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

Abstract

In particular, compounds having the structure of Formulas (X), (I)-(XIII) or substructures thereof, compositions containing same and methods of use are provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 127,859, filed December 18, 2020, which is incorporated by reference in its entirety and 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 called protein misfolding neurodegenerative diseases (PMND). Proteins involved in these diseases misfold to form aggregates of various sizes. Some of these aggregates are highly toxic to neuronal cells, a phenomenon also called proteotoxicity. Protein aggregates can also exhibit "prion-like" properties in the sense 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 diseases 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). There are also non-neurological diseases involving protein misfolding, 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 the 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 such mechanisms, models using the toxic misfolded prion protein (TPrP) have been developed, which reproducibly induces neuronal death in cell culture and after intracerebral injection. 1TPrP induces the death of more than 60% of cultured neuronal cells at nanomolar concentrations, whereas NTPrP, the naturally folded counterpart of the prion protein, does not. Thus, this model provides a highly efficient system to study mechanisms of neuronal cell death associated with proteotoxicity, with broad applicability to protein misfolding diseases. Thus, as shown herein, TPrP-based studies have prompted the development of novel neuroprotective approaches to treat devastating neurodegenerative diseases and other diseases 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] No. 5,403,841 [Patent Document 4] No. 5,212,162 [Patent Document 5] 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.l, 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 pharma- ceutically acceptable salt thereof.

[0011] Ring A is a substituted or unsubstituted heterocycloalkylene, or a substituted or unsubstituted heteroarylene.

[0012] L 1 is -C(O)-, -C(S)-, or -S(O)-.

[0013] L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

[0014] Each R 1A , R 1B and R 1C are independently hydrogen, halogen, -CX 1 3. -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -OR 1D , -SR 1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or R 1B and R 1C together with the nitrogen atom form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.

[0015] R 2 is hydrogen or substituted or unsubstituted alkyl.

[0016] Each R 3A , R 3B , R 3C , R 3D and R 3E are independently hydrogen, 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, or R 3Aand R 3B are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3B and R 3C are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3C and R 3D are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3D and R 3E are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0017] each X 1 and X 3 is independently -F, -Br, -Cl or -I.

[0018] Each R 1D and R 3F is independently hydrogen or substituted or unsubstituted alkyl.

[0019] In an embodiment, the compound has the structure of formula (I)

[0020] [ka]

[0021] or a pharma- ceutically acceptable salt thereof (In the formula, n is an integer from 1 to 5; W 1 HA-CR 4A R 4B -, -NR 4C -, -O- or -S-; W2 is =O or =S, W 3 is -N= or -CH=, Each R 4A , R 4B and R 5 are independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 4C and R 5D are independently hydrogen or substituted or unsubstituted alkyl. L 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D and R 3E is as disclosed herein.

[0022] In an embodiment, the compound has the structure of formula (II)

[0023] [ka]

[0024] or a pharma- ceutically acceptable salt thereof (In the formula, R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. L 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0025] The compound has the structure of formula (III)

[0026] [ka]

[0027] or a pharma- ceutically acceptable salt thereof (In the formula, However, (i) R 5A is a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; R 5B is -NH-(CO)-R 5C or -C(O)-NH-R 5C and R 5C is hydrogen or substituted or unsubstituted alkyl, or (ii) R 5A is a bond, and R 5B is a halogen). 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0028] In an embodiment, the compound has the structure of formula (IV)

[0029] [ka]

[0030] (In the formula, W 4 is -O- or -S-; R 5 are independently hydrogen, -OR 5D, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. L 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0031] In an embodiment, the compound has the formula (V):

[0032] [ka]

[0033] (In the formula, W 5 is =O or =S, W 6 is -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0034] In an embodiment, the compound has the formula (VI):

[0035] [ka]

[0036] (In the formula, W 5 is =O or =S, W 6 is -NH-, -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0037] In an embodiment, the compound has the structure of formula (VII)

[0038] [ka]

[0039] or a pharma- ceutically acceptable salt thereof (In the formula, R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3Eand n is as disclosed herein.

[0040] In one embodiment, the structure of formula (VIII)

[0041] [ka]

[0042] or a pharma- ceutically acceptable salt thereof. (In the formula, z is an integer from 0 to 5; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0043] In one aspect, a pharmaceutical composition is provided that includes a compound described herein, a pharma- ceutically acceptable salt form thereof, an isomer thereof, or a crystalline form thereof.

[0044] In one embodiment, 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.

[0045] 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 may include administering to the patient an effective dose of a compound described herein.

[0046] In one embodiment, 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.

[0047] In one aspect, a method of preventing or treating a protein misfolding neurodegenerative disease in a patient is provided. The method may comprise administering to the patient an effective dose of a compound described herein.

[0048] In one aspect, a method of preventing or treating a retinal disease in a patient is provided. The method may include administering to the patient an effective dose of a compound described herein.

[0049] In one aspect, a method of preventing or treating a metabolic disease, an ischemic disease, hearing loss, or renal failure in a patient is provided. The method may comprise administering to the patient an effective dose of a compound described herein.

[0050] Other aspects of the invention are disclosed below. [Brief description of the drawings]

[0051] [Figure 1] 1A-E show dose-response curves of compounds in the TPrP neuroprotection assay. [Diagram 2] 2A-D show the effect of compounds on the activation rate of the enzyme nicotinamide phosphoribosyltransferase (NAMPT). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] The misfolded, toxic prion protein TPrP induces a severe depletion of neuronal NAD that leads 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 the overconsumption 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, indicating the need to identify new compounds that can interfere with mechanisms acting on misfolded protein-induced toxicity or prevent NAD depletion, regardless of the underlying mechanism of NAD imbalance. Imbalance of NAD metabolism is a pathogenic mechanism of many human conditions, as described herein.

[0053] 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 metabolism pathways such as glycolysis, the TCA cycle, and oxidative phosphorylation leading to ATP production, among others. In addition, NAD functions as a substrate for signal transduction and a post-translational protein modification called ADP-ribosylation. Since 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 in the TPrP assay) could result either from an impairment of NAD biosynthesis or from an increase in NAD consumption. In mammalian cells, NAD is primarily synthesized through the salvage pathway using the precursor nicotinamide (NAM). The rate-limiting enzyme for NAD synthesis in the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT). 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). On the other hand, 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).

[0054] NAD deficiency is a cause of prion disease 2 and PD 3、4 , A.D. 5~8 and ALS 9、10 etc. are characteristic of other PMNDs.

[0055] Dysregulation of NAD is currently a major factor 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. 19 and cardiac ischemia / reperfusion injury 20、21 has been shown to reduce

[0056] Age-related retinal / macular degeneration (AMD) is associated with the death of photoreceptor cells in the retina of the eye and retinal pigment epithelium (RPE) cells, leading to progressive vision loss. NAD levels are reduced in RPE cells isolated from AMD patients. 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 reduced Zn after light-induced retinal damage (LIRD). 2+ staining, loss of NAD+ and cell death were observed.24 Similarly, treatment with nicotinamide riboside (NR), a precursor of NAD, maintained retinal NAD levels and protected retinal morphology and function in a mouse model of LIRD. 25 .

[0057] 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 that is 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 of 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 .

[0058] A significant decrease in NAD levels was found in degenerative renal conditions, and NAD enhancement attenuates acute kidney injury induced by ischemia-reperfusion, toxic insults, and systemic inflammation. 32 .

[0059] Using TPrP as a prototypic 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 NAD depletion induced by TPrP.

