydroxy-2-(2-(trifluoromethyl)pyridin-4-yl)-1H-inden-1-one (0.83 mmol, 0.241 g) and 1.66 mL of hydrazine monohydrate. The vial was sealed with a crimp cap and heated in a microwave reactor at 160 °C for 30 minutes. The cooled reaction mixture was filtered and rinsed with water. The collected solid was dried in a Buchner funnel under airflow for 1 hour to give 0.055 g (22%) of 4-((2-(trifluoromethyl)pyridin-4-yl)methyl)phthalazin-1(2H)-one as a white solid. 1 H NMR (400 MHz, d6-DMSO) δ 12.60 (s, 1H), 8.68 (d, J = 4.9 Hz, 1H), 8.28 (d, J = 7.3 Hz, 1H), 8.01 (m, 1H), 7.94 (m, 2H), 7.87 (m, 1H), 7.64 (d, J = 4.9 Hz, 1H), 4.51 (s, 2H)

[0483] [ka]

[0484] A flame-dried 5 mL vial was charged with 4-((2-(trifluoromethyl)pyridin-4-yl)methyl)phthalazin-1(2H)-one (0.18 mmol, 0.055 g) and placed under an argon atmosphere. Freshly distilled, dry acetonitrile (0.72 mL) and HCl in dioxane (4 M, 0.36 mmol, 0.09 mL) were injected. To the homogeneous solution was added phosphoryl chloride (0.45 mmol, 0.042 mL). The vial was placed in a reactor plate and heated to 50 °C for 24 h. After the reaction was cooled to room temperature, the vial was placed in an ice bath. To the cooled, pale yellow slurry was added 2.5 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 min, and the precipitated solid was filtered and rinsed with water. The material was dried under vacuum to give 0.046 g (79%) of 1-chloro-4-((2-(trifluoromethyl)pyridin-4-yl)methyl)phthalazine as a white solid. LC / MS (ESI, M+1): found 324.5

[0485] Starting material 4

[0486] [ka]

[0487] A flame-dried 500 mL RB was charged with 2-methoxyisonicotinic acid (20 mmol, 3.06 g) and placed under an argon atmosphere. The flask was charged with 80 mL of dry THF and freshly distilled TEA (38 mmol, 5.26 mL). The RB was placed in an ice bath, and the mixture was allowed to equilibrate to temperature. After cooling, isobutyl chloroformate (24 mmol, 3.12 mL) was added dropwise to the solution. After complete addition, the reaction was stirred for 30 min. To this slurry was slowly poured a solution of NaBH (70 mmol, 2.65 g) in 40 mL of water. The ice bath was removed, and the reaction was allowed to warm to rt and stirred for 14 h. The RB was then placed in an oil bath and heated to 50 °C for 1 h. The reaction mixture was recooled in an ice bath and quenched with saturated NH Cl(aq). The mixture was poured into a separatory funnel and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to reduced volume. The crude material was loaded onto a 100 g silica gel cartridge and purified on a Biotage flash system eluting with Hex / EtOAc to give 1.67 g (67%) of (2-methoxypyridin-4-yl)methanol as a clear oil. 1 H NMR (400 MHz, d6-DMSO) δ 8.08 (d, J = 5.3 Hz, 1H), 6.91 (d, J = 5.3 Hz, 1H), 6.73 (s, 1H), 5.39 (bs, 1H), 4.49 (s, 2H), 3.83 (s, 3H)

[0488] [ka]

[0489] To a flame-dried 250 mL RB under an argon atmosphere was added (2-methoxypyridin-4-yl)methanol (12 mmol, 1.67 g), 30 mL DMSO, 30 mL DCM, and freshly distilled DIPEA (38.4 mmol, 6.69 mL). The RB was placed in an ice bath, and the mixture was allowed to equilibrate to temperature. To this mixture was added dropwise a solution of sulfur trioxide pyridine complex (36 mmol, 5.73 g) in 72 mL DMSO, also containing pyridine (10 mmol, 0.80 mL). The reaction was stirred at 0 °C and gradually warmed to rt over 14 h. The reaction mixture was poured into a separatory funnel containing EtOAc and washed with water (x2) and brine. The combined aqueous washes were extracted with EtOAc, which was then washed with water (x2) and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to reduced volume. The crude material was loaded onto a 100 g silica gel cartridge and purified on a Biotage flash system eluting with Hex / EtOAc to give 1.3 g (79%) of 2-methoxyisonicotinaldehyde as a clear, pale yellow oil. 1 H NMR (400 MHz, d6-DMSO) δ 10.03 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.36 (dd, J = 0.7 & 5.2 Hz, 1H), 7.28 (m, 1H), 3.92 (s, 3H)

[0490] [ka]

[0491] A solution of sodium methoxide (120 mmol, 6.48 g) in 60 mL of methanol in a 250 mL R.B. was cooled to 0 °C in an ice bath. In a separate pear-shaped RB, a solution of 1-isobenzofuranone (30 mmol, 4.02 g), 2-methoxyisonicotinaldehyde (31.5 mmol, 4.32 g), and 30 mL of ethyl propionate was prepared and transferred to the methoxide solution via syringe. This was added dropwise over 10 minutes to the methoxide solution via an attached reflux condenser. After complete addition, the reaction was stirred at room temperature for 1 hour. The reaction was heated to reflux (100 °C) for 1.5 hours. The cooled reaction mixture was concentrated to a thick slurry, diluted with water (100 mL), and transferred to a separatory funnel. The dark red solution was extracted with diethyl ether (3 × 50 mL). The aqueous layer in a 250 mL Erlenmeyer flask was acidified with acetic acid. A precipitate formed which was filtered and rinsed with water, EtOAc, and Et 2 O. The material was dried under vacuum to give 4.90 g (64%) of 3-hydroxy-2-(2-methoxypyridin-4-yl)-1H-inden-1-one as a light yellow solid. 1 H NMR (400 MHz, d6-DMSO) δ 13.35 (bs, 1H), 8.37 (dd, J = 1.5 & 6.8 Hz, 1H), 8.27 (d, J = 1.4 Hz, 1H), 7.83 (d, J = 6.7 Hz, 1H), 7.50 (m, 2H), 7.43 (m, 2H), 3.99 (s, 3H)

[0492] [ka]

[0493] A 5 mL microwave vial was charged with 3-hydroxy-2-(2-methoxypyridin-4-yl)-1H-inden-1-one (4 mmol, 1.01 g) and 4 mL of hydrazine monohydrate. The vial was sealed with a crimp cap. The reaction was heated in a microwave reactor at 160 °C for 1 h. The precipitated solid was filtered and rinsed with water. The crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.300 g (28%) of 4-((2-methoxypyridin-4-yl)methyl)phthalazin-1(2H)-one as a white solid. 1 H NMR (400 MHz, d6-DMSO) δ 12.63 (bs, 1H), 8.28 (m, 1H), 7.94 (m, 2H), 7.27 (d, J = 6.7 Hz, 1H), 6.24 (s, 1H), 6.08 (dd, J = 1.7 & 6.8 Hz, 1H), 4.12 (s, 2H), 3.33 (s, 3H)

[0494] [ka]

[0495] A flame-dried 50 mL RB was charged with 4-((2-methoxypyridin-4-yl)methyl)phthalazin-1(2H)-one (3.6 mmol, 0.963 g) and placed under an argon atmosphere. Freshly distilled dry acetonitrile (14.4 mL) and HCl in dioxane (4 M, 7.2 mmol, 1.8 mL) were added. To the homogeneous solution was added phosphoryl chloride (9 mmol, 0.839 mL). The RB was placed in an oil bath and heated to 50 °C for 24 h. After the reaction was cooled to room temperature, the RB was placed in an ice bath. To the cooled pale pink slurry was added 51 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 min. Typically, the product would precipitate out of solution, but this did not occur. Therefore, the reaction mixture was poured into a separatory funnel containing 90 / 10 EtOAc / MeOH. The layers were separated and the aqueous layer was extracted with 90 / 10 EtOAc / MeOH. The combined organic layers were washed with saturated NaHCO, water, and brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to afford 0.762 g (74%) of 1-chloro-4-((2-methoxypyridin-4-yl)methyl)phthalazine as a light tan solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.35 (m, 1H), 8.29 (m, 1H), 8.12 (m, 2H), 8.04 (d, J = 5.3 Hz, 1H), 6.90 (d, J = 5.0 Hz, 1H), 6.78 (s, 1H), 4.71 (s, 2H), 3.79 (s, 3H)

[0496] Starting material 5

[0497] [ka]

[0498] A flame-dried 500 mL RB was charged with 3-(trifluoromethyl)isonicotinic acid (20 mmol, 3.82 g) and placed under an argon atmosphere. The flask was charged with 80 mL of THF and freshly distilled TEA (38 mmol, 5.26 mL). The RB was placed in an ice bath, and the mixture was allowed to equilibrate to temperature. After cooling, isobutyl chloroformate (24 mmol, 3.12 mL) was added dropwise to the solution. After complete addition, the reaction was stirred for 30 min. To the slurry was slowly added a solution of NaBH (70 mmol, 2.65 g) in 40 mL of water. The ice bath was removed, and the reaction was allowed to warm to rt and stirred for 14 h. The RB was placed in an oil bath and heated to 50 °C for 1 h. The reaction mixture was recooled in an ice bath and quenched with saturated NH Cl(aq). The mixture was poured into a separatory funnel and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to reduced volume. The crude material was loaded onto a 100 g silica gel cartridge and purified on a Biotage flash system eluting with Hex / EtOAc to give 1.032 g (29%) of (3-(trifluoromethyl)pyridin-4-yl)methanol as a pale yellow waxy solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.87 (d, J = 5.1 Hz, 1H), 8.84 (s, 1H), 7.81 (d, J = 5.1 Hz, 1H), 5.77 (t, J = 5.7 Hz, 1H), 4.71 (d, J = 5.7 Hz, 1H)

[0499] [ka]

[0500] To a flame-dried 250 mL RB under an argon atmosphere was added (3-(trifluoromethyl)pyridin-4-yl)methanol (5.65 mmol, 1.00 g), 14 mL DMSO, 14 mL DCM, and freshly distilled DIPEA (18.1 mmol, 3.15 mL). The RB was placed in an ice bath, and the mixture was allowed to equilibrate to temperature. A solution of sulfur trioxide pyridine complex (16.95 mmol, 2.70 g) in 34 mL DMSO, also containing pyridine (10 mmol, 0.80 mL), was added dropwise to the mixture. The reaction was stirred at 0 °C and gradually warmed to rt over 14 h. The reaction mixture was poured into a separatory funnel containing EtOAc and washed with water (x2) and brine. The combined aqueous washes were extracted with EtOAc, which was then washed with water (x2) and brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to reduced volume. The crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with Hex / EtOAc to give 0.609 g (61%) of 3-(trifluoromethyl)isonicotinaldehyde as a clear oil. 1 H NMR (400 MHz, d6-DMSO) δ10.30 (q, J = 1.8 Hz, 1H), 9.18 (m, 2H), 8.00 (d, J = 4.9 Hz, 1H)

[0501] [ka]

[0502] A solution of sodium methoxide (13.25 mmol, 0.716 g) in 6.6 mL of methanol in 25 mL L.B. was cooled to 0 °C in an ice bath. In a separate vial, a solution of 1-isobenzofuranone (3.31 mmol, 0.444 g), 3-(trifluoromethyl)isonicotinaldehyde (3.48 mmol, 0.609 g), and 3.5 mL of ethyl propionate was prepared and transferred to the methoxide solution dropwise over 10 min via a syringe attached to a reflux condenser. After complete addition, the reaction was stirred at rt for 1 h. The reaction was heated to reflux (100 °C) for 1.5 h. The cooled reaction mixture was concentrated to a thick slurry, diluted with water (100 mL), and transferred to a separatory funnel. The dark red solution was extracted with diethyl ether (3 × 50 mL). The aqueous layer in a 250 mL Erlenmeyer flask was acidified with acetic acid. Usually, a precipitate formed, but this did not occur, so the aqueous solution was extracted with EtOAc (x2). The organic layer was dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was carried on to the next step. LC / MS (ESI, M+1): Found 292.1

[0503] [ka]

[0504] A 5 mL microwave vial was charged with 3-hydroxy-2-(3-(trifluoromethyl)pyridin-4-yl)-1H-inden-1-one (3 mmol, 0.874 g) and 2 mL of hydrazine monohydrate. The vial was sealed with a crimp cap. The reaction was heated in a microwave reactor at 160 °C for 1 h. The precipitated solid was filtered and rinsed with water. The crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.185 g (20%) of 4-((3-(trifluoromethyl)pyridin-4-yl)methyl)phthalazin-1(2H)-one as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.53 (s, 1H), 8.95 (s, 1H), 8.77 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.96 (m, 2H), 7.94 (m, 1H), 7.47 (d, J = 5.1 Hz, 1H), 4.55 (s, 2H)

[0505] [ka]

[0506] A flame-dried 50 mL RB was charged with 4-((3-(trifluoromethyl)pyridin-4-yl)methyl)phthalazin-1(2H)-one (0.589 mmol, 0.180 g) and placed under an argon atmosphere. Freshly distilled dry acetonitrile (2.35 mL) and HCl in dioxane (4 M, 1.178 mmol, 0.294 mL) were charged. To the homogeneous solution was added phosphoryl chloride (1.473 mmol, 0.137 mL). The RB was placed in an oil bath and heated to 50 °C for 24 h. After the reaction was cooled to room temperature, the RB was placed in an ice bath. To the cooled pale pink slurry was added 8.4 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 min. The precipitated solid was filtered and rinsed with water. The material was dried under vacuum to give 0.123 g (65%) of 1-chloro-4-((3-(trifluoromethyl)pyridin-4-yl)methyl)phthalazine as a tan solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.98 (s, 1H), 8.77 (d, J = 5.1 Hz, 1H), 8.37 (m, 2H), 8.21 (m, 2H), 7.39 (d, J = 5.1 Hz, 1H), 4.97 (s, 2H)

[0507] Starting material 6

[0508] [ka]

[0509] A flame-dried 500 mL LRB was charged with dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (5.78 mmol, 1.40 g) and the system was placed under an argon atmosphere. 157 mL of THF was added to the flask. The RB was placed in a dry ice / acetone bath, and the mixture was allowed to equilibrate to temperature. A solution of Li-HMDS (1 M, 5.78 mmol, 5.78 mL) in THF was added, and the mixture was stirred for 1 h. The reaction mixture turned greenish-yellow. 4-Acetyl-2-methylpyridine (5.78 mmol, 0.64 mL) was added, and the reaction mixture was stirred at -78 °C for 1 h. The bath was then removed, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated NH4Cl(aq) and transferred to a separatory funnel containing EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to reduced volume. The crude material was loaded onto a 100 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 1.3 g (99%) of 3-(1-(pyridin-4-yl)ethylidene)isobenzofuran-1(3H)-one as an off-white waxy solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.81 (m, 1H), 8.74 (m, 2H), 7.93 (m, 1H), 7.82 (m, 1H), 7.51 (m, 2H), 6.70 (m, 1H), 2.31 (s, 3H)

[0510] [ka]

[0511] A 10 mL microwave vial was charged with 3-(1-(pyridin-4-yl)ethylidene)isobenzofuran-1(3H)-one (5.3 mmol, 1.259 g) and 5.3 mL of hydrazine monohydrate. The vial was sealed with a crimp cap, placed in an aluminum heat block, and heated at 70 °C for 14 h. The precipitated solid was filtered and rinsed with EtOH. The filtrate was concentrated to a reduced volume, and the crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.4187 g (31%) of 4-(1-(pyridin-4-yl)ethyl)phthalazin-1(2H)-one as a white solid. 1 H NMR (400 MHz, d6-DMSO) δ 13.30-11.89 (bs, 1H), 8.46 (d, 2H), 8.26 (M, 1H), 7.90-7.75 (m, 3H), 7.33 (d, 2H), 4.85 (q, 1H), 1.58 (d, 3H)

[0512] [ka]

[0513] A flame-dried 50 mL RB was charged with 4-(1-(pyridin-4-yl)ethyl)phthalazin-1(2H)-one (1.66 mmol, 0.418 g) and placed under an argon atmosphere. Freshly distilled dry acetonitrile (6.6 mL) and HCl in dioxane (4 M, 3.32 mmol, 0.83 mL) were added. To the homogeneous solution was added phosphoryl chloride (4.15 mmol, 0.386 mL). The RB was placed in an oil bath and heated to 50 °C for 24 h. After the reaction was cooled to room temperature, the RB was placed in an ice bath. To the cooled slurry was added 23.6 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 min. The precipitated solid was filtered and rinsed with water. The material was dried under vacuum to give 0.374 g (83%) of 1-chloro-4-(1-(pyridin-4-yl)ethyl)phthalazine as an off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.46 (d, 2H), 8.37 (m, 2H), 8.11 (m, 2H), 7.38 (d, 2H), 5.31 (q, J = 7.0 Hz, 1H), 1.79 (d, J = 7.0 Hz, 1H)

[0514] Starting material 7

[0515] [ka]

[0516] A flame-dried 500 mL RRB was charged with dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (5.0 mmol, 1.21 g) and the system was placed under an argon atmosphere. 116 mL of THF was added to the flask. The RB was placed in a dry ice / acetone bath, and the mixture was allowed to equilibrate to temperature. A solution of Li-HMDS (1 M, 5.0 mmol, 5.0 mL) in THF was added, and the mixture was stirred for 1 h. The reaction mixture turned greenish-yellow. A solution of 2,2,2-trifluoro-1-(pyridin-4-yl)ethan-1-one (5 mmol, 0.875 g) in 20 mL of THF, prepared in a flame-dried 100 mL pear-shaped flask under argon, was cannulated into the ylide reaction mixture. The reaction mixture was stirred at -78 °C for 1 h, after which the bath was removed, and the reaction mixture was stirred at rt for 14 h. The reaction mixture was quenched with saturated NH4Cl(aq) and transferred to a separatory funnel containing EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 1.395 g (93%) of 3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethylidene)isobenzofuran-1(3H)-one as a white solid. LC / MS (ESI, M+1): found 292.1

[0517] [ka]

[0518] A 10 mL microwave vial was charged with 3-(2,2,2-trifluoro-1-(pyridin-4-yl)ethylidene)isobenzofuran-1(3H)-one (4.77 mmol, 1.39 g) and 4.77 mL of hydrazine monohydrate. The vial was sealed with a crimp cap, placed in an aluminum heat block, and heated at 70 °C for 14 h. The precipitated solid was filtered and rinsed with EtOH. The filtrate was concentrated to a reduced volume, and the crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.236 g (16%) of 4-(2,2,2-trifluoro-1-(pyridin-4-yl)ethyl)phthalazin-1(2H)-one as a white solid. LC / MS (ESI, M+1): found 306.1

[0519] [ka]

[0520] A flame-dried 50 mL RB was charged with 4-(2,2,2-trifluoro-1-(pyridin-4-yl)ethyl)phthalazin-1(2H)-one (0.773 mmol, 0.236 g) and placed under an argon atmosphere. Freshly distilled dry acetonitrile (3.1 mL) and HCl in dioxane (4 M, 1.546 mmol, 0.386 mL) were added. To the homogeneous solution was added phosphoryl chloride (1.932 mmol, 0.180 mL). The RB was placed in an oil bath and heated to 50 °C for 24 h. After the reaction was cooled to room temperature, the RB was placed in an ice bath. To the cooled slurry was added 11 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 min. The precipitated solid was filtered and rinsed with water. The material was dried under vacuum to give 0.1511 g (60%) of 1-chloro-4-(2,2,2-trifluoro-1-(pyridin-4-yl)ethyl)phthalazine as a pale orange solid. 1H NMR (400 MHz, d6-DMSO) δ 8.38 (m, 3H), 8.29 (m, 3H), 8.25-7.81 (m, 3H) LC / MS (ESI, M+1): Actual value 324.5

[0521] Starting Material 8

[0522] [ka]

[0523] A flame-dried 250 mL RB was charged with 2-methylisonicotinic acid (40 mmol, 5.48 g), N,O-dimethylhydroxylamine hydrochloride (48 mmol, 4.66 g), and HATU (48 mmol, 18.25 g) and flushed with a positive pressure of argon. The flask was charged with 80 mL of DMF, followed by DIPEA (60 mmol, 10.5 mL). The RB was placed in an oil bath heated to 50 °C, and the reaction was stirred for 14 h. The cooled reaction mixture was poured into a separatory funnel containing EtOAc and water. The organic layer was washed with saturated NaHCO3(aq) and then brine. The combined aqueous layers were extracted with EtOAc, which was then washed with water and then brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 220 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 7.19 g (99%) of N-methoxy-N,2-dimethylisonicotinamide as a yellow oil. 1 H NMR (400 MHz, d6-DMSO) δ 8.54 (dd, 1H), 7.37 (s, 1H), 7.30 (d, 1 H), 3.55 (s, 3 H), 3.27 (s, 3 H), 2.52 (s, 3 H)

[0524] [ka]

[0525] A flame-dried 1 L RB was charged with N-methoxy-N,2-dimethylisonicotinamide (40 mmol, 7.2 g) and placed under an argon atmosphere. 200 mL of dry THF was added to the flask. The RB was placed in an ice bath, and the solution was allowed to equilibrate to temperature. A solution of MeMgBr (3 M, 60 mmol, 20 mL) in THF was added dropwise slowly. The reaction was stirred overnight, gradually warming to room temperature. The reaction mixture was recooled in an ice bath and quenched with saturated NH4Cl(aq). The reaction mixture was transferred to a separatory funnel and extracted three times with EtOAc. The combined organic layers were washed with water, then brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 220 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 2.63 g (48%) of 1-(2-methylpyridin-4-yl)ethan-1-one as a dark red oil. 1 H NMR (400 MHz, d6-DMSO) δ 8.66 (dd, 1H), 7.70 (s, 1H), 7.61 (d, 1 H), 2.61 (s, 3 H), 2.57 (s, 3H)

[0526] [ka]

[0527] A flame-dried 1 L RB was connected to the solvent system and approximately 486 mL of dry THF was dispensed. Dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphonate (19.45 mmol, 4.71 g) was added to the flask, and the system was placed under an argon atmosphere. The RB was placed in a dry ice / acetone bath, and the mixture was allowed to equilibrate to temperature. A THF solution of Li-HMDS (1 M, 19.45 mmol, 19.45 mL) was injected, and the mixture was stirred for 1 h. The reaction mixture turned greenish-yellow. 4-Acetyl-2-methylpyridine was injected, and the reaction mixture was stirred at -78 °C for 1 h. The bath was then removed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl(aq) and transferred to a separatory funnel containing EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 220 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 3.9 g (80%) of 3-(1-(2-methylpyridin-4-yl)ethylidene)isobenzofuran-1(3H)-one as a red solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.58 (d, 1H), 7.91 (m, 1 H), 7.57 (m, 2H), 7.36 (s, 1H), 7.28 (d, 1H), 6.72 (m, 1H), 2.52 (s, 3H), 2.27 (s, 3H). LC / MS (ESI, M+1): Actual value 252.2

[0528] [ka]