[0060] The 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 also detailed in International Patent Publication WO2020 / 232255, the entire contents of which are incorporated herein by reference for all purposes.

[0061] 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. Some of the compounds described herein activate the NAD synthesis enzyme NAMPT. In addition, many have advantageous drug-like properties (e.g., they are PAlNS-free). 33 and Lipinski and Veber's law of drug-likeness 34、35 These compounds prevent depletion of cellular NAD levels or increase NAD levels, and are therefore useful in the prevention or treatment of diseases in which an imbalance in NAD metabolism occurs, such as protein misfolding neurodegenerative diseases, amyloidosis, aging, retinal degeneration, ischemic conditions, traumatic brain injury, renal failure, and metabolic diseases including diabetes and non-alcoholic fatty liver disease.

[0062] definition The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulas depicted herein are to be construed in accordance with standard rules of chemical valency known in the chemical arts.

[0063] When substituents are designated by a conventional chemical formula written from left to right, they equally encompass the chemically identical substituents which would occur if the structure were written from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0064] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbons), or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and include monovalent, divalent and polyvalent groups. An alkyl can include the number of carbons specified (e.g., C1-C 10 means 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, its homologs and isomers, such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like groups. Unsaturated alkyl groups are those that have 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. An alkoxy is an alkyl attached to the remainder 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 more than one triple bond in addition to one or more double bonds. An alkynyl may contain more than one triple bond and / or more than one double bond in addition to one or more triple bonds.

[0065] The term "alkylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, exemplified but not limited to, by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those 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.

[0066] The term "heteroalkyl," by itself or in combination with other terms, means, unless otherwise stated, a stable linear or branched chain or combination 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-cyclized 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). The heteroalkyl moiety may contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain four optionally different heteroatoms (e.g., O, N, S, Si, or P). The heteroalkyl moiety may contain five optionally different heteroatoms (e.g., O, N, S, Si, or P). The 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 a heteroalkyl containing at least one double bond, unless otherwise specified. 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. Heteroalkynyl can optionally contain more than one triple bond and / or one or more double bonds in addition to one or more triple bonds.

[0067] Similarly, the term "heteroalkylene," by itself or as part of another substituent, means a divalent radical derived from heteroalkyl, exemplified, but not limited to, by -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-, unless otherwise stated. In the case of heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Still further, 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 that are 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'. When "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 a specific heteroalkyl group, such as -NR'R''.

[0068] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, refer to cyclic versions of "alkyl" and "heteroalkyl", respectively, unless otherwise specified. 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.

[0069] In an embodiment, the heterocycloalkyl is heterocyclyl. The term "heterocyclyl" as used herein means a monocyclic, bicyclic or polycyclic heterocycle. A heterocyclyl monocyclic heterocycle is a 3-, 4-, 5-, 6- or 7-membered ring, the ring being saturated or unsaturated but not aromatic, containing 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-dioxidothiomorpholinyl (thiomorpholine sulfone), 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 that are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5- or 6-membered monocyclic heterocyclyl 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 fused to a phenyl ring, where 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 or nitrogen atom contained within the base ring. In embodiments, the 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, 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.

[0070] 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.

[0071] The term "aryl", unless otherwise specified, refers to a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or multiple rings (preferably 1-3 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 5 members and the other ring has 6 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 remainder 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, 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 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.

[0072] 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. A fused ring heterocycloalkyl-aryl, a fused ring heterocycloalkyl-heteroaryl, a fused ring heterocycloalkyl-cycloalkyl, or a fused ring heterocycloalkyl-heterocycloalkyl can each independently be unsubstituted or substituted with one or more of the substituents described herein.

[0073] A spirocyclic ring is two or more rings in which adjacent rings are linked through a single atom. The individual rings in a spirocyclic ring may be the same or different. The individual rings in a spirocyclic ring may be substituted or unsubstituted and may have different substituents than the other individual rings in a set of spirocyclic rings. The possible substituents for the individual rings in a spirocyclic ring are the possible substituents for the same ring when not part of a spirocyclic ring (e.g., the substituents for a cycloalkyl or heterocycloalkyl ring). A spirocyclic ring may be a substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heterocycloalkylene, and the individual rings in a spirocyclic ring group may be any of the preceding lists, including having all rings of one type (e.g., all rings are substituted heterocycloalkylene, where each ring may 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 a heterocyclic ring 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 be optionally different.

[0074] symbol

[0075] [ka]

[0076] indicates the point of attachment of the chemical moiety to the remainder of the molecule or chemical formula.

[0077] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0078] The term "alkylsulfonyl" as used herein means 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).

[0079] 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.

[0080] 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'', - and n is 0 or 1. The substituent may be one or more of a variety of groups selected from the group consisting of 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'', -NR02R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)-OR'', and -NR'OR''. R, R', R'', R''', and R'''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When the compounds described herein contain 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. 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 substituents above, one of skill in the art will recognize 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 acyls (e.g., -C(O)CH, -C(O)CF, -C(O)CHOCH, etc.).

[0081] 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', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(0)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R'')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', - 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.

[0082] 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 substituents on a single ring) may be a substituent on any of the fused or spirocyclic rings (floating substituents on multiple rings). When a substituent is attached to a ring rather than to a specific atom (floating substituents) and the substituent subscript is an integer greater than 1, the multiple substituents may be on the same atom, on the same ring, on different atoms, on different fused rings, on 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, following the rules of chemical valence. When a ring, fused or spirocyclic ring contains one or more ring heteroatoms and the ring, fused 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, following the rules of chemical valence.

[0083] Two or more substituents may be optionally 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 the 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 the 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.

[0084] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are optionally 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 of 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.

[0085] 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, "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., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 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, -SO3H, -SO4H, -SON2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHSO2H, -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-C8 alkyl, C3-C6 alkyl, or C5-C6 alkyl ... 10 Aryl, C10 aryl or phenyl), or unsubstituted heteroaryl (e.g., 5-10 membered heteroaryl, 5-9 membered heteroaryl, or 5-6 membered heteroaryl).

[0086] 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.

[0087] Certain compounds of the present disclosure have asymmetric carbon atoms (optical or chiral centers) or double bonds, and enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms, and individual isomers that 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 the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0088] As used herein, the term "isomers" refers to compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but differ with respect to the structural or stereochemical arrangement of the atoms.

[0089] 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.

[0090] It will be apparent to one of ordinary skill 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.

[0091] 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.

[0092] 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, thereby including alternative embodiments, and that a Markush group should not be read as a single unit.

[0093] 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 particular group may be substituted with one or more of any or all of the specified substituents. For example, a group such as an alkyl or heteroaryl group may be 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 one or more unsubstituted alkyl, and / or one or more unsubstituted 2-20 membered heteroalkyl.

[0094] 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 may be substituted by one or more of a number of substituents, such substitutions are selected to conform to the principles of chemical bonding and to provide a compound known to those skilled in the art that is not inherently unstable and / or 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 via a ring heteroatom according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0095] One 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 a 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 via 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 a variable is specified in an embodiment as "methane" but the variable is known to be attached to the remainder of the compound via 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, a linker variable (e.g., a linker variable as described herein, e ... 1 , L 2 Or L 3 ), one of skill in the art would understand that the variable is a divalent form of an independent compound (e.g., if in an embodiment a variable is designated "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).

[0096] 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 are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts.

[0097] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the specific 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 a neutral form of such a compound with a sufficient amount of a desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts 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 a neutral form of such a compound with a sufficient amount of a desired acid, either neat or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, oxalic acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid 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.