[0529] A 20 mL vial was charged with 3-(1-(2-methylpyridin-4-yl)ethylidene)isobenzofuran-1(3H)-one (5.13 mmol, 1.29 g) and sealed with a crimp cap. 10.2 mL of a 1 M solution of hydrazine in EtOH was injected into the vial. The vial was placed in a reactor plate, and the reaction was heated to 50 °C overnight. The next day, a light yellow precipitate formed. A small amount of water was added to help break down the precipitate so that it could be filtered, which dissolved it. The reaction mixture was loaded onto a 100 g C18 silica gel cartridge and purified on a Biotage flash system eluting with HO / MeOH + 0.1% TFA to give 0.852 g (63%) of 4-(1-(2-methylpyridin-4-yl)ethyl)phthalazin-1(2H)-one as a dark yellow viscous oil. 1 H NMR (400 MHz, d6-DMSO) δ 12.79 (bs, 1H), 8.70 (d, 1H), 8.29 (m, 1H), 7.96-7.81 (m, 5H), 5.15 (q, 1H), 2.66 (s, 3H), 1.65 (d, 3H). LC / MS (ESI, M+1): Actual value 266.2

[0530] [ka]

[0531] A flame-dried 200 mL RB was charged with 4-(1-(2-methylpyridin-4-yl)ethyl)phthalazin-1(2H)-one (9.61 mmol, 2.55 g) and placed under an argon atmosphere. 36.6 mL of acetonitrile was added to the flask, followed by 4.8 mL of HCl in dioxane (4 M, 19.22 mmol). To the homogeneous solution was added phosphoryl chloride (24.02 mmol, 2.24 mL). The RB was placed in an oil bath and heated to 55°C for 24 hours. After the reaction was cooled to room temperature, the RB was placed in an ice bath. To the cooled solution was slowly added 137 mL of 1 M NaHCO3(aq) solution. The cooled mixture was stirred for 30 minutes. The mixture was transferred to a separatory funnel and extracted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over sodium sulfate, and concentrated down to a dry mass. The crude material was loaded onto a 120 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to afford 1.71 g (63%) of 1-chloro-4-(1-(2-methylpyridin-4-yl)ethyl)phthalazine as a golden yellow solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.39-8.28 (m, 3H), 8.11 (m, 2H), 7.24 (s, 1H), 7.16 (d, 1H), 5.25 (q, 1H), 2.39 (s, 3H), 1.77 (d, 3H). LC / MS (ESI, M+1): Actual value 284.6 Synthesis of SR-35429

[0532] [ka]

[0533] SR-35429: A 20 mL vial was sequentially charged with 1-chloro-4-(1-(2-methylpyridin-4-yl)ethyl)phthalazine (3.52 mmol, 1.0 g), 7 mL of DMF, DIPEA (10.56 mmol, 1.84 mL), and tetrahydropyran-4-ylmethylamine (7.04 mmol, 0.764 mL) and sealed with a crimp cap. The vial was placed in a microwave reactor and heated to 160 °C for 55 min. The reaction mixture was loaded onto a 120 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH. The product-containing fractions were concentrated down, loaded onto a 120 g C18 silica gel cartridge, and purified on a Biotage flash system eluting with HO / MeOH+0.1% TFA to give 1.09 g (85%) of 4-(1-(2-methylpyridin-4-yl)ethyl)-N-((tetrahydro-2H-pyran-4-yl)methyl)phthalazin-1-amine as a clear oil. 1 H NMR (400 MHz, d6-DMSO) δ 10.09 (bt, 1H), 8.77 (m, 1H), 8.73 (d, 1H), 8.20 (m, 1H), 8.12 (m, 1H), 7.87 (s, 1H), 7.82 (m, 1H), 5.37 (q, 1H), 3.89 (m, 2H), 3.53 (m, 2H), 3.30 (m, 2H), 2.66 (s, 3H), 2.06 (m, 1H), 1.76 (m, 1H), 1.72 (m, 3H), 1.31 (m, 2H). 13 C NMR (101 MHz d6-DMSO) δ 158.50, 158.15, 154.12, 151.71, 150.44, 142.08, 135.63, 133.48, 126.25, 126.11, 126.02, 125.02, 123.25, 121.00, 66.53, 55.00, 48.54, 47.45, 33.16, 30.00, 19.90, 19.71. LC / MS (ESI, M+1): Actual value 363.3

[0534] Starting material 9

[0535] [ka]

[0536] A 500 mL RB was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (12 mmol, 2.34 g), KF (30 mmol, 1.74 g), DMSO (100 mL), and water (30 mL). The mixture was degassed by bubbling argon through it for 15 minutes. PdCl2dppf was added to the RB, and the system was flushed with a positive pressure of argon. While flushing the system with argon, 4-bromo-2-methylpyridine (10 mmol, 1.18 mL) was injected and a balloon of argon was attached. The RB was placed in an oil bath and heated to 130 °C for 16 hours. The cooled reaction mixture was filtered through a plug of Celite rinsed with EtOAc. The filtrate was transferred to a separatory funnel containing brine and EtOAc. The aqueous layer was extracted with EtOH (x3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was loaded onto a 220 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 1.0 g of 2-(2-methylpyridin-4-yl)acetonitrile as a dark red oil, which was stored under argon in a −20° C. freezer. 1 H NMR (400 MHz, d6-DMSO) δ 8.45 (d, J = 5.1 Hz, 1H), 7.24 (s, 1H), 7.18 (d, J = 5.1 Hz, 1H), 4.10 (s, 2H), 2.48 (s, 3H)

[0537] Starting material 9-1

[0538] [ka]

[0539] A flame-dried 25 mL LRB was charged with 1,4-dichlorophthalazine (1 mmol, 0.199 g) and placed under an argon atmosphere. To this flask was added 2-(2-methylpyridin-4-yl)acetonitrile (1.2 mmol, 0.158 g) and 2 mL of dry THF. A 1 M solution of NaHMDS (1.3 mmol, 1.3 mL) in THF was added dropwise, and the reaction was stirred at rt. The reaction mixture was quenched with 0.2 mL of saturated NH4Cl(aq) and concentrated down to a reduced volume. The crude material was loaded onto a 220 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.201 g (68%) of 2-(4-chlorophthalazin-1-yl)-2-(2-methylpyridin-4-yl)acetonitrile as a dark red solid. LC / MS (ESI, M+1): Found 295.6

[0540] Starting material 9-2

[0541] [ka]

[0542] A flame-dried 100 mL RRB was charged with 1,4-dichlorophthalazine (1 mmol, 0.199 g) and placed under a positive argon pressure. 20 mL of THF and 2-(2-methylpyridin-4-yl)acetonitrile (1.2 mmol, 0.158 g) were charged to the RB. The argon inlet was removed, but the outlet to the bubbler was still attached. A 1 M solution of NaHMDS (2.5 mmol, 2.5 mL) in THF was added dropwise. The reaction mixture turned dark red upon addition. The reaction was stirred at rt for 12 h. To the reaction was added 5 mL of saturated NHOAc(aq) and sodium peroxide, and the reaction was stirred for an additional 10 h. The insoluble solid was filtered off and rinsed with MeOH. The filtrate was concentrated down to a low volume and the crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.113 g (39%) of (4-chlorophthalazin-1-yl)(2-methylpyridin-4-yl)methanone as a red solid. LC / MS (ESI, M+1): found 284.5

[0543] Starting Material 10

[0544] [ka]

[0545] A flame-dried 500 mL RB was charged with benzofuran-2-carboxylic acid (20 mmol, 3.24 g) and placed under an argon atmosphere. The flask was charged with 80 mL of THF and freshly distilled TEA (38 mmol, 5.26 mL). The RB was placed in an ice bath, and the mixture was allowed to equilibrate to temperature. After cooling, isobutyl chloroformate (24 mmol, 3.12 mL) was added dropwise to the solution. After complete addition, the reaction was stirred for 30 min. To the slurry was slowly added a solution of NaBH4 (70 mmol, 2.65 g) in 40 mL of water. The ice bath was removed, and the reaction was allowed to warm to rt and stirred continuously. The RB was then placed in an oil bath and heated to 50 °C for 1 h. The reaction mixture was recooled in an ice bath and quenched with saturated NH4Cl(aq). The mixture was poured into a separatory funnel and extracted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to reduced volume. The crude material was loaded onto a 120 g silica gel cartridge and purified on a Biotage flash system eluting with DCM to give 2.02 g (68%) of benzofuran-2-ylmethanol as a pale yellow oil. 1 H NMR (400 MHz, d6-DMSO) δ 7.57 (m, 1H), 7.49 (m, 1H), 7.28 (m, 2H), 6.66 (s, 1H), 4.78 (s, 2H), 2.38 (bs, 1H)

[0546] [ka]

[0547] A flame-dried 200 mL RB was charged with phthalimide (16.2 mmol, 2.38 g) and PPh3 (16.2 mmol, 4.25 g). The RB was sealed and placed under an argon atmosphere. Dry THF (67.5 mL) was added, followed by benzofuran-2-ylmethanol (13.5 mmol, 2 g), and the RB was placed in an ice bath. Once the mixture had equilibrated to temperature, DEAD (40 wt% in toluene, 16.2 mmol, 7.37 mL) was added dropwise over 10 min. The reaction was stirred and allowed to gradually warm to rt. The reaction mixture was concentrated down to a reduced volume, and the crude material was loaded onto a 220 g silica gel cartridge and purified on a Biotage flash system eluting with Hex / EtOAc to give 2.22 g (59%) of 2-(benzofuran-2-ylmethyl)isoindoline-1,3-dione as an off-white solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.93 (m, 2H), 7.87 (m, 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.37-7.13 (m, 2H), 6.89 (s, 1H), 4.96 (s, 2H)

[0548] [ka]

[0549] To a concentrated 500 mL LRB flask containing 2-(benzofuran-2-ylmethyl)isoindoline-1,3-dione (8 mmol, 2.22 g) under argon, 40 mL of absolute EtOH was added, followed by 1.56 mL of hydrazine monohydrate. The reaction was stirred at rt. Material precipitated out. The reaction mixture was concentrated to reduce the volume, and the solid material was dissolved in a mixture of EtOAc and 1 M NaOH (aq). The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to reduce the volume. The crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.915 g (77%) of benzofuran-2-ylmethanamine as a clear, pale yellow oil. 1 H NMR (400 MHz, d6-DMSO) δ 7.56 (m, 1H), 7.49 (m, 1H), 7.27-7.16 (m, 2H), 6.68 (m, 1H), 5.50 (bs, 2H), 3.84 (d, J = 1.1 Hz, 2H)

[0550] General Procedure A - Synthesis of 2-amino-benzoxazoles

[0551] [ka]

[0552] A 20 mL vial was charged with 2-aminophenol (5 mmol) and 10 mL of a 1 / 1 MeOH / HO solution. The vial was sealed with a crimp cap and flushed with a positive pressure of argon. The vial was placed in a reactor plate, and a 3 M solution of cyanogen bromide (7.5 mmol, 2.5 mL) in DCM was injected into the solution. The reactor plate was then heated to 50 °C, and the reaction was stirred continuously. The cooled reaction mixture was quenched with 1 M NaOH (aq) until a pH of 7-8 was reached. The mixture was poured into a separatory funnel containing EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organics were washed with water (x2), then brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was used without further purification.

[0553] [ka]

[0554] 6-Methylbenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-5-methylphenol (5 mmol, 0.615 g) gave 0.741 g (100%) of the product as a light brown solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.23 (bs, 2H), 7.14 (s, 1H), 7.06 (m, 1H), 6.90 (m, 1H), 2.33 (s, 3H)

[0555] [ka]

[0556] 5-Fluorobenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-4-fluorophenol (5 mmol, 0.635 g) gave 0.749 g (98%) of the product as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ 7.55 (bs, 2H), 7.31 (dd, J = 4.5 & 8.7 Hz, 1H), 7.02 (dd, J = 2.6 & 9.3 Hz, 1H), 6.75 (ddd, J = 2.7, 8.6 & 10.0 Hz, 1H).

[0557] [ka]

[0558] 5-Nitrobenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-4-nitrophenol (5 mmol, 0.77 g) gave 0.811 g (90%) of the product as a yellow-green solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.00-7.90 (m, 4H), 7.57 (d, J = 8.7 Hz, 1H)

[0559] [ka]

[0560] 4-Nitrobenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-3-nitrophenol (5 mmol, 0.77 g) gave 0.631 g (70%) of the product as an orange solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.34 (bs, 2H), 7.91 (dd, 8.5, 1.0 Hz, 1H), 7.74 (dd, J = 7.8, 1.0 Hz, 1H), 7.11 (dd, J = 8.5, 7.8 Hz, 1H).

[0561] [ka]

[0562] 4-Fluorobenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-3-fluorophenol (5 mmol, 0.635 g) gave 0.495 g (65%) of the product as a deep red solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.60 (bs, 2H), 7.23 - 7.19 (m, 1H), 7.06 - 6.86 (m, 2H)

[0563] [ka]

[0564] 6-Fluorobenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-5-fluorophenol (5 mmol, 0.635 g) gave 0.371 g (49%) of the product as a dark purple solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.41 (bs, 2H), 7.33 (dd, J = 8.6, 2.5 Hz, 1H), 7.16 (dd, J = 8.5, 4.9 Hz, 1H), 6.94 (ddd, J = 10.3, 8.5, 2.6 Hz, 1H).

[0565] [ka]

[0566] 4-Methylbenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-3-methylphenol (5 mmol, 0.615 g) gave 0.646 g (87%) of the product as a reddish-brown solid. LC / MS (ESI, M+1): Found value 149.0

[0567] [ka]

[0568] Naphtho[2,3-d]oxazol-2-amine: Following general procedure A using 3-amino-2-naphthol (5 mmol, 0.796 g) gave 0.323 g (35%) of the product as a reddish-brown solid. LC / MS (ESI, M+1): Found value 185.1

[0569] [ka]

[0570] 7-Fluorobenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-6-fluorophenol (5 mmol, 0.635 g) gave 0.371 g (49%) of the product as a dark purple solid. LC / MS (ESI, M+1): Found value 153.0

[0571] [ka]

[0572] 7-Methylbenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-3-methylphenol (5 mmol, 0.615 g) gave 0.58 g (78%) of the product as an orange solid. LC / MS (ESI, M+1): Found 149.0

[0573] [ka]

[0574] 6-Methoxybenzo[d]oxazol-2-amine: Following general procedure A using 2-amino-4-methoxyphenol (5 mmol, 0.695 g) gave 0.701 g (85%) of the product as a red solid. LC / MS (ESI, M+1): Found 165.0

[0575] [ka]

[0576] Naphtho[1,2-d]oxazol-2-amine: Following general procedure A using 1-aminonaphthalen-2-ol hydrochloride (5 mmol, 0.978 g) and DIPEA (5 mmol, 0.871 mL) gave 0.412 g (44%) of the product as a tan solid. LC / MS (ESI, M+1): Found 185.0

[0577] [ka]

[0578] Naphtho[2,1-d]oxazol-2-amine: General procedure A was followed using 2-amino-1-naphthol hydrochloride (5 mmol, 0.978 g) and DIPEA (5 mmol, 0.871 mL) to give 0.501 g (54%) of the product as a tan solid. 1 H NMR (400 MHz, d6-DMSO) δ 8.02-7.92 (m, 2H), 7.79 (m, 1H), 7.61 (m, 1H, 7.52-7.35 (m, 4H)

[0579] [ka]

[0580] 1-(2-aminobenzo[d]oxazol-7-yl)ethan-1-one: Following general procedure A using 3'-amino-2'-hydroxyacetophenone (5 mmol, 0.756 g) gave 0.598 g (67%) of the product as a tan solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.54 (dd, J = 8.1, 1.4 Hz, 1H), 7.34 (dd, J = 7.7, 1.3 Hz, 1H), 7.26 (dd, J = 8.4, 7.3 Hz, 1H), 2.65 (s, 3H).

[0581] [ka]

[0582] A 200 mL LRB was charged with 3-bromoaniline (10 mmol, 1.09 mL), phthalic anhydride (10 mmol, 1.48 g), and 60 mL of acetic acid. A reflux condenser was attached and the RB was placed in an oil bath. The oil bath was heated to 120 °C and the reaction was refluxed. To the cooled reaction mixture, 50 mL of water was added, and the resulting slurry was stirred for 15 minutes. The precipitated solid was filtered and rinsed with water to give 2.7 g (89%) of 2-(3-bromophenyl)isoindoline-1,3-dione as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.99 (m, 2H), 7.84 (m, 2H), 7.68 (m, 1H), 7.57 (ddd, J = 7.7, 1.9, 1.4 Hz, 1H), 7.50 - 7.35 (m, 2H).

[0583] [ka]

[0584] In an argon-filled glovebox, MgCl (10 mmol, 0.952 g) and zinc powder (-325 mesh, 20 mmol, 1.31 g) were weighed into a 250 mL RB. The RB was sealed and removed from the glovebox. NiI (1 mmol, 0.375 g), dtbbpy (1 mmol, 0.268 g), and 2-(3-bromophenyl)isoindoline-1,3-dione (10 mmol, 3.02 g) were added to the RB, which was then resealed and placed under an argon atmosphere via three vacuum-purge cycles. While under positive argon pressure, pyridine (10 mmol, 0.81 mL), 3-bromooxetane (20 mmol, 1.66 mL), and 60 mL of degassed DMA were injected. An argon balloon was attached, and the RB was placed in an oil bath and stirred at 50 °C for 14 h. The cooled reaction mixture was transferred to a separatory funnel containing EtOAc and water. The organic layer was washed with brine (x2). The combined aqueous layers were extracted with EtOAc, which was washed with water and then brine (x2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 100 g silica gel cartridge and purified on a Biotage flash system eluting with Hex / EtOAc to give 1.364 g (49%) of 2-(3-(oxetan-3-yl)phenyl)isoindoline-1,3-dione as an off-white solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.98 (m, 2H), 7.92 (m, 2H), 7.57-7.48 (m, 3H), 7.36 (m, 1H), 4.98 (dd, J = 8.4, 5.9 Hz, 2H), 4.65 (dd, J = 6.7, 5.9 Hz, 2H), 4.33 (tt, J = 8.4, 6.7 Hz, 1H)

[0585] [ka]

[0586] To a 5 mL vial was added 2-(3-(oxetan-3-yl)phenyl)isoindoline-1,3-dione (0.85 mmol, 0.237 g), 2.8 mL of an EtOH / DCM (5 / 1) solution, and NH2NH2·HO (1.7 mmol, 0.08 mL) sequentially. The vial was sealed and stirred at rt for 14 h. A white precipitate formed. The reaction mixture was filtered and rinsed with diethyl ether. The filtrate was concentrated to a reduced volume, and the crude material was loaded onto a 50 g silica gel cartridge and purified on a Biotage flash system eluting with Hex / EtOAc to give 0.085 g (67%) of 3-(oxetan-3-yl)aniline as a yellow oil. 1 H NMR (400 MHz, d6-DMSO) δ 7.17 (t, J = 7.5 Hz, 1H), 6.89 - 6.74 (m, 2H), 6.63 (m, 1H), 5.05 (dd, J = 8.4, 5.9 Hz, 2H), 4.77 (dd, J = 6.8, 5.9 Hz, 2H), 4.15 (m, 1H), 3.66-3.08 (bs, 2H).

[0587] [ka]

[0588] A 20 mL vial was charged with 3-nitrobenzenesulfonyl chloride (1 mmol, 0.221 g), 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (1.1 mmol, 0.164 g), 5 mL of DCM, and triethylamine (3 mmol, 0.418 mL). The vial was sealed and stirred at room temperature for 12 h. The reaction mixture was loaded directly onto a 50 g silica gel cartridge and purified on a Biotage Flash system eluting with DCM to yield 0.211 g (71%) of 8-((3-nitrophenyl)sulfonyl)-3-oxa-8-azabicyclo[3.2.1]octane as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.74 (t, J = 2.0 Hz, 1H), 8.47 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.23 ​​(ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 4.16 (m, 2H), 3.76 (m, 2H), 3.64 (m, 2H), 1.97 (m, 2H), 1.66 (m, 2H)

[0589] [ka]

[0590] A 20 mL vial was charged with 3-nitrobenzenesulfonyl chloride (1 mmol, 0.221 g), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (1.1 mmol, 0.124 g), 5 mL of DCM, and then triethylamine (2 mmol, 0.279 mL). The vial was sealed and stirred at room temperature for 12 h. The reaction mixture was loaded directly onto a 50 g silica gel cartridge and purified on a Biotage Flash system eluting with DCM to yield 0.211 g (71%) of 8-((3-nitrophenyl)sulfonyl)-3-oxa-8-azabicyclo[3.2.1]octane as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.59 (m, 1H), 8.49 (ddd, J = 8.2, 2.3, 1.1 Hz, 1H), 8.07 (ddd, J = 7.8, 1.7, 1.1 Hz, 1H), 7.80 (t, J = 8.0 Hz, 1H), 4.42 (m, 2H), 3.48 (m, 2H), 2.69 (dd, J = 11.3, 2.3 Hz, 2H), 2.12 - 1.95 (m, 4H).

[0591] [ka]

[0592] 8-((3-Nitrophenyl)sulfonyl)-3-oxa-8-azabicyclo[3.2.1]octane (0.707 mmol, 0.211 g) was reduced to give 0.167 g (88%) of 3-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)aniline as a pale pink solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.09 (t, J = 7.9 Hz, 1H), 6.92 (t, J = 2.0 Hz, 1H), 6.81 (ddd, J = 7.7, 1.9, 1.0 Hz, 1H), 6.70 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 5.50 (bs, 2H), 3.87 (m, 2H), 3.44 (m, 4H), 1.63 - 1.50 (m, 2H), 1.33 - 1.16 (m, 2H).

[0593] [ka]

[0594] 8-((3-Nitrophenyl)sulfonyl)-8-oxa-3-azabicyclo[3.2.1]octane (0.69 mmol, 0.206 g) was reduced to give 0.146 g (79%) of 3-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)aniline as a pink solid. 1 H NMR (400 MHz, d6-DMSO) δ 7.14 (m, 1H), 6.77 (m, 1H), 6.72 (m, 1H), 6.65 (m, 1H), 5.55 (bs, 2H), 4.23 (m, 2H), 3.07 (m, 2H), 2.37 (m, 2H), 1.69 (m, 4H)

[0595] [ka]

[0596] A 250 mL RB was charged with 3'-aminoacetophenone (10 mmol, 1.35 g), p-toluenesulfonic acid monohydrate (12 mmol, 2.28 g), ethylene glycol (30 mmol, 1.67 mL), and 130 mL of toluene. The RB was fitted with a Dean-Stark trap equipped with a reflux condenser and drying tube. The reaction was heated to reflux and stirred for 24 h. The cooled reaction mixture was partially concentrated down to approximately 25 mL, transferred to a separatory funnel with EtOAc, and washed with saturated NaHCO3(aq). The organic layer was dried over sodium sulfate, filtered, and concentrated down to give 0.53 g (29%) of 3-(2-methyl-1,3-dioxolan-2-yl)aniline as a dark tan solid. 1 H NMR (400 MHz, d6-DMSO) δ 6.97 (t, J = 7.8 Hz, 1H), 6.64 (t, J = 2.0 Hz, 1H), 6.54 (dt, J = 7.6, 1.3 Hz, 1H), 6.47 (ddd, J = 7.9, 2.4, 1.0 Hz, 1H), 5.07 (bs, 2H), 3.94 (m, 2H), 3.66 (m, 2H), 1.49 (s, 3H)

[0597] [ka]