[0098] Therefore, the compounds of the present disclosure may exist as salts with pharma- ceutically acceptable acids and the like. 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 mixtures thereof, including racemic mixtures), 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.

[0099] 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.

[0100] 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.

[0101] Certain compounds of the present disclosure may exist in unsolvated 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 may 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.

[0102] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration and absorption of active agents to and by a subject and may 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, carbohydrates such as gelatin, lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring agents and / or aromatic substances 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.

[0103] The term "preparation" is intended to include the formulation of the active compound with an encapsulating material as a carrier to provide a capsule in which the active ingredient is surrounded by a carrier, with or without other carriers. Also included are cachets and lozenges. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0104] The term "about" as used herein 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 range of 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.

[0105] As used herein, "EC 50The term "EC50" or "median effective concentration" refers to the concentration of a molecule (e.g., a small molecule, a drug, an antibody, a chimeric antigen receptor, or a bispecific antibody) that can induce a response halfway between the baseline response and the maximum response after a particular exposure time. In embodiments, the EC50 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 maximum possible effect of that molecule.

[0106] The term "neurodegenerative disorder" as used herein refers to a disease or condition in which the function of the nervous system of a subject is impaired. Examples of neurodegenerative diseases 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-Vogt-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, Krabbe 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, Refsum disease, Sandhoff disease, Schilder's disease, subacute combined spinal degeneration secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (several types with variable features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or tabes dorsalis.

[0107] The term "retinal degeneration" as used herein refers to a disease or condition in which the retina of the eye is impaired and / or damaged, resulting in impaired vision of a subject. 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).

[0108] As used herein, the term "axonopathy" refers to functional or structural damage to nerve cells or peripheral nerves.

[0109] The term "peripheral" as used herein refers to the anatomical parts of the body located outside the central nervous system.

[0110] The term "amyloidosis" as used herein refers to conditions associated with the deposition of protein amyloid. Amyloidosis may occur in the central nervous system and is also referred to as protein misfolding neurodegenerative disease (e.g., prion disease, AD, PD and other synucleinopathies, ALS, tauopathies). Amyloidosis may occur outside the central nervous system and may be widespread, i.e., systemic, or present in various organ systems. When amyloid deposits occur in multiple organs, it is referred to as "multi-organ." Examples of amyloidosis are cardiomyopathy or polyneuritis caused by the 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.

[0111] The term "metabolic disorder" as used herein refers to a disease or condition that interferes with the body's metabolism, 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's disease (lipid metabolism), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (dyslipidemia, abdominal obesity, insulin resistance, pro-inflammatory state).

[0112] 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 a variety of 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 slow loss of kidney function. The condition ultimately leads to the accumulation of dangerous levels of fluids, electrolytes and waste products in the body. End-stage renal failure is fatal without artificial filtration of the blood (dialysis) or a kidney transplant.

[0113] 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.

[0114] The term "treating" or "treatment" refers to an indication of success in treating or ameliorating an injury, disease, pathology, or condition, including objective or subjective parameters such as attenuation, remission, 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, improving the patient's physical or mental well-being, etc. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including the results of a physical examination, a neuropsychiatric examination, and / or a psychiatric evaluation. The term "treating" and conjugations thereof may include prevention of an injury, pathology, condition, or disease. In an embodiment, treating is preventing. In an embodiment, treating does not include preventing.

[0115] As used herein (and as is well understood in the art), "treating" or "treatment" broadly includes any approach to obtain beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results may 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 a disease state, prevention of disease spread or spread, delay or slowing of disease progression, improvement or mitigation of disease state, reduction in disease recurrence, and remission, whether partial or total, and whether detectable or undetectable. In other words, as used herein, "treatment" includes cure, amelioration, or prevention of disease. Treatment can prevent the onset of disease, inhibit the spread of disease, relieve symptoms of disease, completely or partially eliminate the underlying cause of disease, shorten the duration of disease, or a combination thereof.

[0116] The term "prevent" refers to a reduction in the occurrence of disease symptoms in a patient. As noted 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.

[0117] "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, cattle, deer and other non-mammals. In some embodiments, the patient is a human.

[0118] An "effective amount" is an amount sufficient for the 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 a symptom, or the disappearance of a symptom. A "prophylactically effective amount" of a drug is an amount of a drug that, when administered to a subject, exerts an intended prophylactic effect, such as 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 one 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 compared to the absence of the antagonist. As used herein, a "function-disrupting amount" refers to the amount of antagonist required to destroy the function of an enzyme or protein compared to the absence of the antagonist. The exact amount depends on the purpose of the treatment and can be ascertained by the skilled artisan using known techniques (see, for example, 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 Edition, 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0119] 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.

[0120] As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models.For example, human doses can be formulated to achieve concentrations found to be effective in animals.Dosages in humans can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upwards or downwards, as described above.Based on the above and other methods, it is well within the capabilities of those skilled in the art to adjust dosages to achieve maximum efficacy in humans.

[0121] The term "therapeutically effective amount" as used herein 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 at least a 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90% or at least a 100% increase or decrease. 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 over a control.

[0122] Dosage can vary depending on the patient's needs and the compound 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 is also determined by the existence, nature and extent of adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of the physician. Generally, treatment is initiated with a dosage that is less than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect is reached under the circumstances. Dosage amount and interval can be individually adjusted to provide a level of administered compound that is effective for the particular clinical indication being treated. This provides a treatment regimen that is commensurate with the severity of the individual condition.

[0123] The term "administering" as used herein means 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, such as 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 agents described.

[0124] "Cells" as used herein refers to cells that have 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 a particular dye, the ability to produce progeny, or, in the case of gametes, the ability to combine with a second gamete to produce viable progeny. 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 when they are naturally non-adherent or have been treated to prevent them from attaching to a surface, for example, by trypsinization.

[0125] compound In one aspect, compounds are provided herein 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 identified by neuroprotection assays, for example, when used at doses ranging from low nanomolar to low micromolar levels.

[0126] In one embodiment, the structure of formula (A)

[0127] [ka]

[0128] or a pharma- ceutically acceptable salt thereof. (In the formula, Ring A is a substituted or unsubstituted heterocycloalkylene or a substituted or unsubstituted heteroarylene; L 1 is -C(O)-, -C(S)- or -S(O)-, n is an integer from 1 to 5; Each R 1A, R 1B and R 1C are independently hydrogen, halogen, -CX 1 3. -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -OR 1D , -SR 1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or R 1B and R 1C together with the nitrogen atom form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R 2 is hydrogen or substituted or unsubstituted alkyl; Each R 3A , R 3B , R 3C , R 3D and R 3E are independently hydrogen, 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, or R 3A and R 3B are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3B and R 3C are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3C and R 3Dare optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3D and R 3E are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each X 1 and X 3 are independently -F, -Br, -Cl, or -I; Each R 1D and R 3F are independently hydrogen or substituted or unsubstituted alkyl. is provided.

[0129] In one embodiment, the structure of formula (X)

[0130] [ka]

[0131] or a pharma- ceutically acceptable salt thereof.

[0132] L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D and R 3E is as described herein.

[0133] In an embodiment, ring A is a substituted or unsubstituted 5,6-fused ring heteroarylene.

[0134] [ka]

[0135] [In the formula, W 1 is -CH2-, -NH-, -O- or -S-; W 2 are independently =O or =S, W 3 is =N- or =CH-,

[0136] [ka]

[0137] (In the formula, W 4 are independently -O- or -S-. These core structures may be substituted or unsubstituted.