[0598] SR-30013: A 5 mL vial was charged with 1-(3-((4-(pyridin-4-ylmethyl)phthalazin-1-yl)amino)phenyl)ethan-1-one ("SR1-34005", 0.25 mmol, 0.089 g), hydroxylamine hydrochloride (0.375 mmol, 0.026 g), sodium acetate (0.625 mmol, 0.051 g), and 1 mL of a (4 / 1) EtOH / HO solution. The vial was sealed with a crimp cap, placed in a reactor plate preheated to 95 °C, and stirred for 14 h. The reaction mixture was cooled to rt, and the precipitated solid was filtered and rinsed with water, EtOH, and then EtO to give 0.047 g (51%) of SR-30013 as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ11.23 (s, 1H), 9.23 (bs, 1H), 8.64 (m, 1H), 8.45 (m, 2H), 8.34 (t, J = 2.0 Hz, 1H), 8.12 (dd, J = 8.3, 1.2 Hz, 1H), 8.03 - 7.89 (m, 3H), 7.38 (t, J = 7.9 Hz, 1H), 7.34 - 7.27 (m, 3H), 4.60 (s, 2H), 2.20 (s, 3H). LC / MS (ESI, M+1): Actual value 370.3

[0599] [ka]

[0600] SR-30014: A 5 mL vial was charged with SR1-34005 (0.25 mmol, 0.089 g), O-methylhydroxylamine hydrochloride (0.375 mmol, 0.031 g), sodium acetate (0.625 mmol, 0.051 g), and 1 mL of a 4 / 1 EtOH / HO solution. The vial was sealed with a crimp cap and placed in a reactor plate preheated to 95 °C and stirred for 14 h. The reaction mixture was cooled to rt and transferred to a separatory funnel with EtOAc and water. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to a reduced volume. The crude material was loaded onto a 25 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.086 g (89%) of SR-30014 as a pale yellow solid. LC / MS (ESI, M+1): Found value 384.3

[0601] [ka]

[0602] SR-31144: Potassium tert-butoxide was dissolved in 0.5 mL of DMF in a 2 mL dry vial under an argon atmosphere. A separate 5 mL vial was charged with SR1-34005 (0.282 mmol, 0.100 g) and 2-(difluoromethylsulfonyl)pyridine (0.235 mmol, 0.045 g) and subjected to three vacuum / purge cycles with argon. 1 mL of DMF was injected into the vial, and the reaction mixture was cooled in a -50 °C bath. Once equilibrated to temperature, the potassium tert-butoxide solution was injected, and the reaction was allowed to warm slowly to -20 °C over 3 h. The reaction mixture was quenched by the addition of 0.5 mL of saturated NH4Cl(aq), followed by 0.5 mL of 3 M HCl, and allowed to warm to rt. The mixture was loaded onto a 25 g silica gel cartridge and purified on a Biotage flash system eluting with DCM / MeOH to give 0.052 g (47%) of SR-31144 as a red solid. 1 H NMR (400 MHz, d6-DMSO) δ 12.67 (s, 1H), 8.77 (d, J = 5.7 Hz, 2H), 8.67 (d, J = 4.6 Hz, 1H), 8.29 (dd, J = 7.8, 1.4 Hz, 1H), 8.11 (td, J = LC / MS (ESI, M+1): Actual value 389.3

[0603] General Procedure B

[0604] [ka]

[0605] A 5 mL microwave vial was charged with 1-chloro-4-(pyridin-4-ylmethyl)phthalazine (0.25 mmol, 0.064 g), amine (0.3 mmol), BrettPhos-Pd-G3 (0.0025 mmol, 0.002 g), BrettPhos (0.0025 mmol, 0.001 g), and tribasic potassium phosphate (0.3 mmol, 0.064 g), sealed with a crimp cap, and subjected to three vacuum-purge cycles with argon. 1,4-Dioxane was injected while under a forward flow of argon. The cap was wrapped with a layer of parafilm, and the vial was placed in a reactor plate preheated to 100 °C and stirred. The cooled reaction mixture was loaded directly onto a 25 g silica gel cartridge using a portion of 99 / 1 DCM / MeOH and purified on a Biotage flash system eluting with DCM / MeOH. Fractions containing product were concentrated down and loaded onto a 60 g C18 silica gel cartridge and purified on a Biotage flash system eluting with H2O / MeOH+0.1% TFA.

[0606] [ka]

[0607] SR-30010: Following general procedure B using 2-aminobenzoxazole (0.3 mmol, 0.067 g) gave 0.063 g (72%) of SR-30010 as a pale yellow solid. LC / MS (ESI, M+1): Found 354.2

[0608] [ka]

[0609] SR-30011: Following general procedure B using benzofuranmethanamine (0.3 mmol, 0.038 mL) afforded 0.055 g (60%) of SR-30011 as a pale yellow solid. LC / MS (ESI, M+1): found 367.3

[0610] [ka]

[0611] SR-30012: Following general procedure B using 3-(2-methyl-1,3-dioxolan-2-yl)aniline (0.3 mmol, 0.0545) gave 0.049 g (49%) of SR-30012 as a cream solid. LC / MS (ESI, M+1): Found 399.3

[0612] [ka]

[0613] SR-32066: Following general procedure B with 6-methylbenzoxazol-2-amine (0.3 mmol, 0.044 g) gave 0.019 g (20%) of SR-32066 as a yellow solid. LC / MS (ESI, M+1): Found 368.3

[0614] [ka]

[0615] SR-32067: Following general procedure B with 5-fluorobenzoxazol-2-amine (0.3 mmol, 0.046 g) afforded 0.030 g (32%) of SR-32067 as a deep orange solid. 1 H NMR (400 MHz, d6-DMSO) δ 14.34 (s, 1H), 8.49 (ddd, J = 15.3, 4.4, 1.6 Hz, 2H), 8.34 (m, 1H), 8.14 (m, 1H), 8.02 (m, 1H), 7.41 (m, 1H), 7.30 (m, 2H), 7.02 (m, 1H), 6.75 (ddd, J = 10.0, 8.6, 2.6 Hz, 1H), 4.77 (s, 1H), 4.54 (s, 1H). LC / MS (ESI, M+1): Actual value 372.2

[0616] [ka]

[0617] SR-32068: Following general procedure B using 5-nitrobenzoxazol-2-amine (0.3 mmol, 0.054 g) afforded 0.016 g (16%) of SR- as a yellow solid. LC / MS (ESI, M+1): found 399.2

[0618] [ka]

[0619] SR-32069: Following general procedure B with 4-nitrobenzoxazol-2-amine (0.3 mmol, 0.054 g) gave 0.035 g (35%) of SR-32069 as a yellow solid. LC / MS (ESI, M+1): Found 399.2

[0620] [ka]

[0621] SR-32070: Following general procedure B using 4-fluorobenzoxazol-2-amine (0.3 mmol, 0.046 g) gave 0.042 g (45%) of SR-32070 as a pale yellow solid. LC / MS (ESI, M+1): found 372.2

[0622] [ka]

[0623] SR-32071: Following general procedure B using 6-fluorobenzoxazol-2-amine (0.3 mmol, 0.046 g) gave 0.007 g (8%) of SR-32071 as a dark red solid. LC / MS (ESI, M+1): found 372.2

[0624] [ka]

[0625] SR-32072: Following general procedure B with 4-methylbenzoxazol-2-amine (0.3 mmol, 0.044 g) afforded 0.089 g (98%) of SR-32072 as a yellow solid. LC / MS (ESI, M+1): Found 368.3

[0626] [ka]

[0627] SR-32073: Following general procedure B with naphtho[2,3-d]oxazol-2-amine (0.3 mmol, 0.055 g) afforded 0.022 g (21%) of SR-32073 as a yellow solid. LC / MS (ESI, M+1): Found value 404.3

[0628] [ka]

[0629] SR-32074: Following general procedure B using 6-fluorobenzoxazol-2-amine (0.3 mmol, 0.046 g) gave 0.026 g (28%) of SR-32074 as a tan solid. LC / MS (ESI, M+1): found 372.2

[0630] [ka]

[0631] SR-32075: Following general procedure B using 7-methylbenzoxazol-2-amine (0.3 mmol, 0.044 g) gave 0.048 g (52%) of SR-32075 as a light brown solid. LC / MS (ESI, M+1): found 368.3

[0632] [ka]

[0633] SR-32076: Following general procedure B using 5-methoxybenzoxazol-2-amine (0.3 mmol, 0.046 g) gave 0.038 g (39%) of SR-32076 as a light brown solid. LC / MS (ESI, M+1): found 384.3

[0634] [ka]

[0635] SR-32077: Following general procedure B using naphtho[1,2-d]oxazol-2-amine (0.3 mmol, 0.055 g) gave 0.031 g (31%) of SR-32077 as a dark yellow solid. LC / MS (ESI, M+1): Found 404.3

[0636] [ka]

[0637] SR-33872: A modified version of general procedure B was followed using 1-chloro-4-((2-methylpyridin-4-yl)methyl)phthalazine (0.25 mmol, 0.067 g) and 2-aminobenzoxazole (0.3 mmol, 0.040 g) to afford 0.018 g (20%) of SR-33872 as a yellow solid. LC / MS (ESI, M+1): Found value 368.3

[0638] [ka]

[0639] SR-33875: A modified version of general procedure B was followed using 1-chloro-4-((2-methylpyridin-4-yl)methyl)phthalazine (0.25 mmol, 0.067 g) and benzoflunan-2-ylmethanamine (0.3 mmol, 0.044 g) to give 0.042 g (44%) of SR-33875 as a yellow solid. LC / MS (ESI, M+1): found 381.3

[0640] [ka]

[0641] SR-33873: A modified version of general procedure B was followed using 1-chloro-4-((2-(trifluoromethyl)pyridin-4-yl)methyl)phthalazine (0.14 mmol, 0.046 g) and 3-aminoacetophenone (0.17 mmol, 0.023 g) to give 0.042 g (70%) of SR-33873 as a yellow solid. LC / MS (ESI, M+1): found 423.3

[0642] [ka]

[0643] SR-33874: Following a modified version of general procedure B using 1-chloro-4-((2-methoxypyridin-4-yl)methyl)phthalazine (0.25 mmol, 0.071 g) and 3-aminoacetophenone (0.30 mmol, 0.041 g), 0.037 g (38%) of SR-33874 was obtained as a pale yellow solid. LC / MS (ESI, M+1): found 385.3

[0644] [ka]

[0645] SR-33875: A modified version of general procedure B was followed using 1-chloro-4-((2-methoxypyridin-4-yl)methyl)phthalazine (0.25 mmol, 0.071 g) and benzofuran-2-ylmethanamine (0.30 mmol, 0.044 g) to give 0.083 g (83%) of SR-33875 as a pale yellow solid. LC / MS (ESI, M+1): found 397.3

[0646] [ka]

[0647] SR-33876: A modified version of general procedure B was followed using 1-chloro-4-((3-(trifluoromethyl)pyridin-4-yl)methyl)phthalazine (0.25 mmol, 0.081 g) and 3-aminoacetophenone (0.30 mmol, 0.041 g) to afford 0.039 g (37%) of SR-33876 as a yellow solid. LC / MS (ESI, M+1): found 423.3

[0648] [ka]

[0649] SR-32064: A modified version of general procedure B was followed using 1-chloro-4-((2,6-dimethylpyridin-4-yl)methyl)phthalazine (0.25 mmol, 0.071 g) and 3′-aminoacetophenone (0.3 mmol, 0.041 g) to afford 0.041 g (42%) of SR-32064 as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 9.38 (s, 1H), 8.64 (m, 1H), 8.52 (t, J = 2.0 Hz, 1H), 8.33 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H), 8.10 (dd, J = 8.4, 1.2 Hz, 1H), 7.97 (m, 2H), 7.66 (dt, J = 7.8, 1.2 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 6.97 (s, 2H), 4.50 (s, 2H), 2.62 (s, 3H), 2.34 (s, 6H). LC / MS (ESI, M+1): Actual measured value: 383.3

[0650] [ka]

[0651] SR-32065: A modified version of general procedure B was followed using 1-chloro-4-((2,6-dimethylpyridin-4-yl)methyl)phthalazine (0.25 mmol, 0.071 g) and 2-aminobenzoxazole (0.3 mmol, 0.040 g) to give 0.015 g (15%) of SR-32065 as a yellow solid. LC / MS (ESI, M+1): found 382.3

[0652] [ka]

[0653] SR-34644: A modified version of general procedure B was followed using 1-chloro-4-(1-(pyridin-4-yl)ethyl)phthalazine (0.25 mmol, 0.067 g) and 3-aminoacetophenone (0.30 mmol, 0.041 g) to give 0.079 g (86%) of SR-34644 as a dark yellow solid. LC / MS (ESI, M+1): found 369.3

[0654] [ka]

[0655] SR-34645: A modified version of general procedure B was followed using 1-chloro-4-(1-(pyridin-4-yl)ethyl)phthalazine (0.25 mmol, 0.067 g) and benzofuran-2-ylmethanamine (0.30 mmol, 0.044 g) to give 0.077 g (81%) of SR-34645 as a dark orange solid. LC / MS (ESI, M+1): found 381.3

[0656] [ka]

[0657] SR-34646: Following a modified version of general procedure B using 1-chloro-4-(2,2,2-trifluoro-1-(pyridin-4-yl)ethyl)phthalazine (0.25 mmol, 0.081 g) and 3-aminoacetophenone (0.30 mmol, 0.041 g), 0.027 g (25%) of SR-34646 was obtained as a dark yellow solid. LC / MS (ESI, M+1): Found 423.3

[0658] [ka]

[0659] SR-34779: A modified version of general procedure B was followed using 1-chloro-4-(1-(pyridin-4-yl)ethyl)phthalazine (0.25 mmol, 0.067 g) and 2-aminobenzoxazole (0.30 mmol, 0.040 g) to afford 0.025 g (27%) of SR-34779 as a pale yellow gel. 1 H NMR (400 MHz, d6-DMSO) δ 8.75 (m, 3H), 8.47 (m, 1H), 8.36 (m, 1H), 8.28 (m, 1H), 8.17 (m, 2H), 7.99-7.81 (m, 5H), 5.59 (q, J = 7.0 Hz, 1H), 1.84 (d, J = 6.9 Hz, 3H). LC / MS (ESI, M+1): Actual value 368.3

[0660] [ka]

[0661] SR-35424: Following general procedure B using 3-(morpholinosulfonyl)aniline (0.3 mmol, 0.073 g) gave 0.077 g (66%) of SR-35424 as a yellow solid. LC / MS (ESI, M+1): found 462.3

[0662] [ka]

[0663] SR-35425: Following general procedure B using 4-(morpholinosulfonyl)aniline (0.3 mmol, 0.073 g) gave 0.081 g (70%) of SR-35425 as a yellow solid. LC / MS (ESI, M+1): found 462.2

[0664] [ka]

[0665] SR-35426: Following general procedure B using 3-(oxetan-3-yl)aniline (0.3 mmol, 0.044 g) afforded 0.009 g (10%) of SR-35426 as a dark yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 9.20 (s, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.45 (d, J = 5.0 Hz, 2H), 8.11 (m, 1H), 8.04 - 7.88 (m, 4H), 7.40 - 7.30 (m, 3H), 7.07 (d, J = 7.6 Hz, 1H), 5.00 (dd, J = 8.3, 5.8 Hz, 2H), 4.68 (dd, J = 6.9, 5.8 Hz, 2H), 4.60 (s, 2H), 4.28 (quintet, J = 7.6, 7.2 Hz, 1H) LC / MS (ESI, M+1): Actual measured value: 369.3

[0666] [ka]

[0667] SR-35431: A modified version of general procedure B was followed using 1-chloro-4-(1-(2-methylpyridin-4-yl)ethyl)phthalazine (0.25 mmol, 0.071 g) and 3-(oxetan-3-yl)aniline (0.3 mmol, 0.044 g) to give 0.017 g (17%) of SR-35431 as a yellow solid. LC / MS (ESI, M+1): found 367.4

[0668] [ka]

[0669] SR-35427: Following general procedure B using 3-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)aniline (0.3 mmol, 0.080 g) gave 0.038 g (31%) of SR-35427 as a yellow solid. LC / MS (ESI, M+1): found 488.3

[0670] [ka]

[0671] SR-35428: Following general procedure B using 3-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)aniline (0.3 mmol, 0.080 g) gave 0.049 g (40%) of SR-35428 as a yellow solid. LC / MS (ESI, M+1): found 488.3

[0672] General procedure C

[0673] [ka]

[0674] A 0.5-2 mL microwave vial was sequentially charged with 1-chloro-4-(1-(2-methylpyridin-4-yl)ethyl)phthalazine (0.25 mmol, 0.071 g), amine (0.5 mmol), 0.5 mL of DMF, and DIPEA (0.75 mmol, 0.131 mL) and sealed with a crimp cap. The reaction was heated in a microwave reactor at 160 °C for 30 min. The cooled reaction mixture was loaded directly onto a 25 g silica gel cartridge with DCM and purified on a Biotage flash system eluting with DCM / MeOH. Product-containing fractions were concentrated to a reduced volume, loaded onto a 60 g C18 silica gel cartridge, and purified on a Biotage flash system eluting with HO / MeOH + 0.1% TFA.

[0675] [ka]

[0676] SR-27886: Following general procedure C with 3,4-dimethoxybenzylamine (0.5 mmol, 0.075 mL) afforded 0.037 g (38%) of SR-27886 as a red oil. LC / MS (ESI, M+1): found 387.3

[0677] [ka]

[0678] SR-27887: Following general procedure C using (1H-benzo[d]imidazol-2-yl)methanamine (0.375 mmol, 0.055 g) afforded 0.049 g (21%) of SR-27887 as a red-orange oil. 1 H NMR (400 MHz, d6-DMSO) δ 9.94 (bs, 1H), 8.67 (bs, 1H), 8.55 (m, 1H), 8.50 (m, 2H), 8.15 (m, 1H), 8.00 (m, 2H), 7.57 (dd, J = 6.0, 3.2 Hz, 2H), 7.36 (m, 2H), 7.24 (dd, J = 6.0, 3.1 Hz, 2H), 5.09 (s, 2H), 4.58 (s, 2H) LC / MS (ESI, M+1): Actual value 367.3

[0679] [ka]

[0680] SR-27885: Following general procedure C using 2-aminoindan (0.5 mmol, 0.066 g) afforded 0.046 g (19%) of SR-27885 as a yellow-orange oil. 1 H NMR (400 MHz, d6-DMSO) δ 8.45 (m, 2H), 8.17 (m, 1H), 7.91 (m, 1H), 7.77 (m, 2H), 7.27 (m, 4H), 7.18 (m, 2H), 5.11 (m, 1H), 4.53 (s, 2H), 3.50 (dd, J = 16.0, 7.5 Hz, 2H), 3.14 (m, 2H). LC / MS (ESI, M+1): Actual value 353.3

[0681] [ka]

[0682] SR-27889: Following general procedure C using chroman-3-amine hydrochloride (0.5 mmol, 0.092 g) afforded 0.053 g (29%) of SR-27889 as a yellow-orange oil. 1 H NMR (400 MHz, d6-DMSO) δ 8.44 (m, 2H), 8.37 (m, 1H), 7.91 (m, 1H), 7.78 (m, 2H), 7.26 (m, 2H), 7.13 (m, 2H), 6.87 (m, 2H), 6.66 LC / MS (ESI, M+1): Actual value 369.3

[0683] [ka]

[0684] SR-27888: Following general procedure C using 1,3-benzoxazol-2-ylmethylamine hydrochloride (0.5 mmol, 0.092 g) gave 0.012 g (13%) of SR-27888 as a tan solid. LC / MS (ESI, M+1): Found 368.3

[0685] [ka]

[0686] SR-27890: General procedure C was followed using chroman-3-yl-methylamine (0.5 mmol, 0.076 mL) to give 0.006 g (7%) of SR-27890 as a pale yellow film. LC / MS (ESI, M+1): found 383.4

[0687] [ka]

[0688] SR-27891: Following general procedure C with chroman-4-ylamine (0.5 mmol, 0.067 mL) gave 0.013 g (14%) of SR-27891 as a pale yellow film. LC / MS (ESI, M+1): Found 369.3

[0689] [ka]

[0690] SR-27884: Following general procedure C using 1-aminoindan (0.5 mmol, 0.063 mL) gave 0.032 g (36%) of SR-27884 as a yellow solid. LC / MS (ESI, M+1): Found 353.3

[0691] [ka]

[0692] SR-27892: Following general procedure C with 2-phenoxyethanolamine (0.5 mmol, 0.067 mL) gave 0.039 g (43%) of SR-27892 as a yellow solid. LC / MS (ESI, M+1): Found 357.3

[0693] [ka]

[0694] SR-30004: Following general procedure C with tetrahydrofurfurylamine (0.5 mmol, 0.052 mL) afforded 0.071 g (88%) of SR-30004 as a yellow oil. LC / MS (ESI, M+1): found 321.3

[0695] [ka]

[0696] SR-30005: Following general procedure C with furfurylamine (0.5 mmol, 0.044 mL) gave 0.035 g (44%) of SR-30005 as a yellow oil. LC / MS (ESI, M+1): Found 317.2

[0697] [ka]

[0698] SR-30024: Following general procedure C with (2,3-dihydrobenzofuran-2-yl)methanamine (0.5 mmol, 0.044 mL) afforded 0.054 g (59%) of SR-30024 as a pale orange solid. LC / MS (ESI, M+1): found 369.3

[0699] [ka]

[0700] SR-30006: Following general procedure C using 1H-indole-2-methanamine (0.5 mmol, 0.073 mL) gave 0.054 g (59%) of SR-30006 as a dark red solid. LC / MS (ESI, M+1): found 366.3

[0701] [ka]

[0702] SR-30007: Following general procedure C with tetrahydropyran-2-ylmethylamine (0.5 mmol, 0.060 mL) afforded 0.041 g (49%) of SR-30007 as a yellow solid. LC / MS (ESI, M+1): Found 335.3

[0703] [ka]

[0704] SR-30008: Following general procedure C with tetrahydropyran-4-ylmethylamine (0.5 mmol, 0.060 mL) afforded 0.043 g (51%) of SR-30008 as a pale yellow solid. LC / MS (ESI, M+1): found 335.3

[0705] [ka]

[0706] SR-35430: Following general procedure C using 1-aminoindan (0.5 mmol, 0.063 g) gave 0.046 g (48%) of SR-35430 as a pale yellow solid. LC / MS (ESI, M+1): Found 381.4

[0707] [ka]

[0708] SR-35432: Following general procedure C with chroman-3-yl-methylamine (0.5 mmol, 0.081 g) afforded 0.025 g (24%) of SR-35432 as a pale yellow solid. LC / MS (ESI, M+1): Found 411.3

[0709] [ka]

[0710] SR-35433: Following general procedure C using furfurylamine (0.5 mmol, 0.044 g) gave 0.019 g (22%) of SR-35433 as a dark yellow solid. LC / MS (ESI, M+1): found 345.3

[0711] [ka]

[0712] SR-36584: Following general procedure C using (4-methyltetrahydropyran-4-yl)methylamine (0.5 mmol, 0.070 mL) and heating for 45 min gave 0.091 g (96%) of SR-36584 as a pale yellow oil. LC / MS (ESI, M+1): found 377.4

[0713] General Procedure D A 0.5-2 mL microwave vial was sequentially charged with 1-chloro-4-(1-(2-methylpyridin-4-yl)ethyl)phthalazine (0.1 mmol, 0.028 g), amine (0.2 mmol), 0.2 mL of DMF, and DIPEA (0.3 mmol, 0.052 mL) and sealed with a crimp cap. The reaction was heated in a microwave reactor at 160 °C for 45-50 min. The cooled reaction mixture was directly loaded onto a 10 g silica gel cartridge with DCM and purified on a Biotage flash system eluting with DCM / MeOH. The product-containing fractions were concentrated to a reduced volume, loaded onto a 30 g C18 silica gel cartridge, and purified on a Biotage flash system eluting with HO / MeOH + 0.1% TFA.