[0138] In embodiments, ring A can be substituted or unsubstituted.

[0139] [ka]

[0140] In embodiments, ring A may be substituted or unsubstituted.

[0141] [ka]

[0142] In embodiments, ring A may be substituted or unsubstituted.

[0143] [ka]

[0144] In embodiments, ring A may be substituted or unsubstituted.

[0145] [ka]

[0146] The core structure may be:

[0147] In an embodiment, ring A is R 5 or R 5 In an embodiment, R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl.

[0148] In embodiments, R 5D is hydrogen. In embodiments, R 5D is methyl. In an embodiment, R 5D is ethyl. In an embodiment, R 5D is propyl. In embodiments, R 5D is isopropyl. In embodiments, R 5D is butyl. In an embodiment, R 5D is t-butyl. In embodiments, R 5D is -CF3, -CH2F, or -CHF2.

[0149] In embodiments, R 5 is hydrogen, methyl, -OCH3 or -SCH3. 5 is hydrogen. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is butyl. In an embodiment, R 5 is t-butyl. In embodiments, R5 is -CF3, -CH2F or -CHF2.

[0150] In embodiments, R 1D is independently hydrogen or substituted or unsubstituted alkyl. 1D is independently hydrogen or a substituted or unsubstituted C1-C4 alkyl. 1D is independently hydrogen. In an embodiment, R 1D is a substituted C1-C4 alkyl. In an embodiment, R 1D is unsubstituted C1-C4 alkyl. In embodiments, R 1D is independently methyl. In an embodiment, R 1D is independently ethyl. In an embodiment, R 1D are independently isopropyl.

[0151] In embodiments, R 3F is independently hydrogen or substituted or unsubstituted alkyl. 3F is independently hydrogen or a substituted or unsubstituted C1-C4 alkyl. 3F is independently hydrogen. In an embodiment, R 3F is a substituted C1-C4 alkyl. In an embodiment, R 3F is unsubstituted C1-C4 alkyl. In embodiments, R 3F is independently methyl. In an embodiment, R 3F is independently ethyl. In an embodiment, R 3F are independently isopropyl.

[0152] In an embodiment, L 2 is a bond. In embodiments, L 2 is substituted or unsubstituted alkylene. In embodiments, L 2 is a substituted or unsubstituted heteroalkylene.

[0153] In an embodiment, L 2are independently substituted or unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4 or C1 to C2). 2 are independently substituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4 or C1 to C2). 2 are independently unsubstituted alkylene (e.g., C1-C 20 , C1~C 12 , C1 to C8, C1 to C6, C1 to C4 or C1 to C2). 2 are independently substituted or unsubstituted C1-C 20 In an embodiment, L is an alkylene. 2 are independently substituted C1 to C 20 In an embodiment, L is an alkylene. 2 are independently unsubstituted C1 to C 20 In an embodiment, L is an alkylene. 2 are independently substituted or unsubstituted C1-C 12 In an embodiment, L is an alkylene. 2 are independently substituted C1 to C 12 In an embodiment, L is an alkylene. 2 are independently unsubstituted C1 to C 12 In an embodiment, L is an alkylene. 2 is independently a substituted or unsubstituted C1-C8 alkylene. 2 is independently a substituted C1-C8 alkylene. 2 is independently an unsubstituted C1-C8 alkylene. 2 is independently a substituted or unsubstituted C1-C6 alkylene. 2 is independently a substituted C1-C6 alkylene. 2 is independently an unsubstituted C1-C6 alkylene. 2 is independently a substituted or unsubstituted C1-C4 alkylene.2 is independently a substituted C1-C4 alkylene. 2 is independently an unsubstituted C1-C4 alkylene. 2 is independently substituted or unsubstituted ethylene. 2 is independently a substituted ethylene. 2 is independently unsubstituted ethylene. 2 is independently substituted or unsubstituted methylene. 2 is independently substituted methylene. 2 is independently unsubstituted methylene.

[0154] In an embodiment, L 2 is independently a substituted or unsubstituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). 2 is independently a substituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). 2 is independently an unsubstituted heteroalkylene (e.g., 2 to 20 members, 2 to 12 members, 2 to 8 members, 2 to 6 members, 4 to 6 members, 2 to 3 members, or 4 to 5 members). 2 is independently a substituted or unsubstituted 2- to 20-membered heteroalkylene. 2 is independently a substituted 2- to 20-membered heteroalkylene. 2 is independently an unsubstituted 2- to 20-membered heteroalkylene. 2 is independently a substituted or unsubstituted 2-8 membered heteroalkylene. 2 is independently a substituted 2-8 membered heteroalkylene. 2 is independently an unsubstituted 2-8 membered heteroalkylene. 2 is independently a substituted or unsubstituted 2-6 membered heteroalkylene. 2is independently a substituted 2-6 membered heteroalkylene. 2 is independently an unsubstituted 2-6 membered heteroalkylene. 2 is independently a substituted or unsubstituted 4- to 6-membered heteroalkylene. 2 is independently a substituted 4- to 6-membered heteroalkylene. 2 is independently an unsubstituted 4- to 6-membered heteroalkylene. 2 is independently a substituted or unsubstituted 2-3 membered heteroalkylene. 2 is independently a substituted 2-3 membered heteroalkylene. 2 is independently an unsubstituted 2-3 membered heteroalkylene. 2 is independently a substituted or unsubstituted 4- to 5-membered heteroalkylene. 2 is independently a substituted 4- to 5-membered heteroalkylene. 2 is independently unsubstituted 4- to 5-membered heteroalkylene.

[0155] In an embodiment, the compound has the structure of formula (I)

[0156] [ka]

[0157] or a pharma- ceutically acceptable salt thereof (In the formula, W 1 -CR 4A R 4B -, -NR 4C -, -O-, or -S-; W 2 is =O or =S, W 3 is -N= or -CH=, Each R 4A , R 4B and R 5are independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 4C and R 5D are independently hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0158] In an embodiment, the compound has the structure of formula (XI)

[0159] [ka]

[0160] or a pharma- ceutically acceptable salt thereof. 1 , L 2 , W 1 , W 2 , W 3 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E , R 5 and n is as disclosed herein.

[0161] In the embodiment, W 3 is -N= or -CH=. In an embodiment, W 3 In an embodiment, W is -N=. 3 is -CH=.

[0162] In the embodiment, W 1 Ha-NR 4C - or -O-. In embodiments, W 1 Ha-NR 4C In an embodiment, W 1 is -O-.

[0163] In embodiments, R 4C is hydrogen or C1-C4 unsubstituted alkyl. 4C is hydrogen or methyl. In an embodiment, R 4C is hydrogen. In embodiments, R 4C is methyl. In an embodiment, R 4C is ethyl.

[0164] In an embodiment, L 1 is -C(O)- or -C(S)-. 1 is -C(O)- or -C(S)-. 1 is -C(S)-.

[0165] In an embodiment, the compound has the structure of formula (Ia-1)

[0166] [ka]

[0167] R 1A , R 1B , R 1C , R 2 , W 2 , R 3A , R 3B , R 3C , R 3D , R 3E , R 4C and n is as described herein.

[0168] In an embodiment, the compound has the structure of formula (Ib-1)

[0169] [ka]

[0170] R 1A , R 1B , R 1C , R 2 , W 2 , R 3A , R 3B , R 3C , R 3D , R 3E , R 4C and n is as described herein.