[0714] [ka]

[0715] SR-36585: Following general procedure D with (4-fluorotetrahydropyran-4-yl)methylamine (0.2 mmol, 0.029 mL) gave 0.018 g (49%) of SR-36585 as a clear film. LC / MS (ESI, M+1): found 381.3

[0716] [ka]

[0717] SR-36586: Following general procedure D with 4-(2-aminoethyl)morpholine (0.2 mmol, 0.026 mL) gave 0.036 g (99%) of SR-36586 as a clear film. LC / MS (ESI, M+1): found 378.4

[0718] [ka]

[0719] SR-36587: Following general procedure D with tetrahydropyran-2-ylmethylamine (0.2 mmol, 0.023 g) gave 0.024 g (68%) of SR-36587 as a clear film. LC / MS (ESI, M+1): found 363.4

[0720] [ka]

[0721] SR-36588: Following general procedure D with 4-aminotetrahydropyran (0.2 mmol, 0.020 mL) gave 0.023 g (66%) of SR-36588 as a clear film. LC / MS (ESI, M+1): found 349.4

[0722] [ka]

[0723] SR-36589: Following general procedure D with 3-oxetanemethanamine (0.2 mmol, 0.017 mL) gave 0.028 g (83%) of SR-36589 as a clear film. LC / MS (ESI, M+1): found 335.3

[0724] [ka]

[0725] SR-36590: General procedure D was followed using (3-methyloxetan-3-yl)methanamine (0.2 mmol, 0.022 mL) to give 0.030 g (88%) of SR-36590 as a clear film. LC / MS (ESI, M+1): found 349.4

[0726] [ka]

[0727] SR-36591: Following general procedure D with tetrahydropyran-3-ylmethylamine hydrochloride (0.2 mmol, 0.030 g) gave 0.029 g (82%) of SR-36591 as a clear film. LC / MS (ESI, M+1): found 363.4

[0728] [ka]

[0729] SR-36592: Following general procedure D with (2,3-dihydrobenzo[1,4]dioxin-2yl)methylamine (0.2 mmol, 0.033 g) gave 0.027 g (67%) of SR-36592 as a clear film. LC / MS (ESI, M+1): found 413.4

[0730] [ka]

[0731] SR-36593: Following general procedure D with (tetrahydropyran-4-yl)hydrazine (0.2 mmol, 0.023 g) afforded 0.036 g (99%) of SR-36593 as a red-orange solid. LC / MS (ESI, M+1): found 364.3

[0732] [ka]

[0733] SR-36595-1: Following general procedure D with (S)-tetrahydropyran-3-amine hydrochloride (0.2 mmol, 0.027 g) gave 0.025 g (73%) of SR-36595-1 as a clear film. LC / MS (ESI, M+1): found 349.3

[0734] [ka]

[0735] SR-36595-2: Following general procedure D with (R)-tetrahydropyran-3-amine hydrochloride (0.2 mmol, 0.027 g) gave 0.028 g (80%) of SR-36595-2 as a clear film. LC / MS (ESI, M+1): found 349.3

[0736] [ka]

[0737] SR-36596: Following general procedure D with 2,2-dimethyltetrahydropyran-4-amine (0.2 mmol, 0.026 g) gave 0.022 g (61%) of SR-36596 as a clear film. LC / MS (ESI, M+1): found 377.4

[0738] [ka]

[0739] SR-36597: General procedure D was followed using 4-(aminomethyl)tetrahydropyran-4-ol hydrochloride (0.2 mmol, 0.033 g) to give 0.037 g (99%) of SR-36597 as a pale yellow oil. This procedure was modified in that only one purification on a 10 g silica gel cartridge was required. LC / MS (ESI, M+1): Found 379.4

[0740] [ka]

[0741] SR-36598: Following general procedure D using 8-oxa-2-azaspiro[4.5]decane (0.2 mmol, 0.028 g) gave 0.022 g (58%) of SR-36598 as a clear oil. LC / MS (ESI, M+1): Found 389.4

[0742] [ka]

[0743] SR-36599: General procedure D was followed using 1-(2-aminoethyl)piperidin-2-one (0.2 mmol, 0.028 g) to afford 0.022 g (56%) of SR-36599 as a clear oil. LC / MS (ESI, M+1): Found 390.4

[0744] [ka]

[0745] SR-36600: General procedure D was followed using (8-oxabicyclo[3.2.1]octan-3-yl)methanamine (0.2 mmol, 0.028 g) to give 0.024 g (61%) of SR-36600 as a clear film. LC / MS (ESI, M+1): found 389.3

[0746] [ka]

[0747] SR-36601: General procedure D was followed using (2-oxabicyclo[2.2.2]octan-4-yl)methanamine (0.2 mmol, 0.028 g) to afford 0.037 g (99%) of SR-36601 as a clear oil. LC / MS (ESI, M+1): Found 389.4

[0748] It is understood that the examples, schemes, and embodiments described herein are for illustrative purposes only, and that various modifications or variations therein will be suggested to those skilled in the art and are within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

[0749] (References) TIFF2024505256000228.tif213170TIFF2024505256000229.tif213170TIFF2024505256000230.tif213170TIFF2024505256000231.tif176170

Claims

1. (A) Formula (X) 【Chemistry 1】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl; R 20 -L 1 -R 21 and L 1 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; R 21 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10 and R 20 are optionally linked to form a substituted or unsubstituted bicyclic heterocycloalkyl; R 1 are independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2 , -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 , -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is hydrogen, D, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCX 3 3 , -OCH 2 X 3 , -OCHX 3 2 , -OR 3F , -SR 3F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 30 are independently halogen, -CX 30 3 , -CHX 30 2 , -CH 2 X 30 , -OCX 30 3 , -OCH 2 X 30 , -OCHX 30 2 , -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, z is an integer from 0 to 4; each X 1 , X 2 , X 3 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F , R 3F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; However, R 10 is hydrogen and L 1 If is a bond, R 21 is unsubstituted phenyl, halogen, -C(O)CH 3 , -S(O) 2 -NH 2 or phenyl substituted with substituted or unsubstituted alkyl; 1 is methylene, R 21 is not unsubstituted tetrahydropyranyl; or (B) Formula (XII) 【Chemistry 2】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2 , -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R2 is hydrogen, D, halogen, -CX23, -CHX22, -CH2X2, -OCX23, -OCH2X2, -OCHX22, -OR2F, -SR2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3 is hydrogen, D, halogen, -CX33, -CHX32, -CH2X3, -OCX33, -OCH2X3, -OCHX32, -OR3F, -SR3F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 and R 3 are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each R 6 and R 7 is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl, or R 6 and R 7 are optionally joined together to form a substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl; R 8 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 30 is independently halogen, -CX 30 3 , -CHX 30 2 , -CH 2 X 30 , -OCX 30 3 , -OCH 2 X 30 , -OCHX 30 2 , -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, z is an integer from 0 to 4; each X 1 , X 2 , X 3 and X 30 is independently -F, -Br, -Cl, or -I; each R 1F , R 2F , R 3F , and R 30F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; with the proviso that when n is 0, L 1 is a bond, and R 6 and R 7 are hydrogen, then R 8 is not unsubstituted tetrahydro-pyranyl; or (C) Formula (XIII) 【Chemistry 3】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2 is -C(=O)-, -C(=CR 9A R 9B )-, -CR 10A R 10B - or -C(=NR 11 )-; R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2 , -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R 9A and R 9B is independently hydrogen, -CX 93 , -CHX 92 , -CH 2 X 9 , -OCX 93 , -OCH 2 X 9 , -OCHX 92 , -CN, -OR 9F , -SR 9F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R 10A and R 10B is independently hydrogen, D, halogen, -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -OCX 10 3 , -OCH 2 X 10 , -OCHX 10 2 , -CN, -OR 10F , -SR 10F , -C(O)OR 10F , -C(O)NHR 10F , -C(O)N(R 10F ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10A and R 10B are optionally joined together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 11 is -R 11F , -OR 11F , -S(O 2 )-R 11F , or -C(O)-R 11F ; R 30 is independently halogen, -CX 30 3 , -CHX 30 2 , -CH 2 X 30 , -OCX 30 3 , -OCH 2 X 30 , -OCHX 30 2 , -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 1 to 4, z is an integer from 0 to 4; each X 1 , X 8 , X 9 , X 10 and X 30 is independently -F, -Br, -Cl, or -I; each R 1F , R 8F , R 9F , R 10F and R 30F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. A compound having the structure:

2. The compound (A) is L 1 is a bond, substituted or unsubstituted C 1 ~C 4 alkylene, or substituted or unsubstituted 2-4 membered heteroalkylene; Optionally, (a) R 10 and R 20 are linked to form a substituted or unsubstituted 【Chemistry 4】 form; or (b) R 21 is substituted or unsubstituted 【Chemistry 5】 is; and / or (c) R 1 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 1F , where R 1F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (d) R 2 is hydrogen and R 3 is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; and / or (e) R 30 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 30F ; R 30F is hydrogen or unsubstituted C 1 -C 4 alkyl; 2. The compound according to claim 1, or a pharma- ceutically acceptable salt or isomer thereof, wherein:

3. The compound of (A) has the structure of formula (XI): 【Chemistry 6】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, Each R A , R B , R C and R D are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or R A , R B , R C and R D two of which are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; having Optionally, (a) RA and RB join to form a substituted or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; RB and RC join to form a substituted or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; or RC and RD join to form a substituted or unsubstituted C 5 -C 6 cycloalkyl, substituted or unsubstituted 5-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; and / or (b) The compound of (B) has the structure of formula (XI-a), (XI-b) or (XI-c) 【Chemistry 7】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, each W, X, Y and Z is independently =N- or -CH=; each R4 is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -OR4F, -SR4F, -C(O)R4F, -C(O)OR4F, S(O)2R4F, -C(O)NHR4F, -C(O)N(R4F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R5 is independently halogen, -CX53, -CHX52, -CH2X5, -OCX53, -OCH2X5, -OCHX52, -CN, -OR5F, -SR5F, -C(O)OR5F, -S(O)2R5F, -C(O)NHR5F, -C(O)N(R5F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 2, m is an integer from 0 to 4; each X 4 and X 5 is independently -F, -Br, -Cl, or -I; Each R 4F and R 5F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. having Optionally, The compound (B) has the structure (XI-a-1), (XI-ba) or (XI-c-1) 【Chemistry 8】 or a pharma- ceutically acceptable salt or isomer thereof; and / or (c) R 2 is H, D, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CX 2 3 , or OR 2F and R 3 is H, D, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CX 3 3 , or OR 3F , each R 2F and R 3F being independently hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (d) k is 1 or 2 and m is 1 or 2; and / or (e) each R 4 is independently halogen, —CX 4 3 , —OCX 4 3 , —CN, —OR 4F , —C(O)R 4F , —C(O)OR 4F , —S(O) 2 R 4F , —C(O)NHR 4F , —C(O)N(R 4F ) 2 , or substituted or unsubstituted C 1 -C 4 alkyl; each R 5 is independently halogen, -CX 45 3 , -OCX 5 3 , -CN, -OR 5F , -C(O)OR 5F , -S(O) 2 R 5F , -C(O)NHR 5F , -C(O)N(R 5F ) 2 , or substituted or unsubstituted C 1 -C 4 alkyl; each R 4F and R 5F is independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; and / or (f) R 1 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 1F , where R 1F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (g) R 2 is hydrogen and R 3 is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; and / or (h) R 30 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 30F , where R 30F is hydrogen or unsubstituted C 1 -C 4 alkyl; 2. The compound of claim 1.