[0171] In an embodiment, the compound has the structure of formula (XI-a-1)

[0172] [ka]

[0173] L 2 , R 1A , R 1B , R 1C , R 2 , W 2 , R 3A , R 3B , R 3C , R 3D , R 3E , R 4C and n is as described herein.

[0174] In an embodiment, the compound has the structure of formula (XI-b-1)

[0175] [ka]

[0176] L 2 , R 1A , R 1B , R 1C , R 2 , W 2 , R 3A, R 3B , R 3C , R 3D , R 3E , R 4C and n is as described herein.

[0177] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0178] In embodiments, R 3B and R 3C are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl, a substituted or unsubstituted 5-8 membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-8 membered heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted 5-8 membered heterocycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted phenyl.

[0179] In embodiments, R 3B and R 3C is linked together with the phenyl ring attached to it

[0180] [ka]

[0181] Form each Y 1 and Y 2 is independently -CH- or -O-, and m is 1 or 2. In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0182] [ka]

[0183] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0184] [ka]

[0185] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0186] [ka]

[0187] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0188] [ka]

[0189] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0190] [ka]

[0191] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0192] [ka]

[0193] Form.

[0194] In embodiments, R 3C and R 3D are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3C and R 3D are linked to form a substituted or unsubstituted C5-C8 cycloalkyl, a substituted or unsubstituted 5-8 membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-8 membered heteroaryl. 3C and R 3D are linked to form a substituted or unsubstituted C5-C8 cycloalkyl. 3C and R 3D are linked to form a substituted or unsubstituted 5-8 membered heterocycloalkyl. 3C and R 3D are linked to form a substituted or unsubstituted phenyl.

[0195] In embodiments, R 3C and R 3D is linked together with the phenyl ring attached to it

[0196] [ka]

[0197] Form each Y 1 and Y 2 is independently -CH- or -O-, and m is 1 or 2. In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0198] [ka]

[0199] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0200] [ka]

[0201] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0202] [ka]

[0203] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0204] [ka]

[0205] In an embodiment, R 3C and R 3Dis linked together with the phenyl ring attached to it

[0206] [ka]

[0207] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0208] [ka]

[0209] Form.

[0210] In embodiments, R 3A is hydrogen. In embodiments, R 3B is hydrogen. In embodiments, R 3D is hydrogen. In embodiments, R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen.

[0211] In embodiments, the compound has the structure of formula (Ic) or (Id)

[0212] [ka]

[0213] R 1A , R 1B , R 1C , W 2 , R 3C and n is as described herein.

[0214] In an embodiment, n is 2, 3 or 4. In an embodiment, n is 2, and in an embodiment, n is 3. In an embodiment, n is 4.

[0215] In embodiments, the compound has the structure of formula (XI-c) or (XI-d)

[0216] [ka]

[0217] (Wherein, ring B is

[0218] [ka]

[0219] and each Y 1 and Y 2 is independently -CH2- or -O-, and m is 1 or 2. 2 , R 1A , R 1B , R 1C , W 2 is as described herein.

[0220] In an embodiment, ring B is

[0221] [ka]

[0222] In an embodiment, ring B is

[0223] [ka]

[0224] In an embodiment, ring B is

[0225] [ka]

[0226] In an embodiment, ring B is

[0227] [ka]

[0228] In an embodiment, ring B is

[0229] [ka]

[0230] In an embodiment, ring B is

[0231] [ka]

[0232] It is.

[0233] In embodiments, R 4C is hydrogen or C1-C4 unsubstituted alkyl. 4C is hydrogen or methyl. In an embodiment, R 4C is hydrogen. In embodiments, R 4C is methyl. In an embodiment, R 4C is ethyl.

[0234] In embodiments, R 3A is hydrogen. In embodiments, R 3B is hydrogen. In embodiments, R 3D is hydrogen. In embodiments, R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen. In embodiments, R 3A , R 3B , R3D and R 3E is hydrogen, and R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0235] In embodiments, R IB and R 1C is hydrogen. In embodiments, R 1A is hydrogen, halogen, -CH, -CHCH, -OCHCH, -CF, or -OCF. 1A is methyl.

[0236] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0237] Exemplary compounds of formula (I) are shown in Table 1.

[0238] [Table 1]

[0239] In an embodiment, the compound has the structure of formula (III)

[0240] [ka]

[0241] or a pharma- ceutically acceptable salt thereof (In the formula, However, (i) R 5A is a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; R 5B is -NH-(CO)-R 5C or -C(O)-NH-R 5C and R 5C is hydrogen or substituted or unsubstituted alkyl, or (ii) R 5A is a bond, and R 5B is a halogen). 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0242] In an embodiment, the compound has the structure of formula (XIII)

[0243] [ka]

[0244] or a pharma- ceutically acceptable salt thereof. 1 , L 2 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E , R 5A and R 5B is as disclosed herein.

[0245] In an embodiment, L 1 is -C(O)- or -C(S)-. 1 is -C(O)- or -C(S)-. 1 is -C(S)-.

[0246] In embodiments, R 3A is hydrogen. In embodiments, R 3B is hydrogen. In embodiments, R 3D is hydrogen. In embodiments, R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen, and R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0247] In embodiments, R 5A is a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; R 5B is -NH-(CO)-R 5C or -C(O)-NH-R 5C In an embodiment, R 5A is a substituted or unsubstituted C5-C6 cycloalkylene or a substituted or unsubstituted 5- to 6-membered heterocycloalkylene; R 5Bis -NH-(CO)-R 5C or -C(O)-NH-R 5C In an embodiment, R 5A is a substituted or unsubstituted C5-C6 cycloalkylene or substituted, R 5B is -NH-(CO)-R 5C or -C(O)-NH-R 5C In an embodiment, R 5A is a substituted or unsubstituted C5-C6 cycloalkylene or substituted, R 5B is -NH-(CO)-R 5C In an embodiment, R 5A is a substituted or unsubstituted C5-C6 cycloalkylene or substituted, R 5B is -C(O)-NH-R 5C In an embodiment, R 5A is a substituted or unsubstituted 5- to 6-membered heterocycloalkylene; R 5B is -NH-(CO)-R 5C or -C(O)-NH-R 5C In an embodiment, R 5A is a substituted or unsubstituted 5- to 6-membered heterocycloalkylene; R 5B is -NH-(CO)-R 5C In an embodiment, R 5A is a substituted or unsubstituted 5- to 6-membered heterocycloalkylene; R 5B is -C(O)-NH-R 5C It is.

[0248] In an embodiment, the compound has the structure of formula (Ill-a) or (Ill-b)

[0249] [ka]

[0250] R 1A , R 1B , R 1C , R 3C , R 5C and n is as described herein.

[0251] In embodiments, the compound has the structure of formula (XIII-a) or (XIII-b)

[0252] [ka]

[0253] L 2 , R 1A , R 1B , R 1C , R 3C and R 5C is as described herein.

[0254] In embodiments, the compound has the structure of formula (III-a-1), (III-a-2), (III-b-1) or (III-b-2)

[0255] [ka]

[0256] R 1A , R 1B , R 1C , R 3C , R 5C and n is as described herein.

[0257] In embodiments, the compound has the structure of formula (XIII-a-1), (XIII-a-2), (XIII-b-1) or (XIII-b-2)

[0258] [ka]

[0259] L 2 , R 1A , R 1B , R 1C , R 3C and R 5C is as described herein.

[0260] In embodiments, R 5C is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 5C is hydrogen or a substituted or unsubstituted C1-C4 alkyl. 5C is hydrogen. In embodiments, R 5C is unsubstituted C1-C4 alkyl. In embodiments, R 5C is methyl. In an embodiment, R 5C is ethyl.

[0261] In embodiments, R 3B and R 3C are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl, a substituted or unsubstituted 5-8 membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-8 membered heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted 5-8 membered heterocycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted phenyl.

[0262] In embodiments, R 3B and R 3C is linked together with the phenyl ring attached to it

[0263] [ka]

[0264] Form each Y 1 and Y2 is independently -CH- or -O-, and m is 1 or 2. In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0265] [ka]

[0266] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0267] [ka]

[0268] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0269] [ka]

[0270] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0271] [ka]

[0272] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0273] [ka]

[0274] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0275] [ka]

[0276] Form.

[0277] In embodiments, R 3C and R 3D are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3C and R 3D are linked to form a substituted or unsubstituted C5-C8 cycloalkyl, a substituted or unsubstituted 5-8 membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-8 membered heteroaryl. 3C and R 3D are linked to form a substituted or unsubstituted C5-C8 cycloalkyl. 3C and R 3D are linked to form a substituted or unsubstituted 5-8 membered heterocycloalkyl. 3C and R 3D are linked to form a substituted or unsubstituted phenyl.

[0278] In embodiments, R 3C and R 3D is linked together with the phenyl ring attached to it

[0279] [ka]

[0280] Form each Y1 and Y 2 is independently -CH- or -O-, and m is 1 or 2. In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0281] [ka]

[0282] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0283] [ka]

[0284] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0285] [ka]

[0286] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0287] [ka]

[0288] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0289] [ka]

[0290] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0291] [ka]

[0292] Form.

[0293] In embodiments, R 5A is -S- and R 5B is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl. 5A is -S- and R 5B is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2-4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4-6 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5-8 membered heteroaryl. 5A is -S- and R 5B is hydrogen. In embodiments, R 5A is -S- and R 5B is a substituted or unsubstituted C1-C4 alkyl. 5A is -S- and R 5B is unsubstituted C1-C4 alkyl. In embodiments, R 5A is -S- and R 5B is methyl. In an embodiment, R 5A is -S- and R 5B is ethyl.

[0294] In an embodiment, the compound has the structure of formula (III-c)

[0295] [ka]

[0296] R 1A , R 1B , R 1C and n are as described herein. 5B is a halogen.

[0297] In an embodiment, n is 2, 3 or 4. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0298] In an embodiment, the compound has the structure of formula (XIII-c)

[0299] [ka]

[0300] L 2 , R 1A , R 1B , R 1C and R 5B is as described herein.

[0301] In embodiments, R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is SCH3 or -SCH2CH3.

[0302] In embodiments, R 1B and R1C is hydrogen. In embodiments, R 1A is hydrogen, halogen, -CH, -CHCH, -OCHCH, -CF, or -OCF. 1A is methyl.

[0303] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. In an embodiment, R 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0304] In an embodiment, the compound has the structure of formula (IV)

[0305] [ka]

[0306] (In the formula, W 4 is -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0307] In an embodiment, the compound has the structure of formula (XIV)

[0308] [ka]

[0309] has.

[0310] In embodiments, R 3B and R 3C are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl, a substituted or unsubstituted 5-8 membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-8 membered heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted 5-8 membered heterocycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted phenyl.

[0311] In embodiments, R 3B and R 3C is linked together with the phenyl ring attached to it

[0312] [ka]

[0313] Form each Y 1 and Y 2 is independently -CH- or -O-, and m is 1 or 2. In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0314] [ka]

[0315] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0316] [ka]

[0317] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0318] [ka]

[0319] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0320] [ka]

[0321] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0322] [ka]

[0323] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0324] [ka]

[0325] Form.

[0326] In embodiments, the compound has the structure of formula (IV-a) or (IV-b)

[0327] [ka]

[0328] R 1A , R 1B , R 1C , R 5 and n is as described herein.

[0329] In embodiments, the compound has the structure of formula (IV-c) or (IV-d)

[0330] [ka]

[0331] R 1A , R 1B , R 1C , R 3C , R 5 and n is as described herein.

[0332] In an embodiment, n is 2, 3 or 4. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0333] In an embodiment, the compound has the structure of formula (XIV-a) or (XIV-b)

[0334] [ka]

[0335] L 2 , R 1A , R 1B , R 1C , R 3C and R 5 is as described herein.

[0336] In embodiments, the compound has the structure of formula (XIV-c) or (XIV-d)

[0337] [ka]

[0338] L 2 , R 1A , R 1B , R 1C , R 3C and R 5 is as described herein.

[0339] In embodiments, R 5 is hydrogen or substituted or unsubstituted alkyl. In embodiments, R 5 is hydrogen or a substituted or unsubstituted C1-C4 alkyl. 5 is hydrogen. In embodiments, R 5 is unsubstituted C1-C4 alkyl. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl.

[0340] In embodiments, R 1B and R 1C is hydrogen. In embodiments, R 1A is hydrogen, halogen, -CH, -CHCH, -OCHCH, -CF, or -OCF. 1A is methyl.

[0341] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0342] Exemplary compounds of formulas (III) and (IV) are shown in Table 2.

[0343] [Table 2]

[0344] In an embodiment, the compound has the formula (V):

[0345] [ka]

[0346] or a pharma- ceutically acceptable salt thereof (In the formula, W 5 is =O or =S, W 6 is -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0347] In an embodiment, the compound has the formula (XV):

[0348] [ka]

[0349] or a pharma- ceutically acceptable salt thereof. 5 , W 6 , L 1 , L 2 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and R 5 is as disclosed herein.

[0350] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0351] In an embodiment, L 1 is -C(O)- or -C(S)-. 1 is -C(O)- or -C(S)-. 1 is -C(S)-.

[0352] In embodiments, R 3A is hydrogen. In embodiments, R 3B is hydrogen. In embodiments, R 3D is hydrogen. In embodiments, R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R3E is hydrogen, and R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0353] In embodiments, R 5 is hydrogen, methyl, -OCH3 or -SCH3. 5 is hydrogen. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is butyl. In an embodiment, R 5 is t-butyl. In embodiments, R 5 is -CF3, -CH2F or -CHF2.

[0354] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0355] In embodiments, the compound has formula (Va), (Vb), (Vc) or (Vd):

[0356] [ka]

[0357] R 1A , R 1B , R 1C , R 2 , R 3C , R 5 and n is as disclosed herein.

[0358] In embodiments, the compound has formula (XV-a), (XV-b), (XV-c) or (XV-d)

[0359] [ka]

[0360] L 2 , R 1A , R 1B , R 1C , R 2 , R 3C and R 5 is as disclosed herein.

[0361] In embodiments, R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0362] In an embodiment, n is 2, 3 or 4. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0363] In embodiments, R 5 is hydrogen, methyl, -OCH3 or -SCH3. 5 is hydrogen. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is butyl. In an embodiment, R 5 is t-butyl. In embodiments, R 5 is -CF3, -CH2F or -CHF2.

[0364] In embodiments, R 1B and R 1C is hydrogen. In embodiments, R 1A is hydrogen, halogen, -CH, -CHCH, -OCHCH, -CF, or -OCF. 1A is methyl.

[0365] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0366] In an embodiment, the compound has the formula (VI):

[0367] [ka]

[0368] or a pharma- ceutically acceptable salt thereof (In the formula, W 5 is =O or =S, W 6 is -NH-, -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0369] In an embodiment, the compound has the formula (XVI):

[0370] [ka]

[0371] or a pharma- ceutically acceptable salt thereof. 1 , L 2 , W 5 , W 6 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and R 5 is as disclosed herein.