4. The compound of (B) has the structure of formula (XI-d), (XI-e), (XI-f), (XI-d'), (XI-e') or (XI-f') 【Chemistry 9】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, X' is -O-, -NH-, or -CH 2 - and Y' is -NH= or -CH=; k is an integer from 0 to 2, m is an integer from 0 to 3; Each R 4 are independently halogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -OCX 4 3 , -OCH 2 X 4 , -OCHX 4 2 , -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , S(O) 2 R 4F , -C(O)NHR 4F , -C(O)N(R 4F ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 5 are independently halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCX 5 3 , -OCH 2 X 5 , -OCHX 5 2 , -CN, -OR 5F , -SR 5F , -C(O)OR 5F , -S(O) 2 R 5F , -C(O)NHR 5F , -C(O)N(R 5F ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each X 4 and X 5 are independently -F, -Br, -Cl, or -I; Each R 4F and R 5F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. having Optionally, (a) R 2 is H, D, halogen, substituted or unsubstituted C 1 -C 4 alkyl, —CX 2 O 3 , or OR 2F; R 3 is H, D, halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CX 3 3 , or OR 3F; each R 2F and R 3F is independently hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (b) k is 1 or 2 and m is 1 or 2; and / or (c) each R 4 is independently halogen, —CX 4 3 , —OCX 4 3 , —CN, —OR 4F , —C(O)R 4F , —C(O)OR 4F , —S(O) 2 R 4F , —C(O)NHR 4F , —C(O)N(R 4F ) 2 , or substituted or unsubstituted C 1 -C 4 alkyl; each R 5 is independently halogen, -CX 45 3 , -OCX 5 3 , -CN, -OR 5F , -C(O)OR 5F , -S(O) 2 R 5F , -C(O)NHR 5F , -C(O)N(R 5F ) 2 , or substituted or unsubstituted C 1 -C 4 alkyl; each R 4F and R 5F is independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-6 membered heteroaryl; and / or (d) R 1 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 13 , or -OR 1F; R 1F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (e) R 2 is hydrogen and R 3 is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; and / or (f) R 30 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 30F , where R 30F is hydrogen or unsubstituted C 1 -C 4 alkyl; 4. The compound according to claim 3.

5. The compound (B) has the structure of formula (XII) 【Chemistry 10】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; R 1 are independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2 , -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, D, halogen, -CX 2 3 , -CHX 2 2 , -CH 2 X 2 , -OCX 2 3 , -OCH 2 X 2 , -OCHX 2 2 , -OR 2F , -SR 2F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3 is hydrogen, D, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCX 3 3 , -OCH 2 X 3 , -OCHX 3 2 , -OR 3F , -SR 3F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 and R 3 are optionally linked together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; Each R 6 and R 7 are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; or R 6 and R 7 are optionally linked together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 8 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 30 are independently halogen, -CX 30 3 , -CHX 30 2 , -CH 2 X 30 , -OCX 30 3 , -OCH 2 X 30 , -OCHX 30 2 , -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 0 to 4, z is an integer from 0 to 4; each X 1 , X 2 , X 3 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 2F , R 3F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; where n is 0 and L 1 is a bond and R 6 and R 7 If is hydrogen, R 8 is not unsubstituted tetrahydropyranyl) 2. The compound of claim 1 having the formula:

6. (a)R 8 is substituted or unsubstituted 【Chemistry 11】 is; or (b) R8 is 【Chemistry 12】 and each R4 is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -OR4F, -SR4F, -C(O)R4F, -C(O)OR4F, S(O)2R4F, -C(O)NHR4F, -C(O)N(R4F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 5; X 4 is independently -F, -Br, -Cl, or -I; each R 4F is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and / or (c) at least one of R2 and R3 is not hydrogen; and / or (d) R 1 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, —CN, —CX 13 , or OR 1F , where R 1F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (e) R 2 is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl and R 3 is substituted or unsubstituted C 1 -C 4 alkyl; and / or (f) R 30 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 30F , where R 30F is hydrogen or unsubstituted C 1 -C 4 alkyl; 6. The compound according to claim 5, or a pharma- ceutically acceptable salt or isomer thereof. (a) The compound has the structure of formula (XII-a) 【Chemistry 13】 (In the formula, W 1 is -O- or CH 2 - and L 1 is a bond or C 1 ~C 4 is alkylene, Each R 4 are independently halogen, -CX 4 3 , -CHX 4 2 , -CH 2 X 4 , -OCX 4 3 , -OCH 2 X 4 , -OCHX 4 2 , -CN, -OR 4F , -SR 4F , -C(O)R 4F , -C(O)OR 4F , S(O) 2 R 4F , -C(O)NHR 4F , -C(O)N(R 4F ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 5; X 4 are independently -F, -Br, -Cl, or -I; Each R 4F are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. and / or (b) each R 4 is independently halogen, —CX 4 3 , —OCX 4 3 , —CN, —OR 4F , —C(O)R 4F , —C(O)OR 4F , —S(O) 2 R 4F , —C(O)NHR 4F , —C(O)N(R 4F ) 2 , or substituted or unsubstituted C 1 -C 4 alkyl; each R 4F is independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 5- to 12-membered monocyclic or bicyclic heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; and / or (c) R 1 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, —CN, —CX 13 , or OR 1F ; R 1F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (d) R 2 is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl and R 3 is substituted or unsubstituted C 1 -C 4 alkyl; and / or (e) R 30 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 30F ; R 30F is hydrogen or unsubstituted C 1 -C 4 alkyl; 7. The compound according to claim 5 or 6, or a pharma- ceutically acceptable salt or isomer thereof.

8. The compound (C) has the structure of formula (XIII) 【Chemistry 14】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, L 1 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; L 2 -C(=O)-, -C(=CR 9A R 9B )-, -CR 10A R 10B - or -C(=NR 11 )-and R 1 are independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2 , -CN, -OR 1F , -SR 1F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 8 is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 9A and R 9B are independently hydrogen, -CX 9 3 , -CHX 9 2 , -CH 2 X 9 , -OCX 9 3 , -OCH 2 X 9 , -OCHX 9 2 , -CN, -OR 9F , -SR 9F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Each R 10A and R 10B are independently hydrogen, D, halogen, -CX 10 3 , -CHX 10 2 , -CH 2 X 10 , -OCX 10 3 , -OCH 2 X 10 , -OCHX 10 2 , -CN, -OR 10F , -SR 10F , -C(O)OR 10F , -C(O)NHR 10F , -C(O)N(R 10F ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 10A and R 10B are optionally linked together to form a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R 11 -R 11F , -OR 11F , -S(O 2 )-R 11F , or -C(O)-R 11F and R 30 are independently halogen, -CX 30 3 , -CHX 30 2 , -CH 2 X 30 , -OCX 30 3 , -OCH 2 X 30 , -OCHX 30 2 , -CN, -OR 30F , -SR 30F , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; n is an integer from 1 to 4, z is an integer from 0 to 4; each X 1 , X 8 , X 9 , X 10 and X 30 are independently -F, -Br, -Cl, or -I; Each R 1F , R 8F , R 9F , R 10F and R 30F are independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 11F is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

2. The compound of claim 1 having the formula:

9. (a)R 8 is substituted or unsubstituted 【Chemistry 15】 is; or (b) R8 is 【Chemistry 16】 and each R4 is independently halogen, -CX43, -CHX42, -CH2X4, -OCX43, -OCH2X4, -OCHX42, -CN, -OR4F, -SR4F, -C(O)R4F, -C(O)OR4F, S(O)2R4F, -C(O)NHR4F, -C(O)N(R4F)2, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; k is an integer from 0 to 5; X 4 is independently -F, -Br, -Cl, or -I; each R 4F is independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 5- to 12-membered monocyclic or bicyclic heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; Optionally, each R 4 is independently halogen, -CX 4 3 , -OCX 4 3 , -CN, -OR 4F , -C(O)R 4F , -C(O)OR 4F , -S(O) 2 R 4F , -C(O)NHR 4F , -C(O)N(R 4F ) 2 , or substituted or unsubstituted C 1 -C 4 alkyl; each R 4F is independently hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 5- to 12-membered monocyclic or bicyclic heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5- to 6-membered heteroaryl; and / or (c) at least one of R 10A and R 10B is not hydrogen; and / or (d) R 1 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, —CN, —CX 13 , or OR 1F , where R 1F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (e) R 30 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 3 , or -OR 30F , where R 30F is hydrogen or unsubstituted C 1 -C 4 alkyl; 9. The compound according to claim 8, or a pharma- ceutically acceptable salt or isomer thereof. (a) The compound has the structure of formula (XIII-a), (XIII-b) or (XIII-c) 【Chemistry 17】 or a pharma- ceutically acceptable salt or isomer thereof (wherein n is an integer from 1 to 4). and / or (b) L 1 is a bond or unsubstituted C 1 -C 4 alkylene; Optionally, In the above (a), (I) R 10A and R 10B join together to form a substituted or unsubstituted C 3 -C 6 cycloalkyl or a substituted or unsubstituted 4- to 6-membered heterocycloalkyl; Optionally, The compound has the structure of formula (XIII-c-1) or (XIII-c-2) 【Chemistry 18】 or a pharma- ceutically acceptable salt or isomer thereof (In the formula, each R 12 is independently halogen, -CX 12 3 , -CHX 12 2 , -CH 2 X 12 , -OCX 12 3 , -OCH 2 X 12 , -OCHX 12 2 , -CN, -OR 12F , -SR 12F , -C(O)OR 12F , -C(O)NHR 12F , -C(O)N(R 12F ) 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; X 12 is independently -F, -Br, -Cl, or -I; each R 12F is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; p is an integer from 0 to 4. or (II) The compound has the structure of formula (XIII-c-3), (XIII-c-4) or (XIII-c-5) 【Chemistry 19】 or a pharma- ceutically acceptable salt or isomer thereof having Optionally, R 10A is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl, and R 10B is substituted or unsubstituted C 1 -C 4 alkyl; 10. A compound according to claim 8 or 9.

11. The compound has the structure of formula (XIII-d-1), (XIII-d-2), (XIII-d-3) or (XIII-d-4) 【Chemistry 20】 or a pharma- ceutically acceptable salt or isomer thereof having Optionally, (a) R 11F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (b) R 1 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, —CN, —CX 13 , or —OR 1F ; R 1F is hydrogen or unsubstituted C 1 -C 4 alkyl; and / or (c) R 30 is halogen, substituted or unsubstituted C 1 -C 4 alkyl, -CN, -CX 1 -3 , or -OR 30F ; R 30F is hydrogen or unsubstituted C 1 -C 4 alkyl; 11. A compound according to any one of claims 8 to 10.

12. The compound is a compound in the following table: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt or isomer thereof, selected from:

13. 13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, a pharma- ceutically acceptable salt form thereof, an isomer thereof, or a crystalline form thereof, and a pharma- ceutically acceptable carrier.

14. Use of a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt or isomer thereof, or a pharmaceutical composition according to claim 13, for inhibiting NAD consumption, for increasing NAD synthesis, for preventing or inhibiting NAD depletion, for improving a condition associated with altered NAD metabolism, or for providing protection from misfolded protein toxicity in a subject.

15. Use of a compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt or isomer thereof, or a pharmaceutical composition according to claim 13, for preventing or treating a disease or condition in a patient, wherein the disease or condition is selected from a degenerative disease, a retinal disease, hearing loss, a mitochondrial disease, a kidney disease, diabetes, non-alcoholic fatty liver disease or other metabolic disorder, and the health effects of ageing; Optionally, the degenerative disease is peripheral amyloidosis, or a neurodegenerative disorder associated with misfolded protein-induced neurodegeneration and / or NAD depletion; or the degenerative disease is Creutzfeldt-Jakob disease or other prion diseases, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia or other tauopathies, multiple sclerosis, chronic traumatic encephalopathy, ATTR amyloidosis, cerebral ischemia or axonopathy; use.

16. A compound according to any one of claims 1 to 12 or a pharma- ceutically acceptable salt thereof, To inhibit NAD consumption To increase NAD synthesis To prevent or inhibit NAD depletion, To improve conditions associated with alterations in NAD metabolism To provide protection from the toxicity of misfolded proteins, To reduce the health effects of aging, or For preventing or treating a degenerative disease, a retinal disease, hearing loss, a mitochondrial disease, a kidney disease, diabetes, non-alcoholic fatty liver disease or other metabolic disorder in a subject in need thereof. Use in the manufacture of compositions and / or medicaments and / or products.

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