[0372] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0373] In an embodiment, L 1 is -C(O)- or -C(S)-. 1 is -C(O)- or -C(S)-. 1 is -C(S)-.

[0374] In embodiments, R 3A is hydrogen. In embodiments, R 3B is hydrogen. In embodiments, R 3D is hydrogen. In embodiments, R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen, and R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0375] In embodiments, R 5 is hydrogen, methyl, -OCH3 or -SCH3. 5 is hydrogen. In embodiments, R5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is butyl. In an embodiment, R 5 is t-butyl. In embodiments, R 5 is -CF3, -CH2F or -CHF2.

[0376] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. In an embodiment, R 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0377] In an embodiment, the compound has the formula (VI-a), (VI-b), (VI-c), (VI-d), (VI-e) or (VI-f):

[0378] [ka]

[0379] [ka]

[0380] R 1A , R 1B , R 1C , R 2 , R 3C , R 5 and n is as disclosed herein.

[0381] In an embodiment, the compound has the formula (XVI-a), (XVI-b), (XVI-c), (XVI-d), (XVI-e) or (XVI-f)

[0382] [ka]

[0383] [ka]

[0384] L 2 , R 1A , R 1B , R 1C , R 2 , R 3C and R 5 is as disclosed herein.

[0385] In embodiments, R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0386] In an embodiment, n is 2, 3 or 4. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0387] In embodiments, R 5 is hydrogen, methyl, -OCH3 or -SCH3. 5 is hydrogen. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is butyl. In an embodiment, R 5 is t-butyl. In embodiments, R 5 is -CF3, -CH2F or -CHF2.

[0388] In embodiments, R 1B and R 1C is hydrogen. In embodiments, R 1A is hydrogen, halogen, -CH, -CHCH, -OCHCH, -CF, or -OCF. 1A is methyl.

[0389] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2 is hydrogen or methyl. 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0390] In an embodiment, the compound has the structure of formula (VII)

[0391] [ka]

[0392] or a pharma- ceutically acceptable salt thereof (In the formula, R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl. 1 , R 1A , R 1B , R 1C , R 2 , R3A , R 3B , R 3C , R 3D , R 3E and n is as disclosed herein.

[0393] In an embodiment, the compound has the structure of formula (XVII)

[0394] [ka]

[0395] or a pharma- ceutically acceptable salt thereof. 1 , L 2 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and R 5 is as disclosed herein.

[0396] In an embodiment, L 1 is -C(O)- or -C(S)-. 1 is -C(O)- or -C(S)-. 1 is -C(S)-.

[0397] In embodiments, R 3A is hydrogen. In embodiments, R 3B is hydrogen. In embodiments, R 3D is hydrogen. In embodiments, R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen, and R 3Cis hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0398] In embodiments, R 5 is hydrogen, methyl, -OCH3 or -SCH3. 5 is hydrogen. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is butyl. In an embodiment, R 5 is t-butyl. In embodiments, R 5 is -CF3, -CH2F or -CHF2.

[0399] In an embodiment, the compound has the structure of formula (VII-a)

[0400] [ka]

[0401] R 1A , R 1B , R 1C , R 5 and n is as described herein.

[0402] In an embodiment, n is 2, 3 or 4. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0403] In an embodiment, the compound has the structure of formula (XVII-a)

[0404] [ka]

[0405] L 2 , R 1A , R 1B , R 1C and R 5 is as described herein.

[0406] In embodiments, R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0407] In embodiments, R 1B and R 1C is hydrogen. In embodiments, R 1A is hydrogen, halogen, -CH, -CHCH, -OCHCH, -CF, or -OCF. 1A is methyl.

[0408] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2is hydrogen or methyl. In an embodiment, R 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0409] In one embodiment, the structure of formula (XVIII)

[0410] [ka]

[0411] or a pharma- ceutically acceptable salt thereof. (wherein z is an integer of 0 to 5). 2 , R 1A , R 1B , R 1C , R 2 , R 3A , R 3B , R 3C , R 3D , R 3E and R 5 is as disclosed herein.

[0412] In an embodiment, L 1 is -C(O)- or -C(S)-. 1 is -C(O)- or -C(S)-. 1 is -C(S)-.

[0413] In an embodiment, ring A is R 5 or R 5 In an embodiment, R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl.

[0414] In embodiments, R5D is hydrogen. In embodiments, R 5D is methyl. In an embodiment, R 5D is ethyl. In an embodiment, R 5D is propyl. In embodiments, R 5D is isopropyl. In embodiments, R 5D is butyl. In an embodiment, R 5D is t-butyl. In embodiments, R 5D is -CF3, -CH2F or -CHF2.

[0415] In embodiments, R 5 is hydrogen, methyl, -OCH3 or -SCH3. 5 is hydrogen. In embodiments, R 5 is methyl. In an embodiment, R 5 is ethyl. In an embodiment, R 5 is propyl. In embodiments, R 5 is isopropyl. In embodiments, R 5 is butyl. In an embodiment, R 5 is t-butyl. In embodiments, R 5 is -CF3, -CH2F or -CHF2.

[0416] In embodiments, R 3A is hydrogen. In embodiments, R 3B is hydrogen. In embodiments, R 3D is hydrogen. In embodiments, R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen. In embodiments, R 3A , R 3B , R 3D and R 3E is hydrogen, and R 3Cis hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0417] In an embodiment, the compound has formula (VIII)

[0418] [ka]

[0419] (wherein z is an integer of 0 to 4). 1A , R 1B , R 1C , R 3A , R 3B , R 3C , R 3D , R 3E , R 5 and n is as described herein.

[0420] In an embodiment, the compound has formula (VIII-a)

[0421] [ka]

[0422] R 1A , R 1B , R 1C , R 3C , R 5 , z and n are as described herein.

[0423] In an embodiment, the compound has formula (VIII-b)

[0424] [ka]

[0425] R 1A , R 1B , R 1C , R 3C and n is as described herein.

[0426] In embodiments, R 3C is hydrogen, halogen, -CH, -CHCH, -OCH, -OCHCH, -SCH, -SCHCH, -CF, or -OCF. 3C is hydrogen, -CH, -CHCH, -OCH, or -OCHCH. In an embodiment, R 3C is hydrogen. In embodiments, R 3C is -CH3 or -CH2CH3. In an embodiment, R 3C is -OCH3 or -OCH2CH3. In an embodiment, R 3C is -SCH3 or -SCH2CH3.

[0427] In an embodiment, n is 2, 3 or 4. In an embodiment, n is 2. In an embodiment, n is 3. In an embodiment, n is 4.

[0428] In embodiments, R 1B and R 1C is hydrogen. In embodiments, R 1A is hydrogen, halogen, -CH, -CHCH, -OCHCH, -CF, or -OCF. 1A is methyl.

[0429] In embodiments, R 2 is hydrogen or C1-C4 unsubstituted alkyl. 2is hydrogen or methyl. In an embodiment, R 2 is hydrogen. In embodiments, R 2 is methyl. In an embodiment, R 2 is ethyl.

[0430] In an embodiment, in formula (B), R 3B and R 3C are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl, a substituted or unsubstituted 5-8 membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-8 membered heteroaryl. 3B and R 3C are linked to form a substituted or unsubstituted C5-C8 cycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted 5-8 membered heterocycloalkyl. 3B and R 3C are linked to form a substituted or unsubstituted phenyl.

[0431] In embodiments, R 3B and R 3C is linked together with the phenyl ring attached to it

[0432] [ka]

[0433] Form each Y 1 and Y 2 is independently -CH- or -O-, and m is 1 or 2. In embodiments, R 3B and R 3C is linked together with the phenyl ring attached to it

[0434] [ka]

[0435] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0436] [ka]

[0437] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0438] [ka]

[0439] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0440] [ka]

[0441] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0442] [ka]

[0443] In an embodiment, R 3B and R 3C is linked together with the phenyl ring attached to it

[0444] [ka]

[0445] Form.

[0446] In embodiments, R 3C and R 3D are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3C and R 3D are linked to form a substituted or unsubstituted C5-C8 cycloalkyl, a substituted or unsubstituted 5-8 membered heterocycloalkyl, a substituted or unsubstituted phenyl, or a substituted or unsubstituted 5-8 membered heteroaryl. 3C and R 3D are linked to form a substituted or unsubstituted C5-C8 cycloalkyl. 3C and R 3D are linked to form a substituted or unsubstituted 5-8 membered heterocycloalkyl. 3C and R 3D are linked to form a substituted or unsubstituted phenyl.

[0447] In embodiments, R 3C and R 3D is linked together with the phenyl ring attached to it

[0448] [ka]

[0449] Form each Y 1 and Y 2 is independently -CH- or -O-, and m is 1 or 2. In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0450] [ka]

[0451] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0452] [ka]

[0453] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0454] [ka]

[0455] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0456] [ka]

[0457] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0458] [ka]

[0459] In an embodiment, R 3C and R 3D is linked together with the phenyl ring attached to it

[0460] [ka]

[0461] Form.

[0462] [Table 3]

[0463] Pharmaceutical Compositions In one aspect, provided are pharmaceutical compositions comprising a compound described herein, a pharma- ceutically acceptable salt form thereof, an isomer thereof, or a crystalline form thereof. Also provided herein are pharmaceutical formulations. In an embodiment, the pharmaceutical formulation comprises a compound (e.g., Formulas (X), (I), (III), (IV), (V), (VI), (VII), and (VIII), including any embodiment thereof, or the compounds of Tables 1-3 above) and a pharma- ceutically acceptable excipient.

[0464] The pharmaceutical composition may include a therapeutically effective amount of the compound administered.

[0465] In embodiments, the pharmaceutical composition comprises any of the compounds described above.

[0466] 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, intradermally, subcutaneously, intraduodenally, or intraperitoneally).

[0467] For preparing pharmaceutical compositions from the compounds described herein, pharma-ceutically 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, flavorings, binders, preservatives, tablet disintegrating agents or encapsulating materials.

[0468] 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 the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0469] Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, 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. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0470] 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.

[0471] 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.

[0472] 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.

[0473] Also included are solid preparations that 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, and the like.

[0474] The pharmaceutical preparation is preferably in unit dosage form.In such 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.

[0475] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg depending on the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0476] Some compounds may have limited solubility in water and therefore may require a surfactant or other suitable co-solvent in the composition. Such co-solvents include polysorbate 20, 60 and 80, pluronic F-68, F-84 and P-103, cyclodextrin and polyoxyl 35 castor oil. Such co-solvents 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 variability in dispensing the formulation, to reduce physical separation of the suspension or emulsion components of the formulation, and / or to otherwise enhance the formulation. Such viscosity enhancing agents include, for example, 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.

[0477] The pharmaceutical composition may further comprise ingredients for sustained release and / or comfort. Such ingredients include high molecular weight anionic mucus-mimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. 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 these patents are incorporated herein by reference in their entirety for all purposes.

[0478] The pharmaceutical composition may be intended for intravenous use. The pharma- ceutically acceptable excipient may include a buffering agent to adjust the pH to a desired range for intravenous use. Many buffering agents are known, including salts of inorganic acids such as phosphates, borates, and sulfates.

[0479] 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.

[0480] The dosage and frequency of the administered compound (single or multiple doses) 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 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.

[0481] The therapeutically effective amount for use in humans can be determined from animal models.For example, the dose for humans can be formulated to achieve the concentration found to be effective in animals.The dose for humans can be adjusted by monitoring the response of constipation or dry eye to treatment and adjusting the dose upward or downward, as described above.

[0482] Dosage can vary depending on the needs of the subject and the compound utilized.The dosage administered to the subject should be sufficient to induce a beneficial therapeutic response in the subject over time in the context of the pharmaceutical compositions presented herein.The size of the dosage is also determined by the existence, nature and extent of adverse side effects.Generally, treatment is initiated with smaller dosages that are 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.

[0483] Dosage amount and interval can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, thereby providing a therapeutic regimen commensurate with the severity of the particular disease state.

[0484] Utilizing the teachings provided herein, one can design an effective prophylactic or therapeutic treatment regimen that does not cause substantial toxicity, yet is completely 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 potency of the compound, 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.

[0485] 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 (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 administered at a dose that is consistent with little or no toxicity, such as the ED 50 The plasma concentration range includes: 0.1 to 0.5 mg / kg / day, 0.1 to 0.5 mg / kg / day, 0.2 to 0.5 mg / kg / day, 0.3 to 0.5 mg / kg / day, 0.4 to 0.5 mg / kg / day, 0.5 to 0.5 mg / kg / day, 0.6 to 0.7 mg / kg / day, 0.7 to 0.8 mg / kg / day, 0.8 to 0.9 mg / kg / day, 0.9 ...

[0486] When parenteral application is necessary or desired, the particularly suitable admixture for the compound contained in the pharmaceutical composition may be injectable sterile solution, oily or aqueous solution, and suspension, emulsion or implant, including suppository.In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline, pure 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 may 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.

[0487] 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 as described above (e.g., (X), (I), (III), (IV), (V), (VI), (VII), and (VIII), including any of its embodiments or the compounds of Tables 1-3 above).

[0488] The compound can inhibit NAD consuming reactions such as protein ADP-ribosylation reactions. The compound can inhibit NAD cleavage by protein deacetylases or NAD hydrolases. 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 or another protein misfolding disease.

[0489] 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.

[0490] 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.

[0491] The conditions include metabolic disorders, liver damage, aging, degenerative diseases, neurodegenerative diseases, neuronal degeneration associated with multiple sclerosis, hearing loss, retinal damage, macular degeneration, cerebral or cardiac ischemia, renal failure, renal disease, traumatic brain injury or axonal damage.

[0492] In one aspect, a method is provided for providing protection from misfolded protein toxicity in a patient, the method comprising administering to the patient an effective dose of a compound described herein, the patient suffering from prion disease, Parkinson's disease or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, tauopathy, amyloidosis, or diabetes.

[0493] 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.

[0494] In an embodiment, the protein misfolding neurodegenerative disease is a disorder associated with protein aggregate-induced neurodegeneration and NAD depletion.In an embodiment, the protein misfolding neurodegenerative disease includes prion disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy or other synucleinopathy, Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia or other tauopathy, chronic traumatic encephalopathy.In an embodiment, the neurodegenerative disease is multiple sclerosis, cerebral ischemia or axonopathy.

[0495] In an embodiment, the metabolic disorder comprises diabetes or liver disorder.

[0496] In an embodiment, the condition associated with an alteration in NAD metabolism includes aging, retinal disease, or renal disease.

[0497] 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.

[0498] 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.

[0499] In one aspect, there is provided a method of preventing or treating renal disease in a patient, comprising administering to the patient an effective dose of a compound described herein.

[0500] In one aspect, there is provided a method of reducing the health effects of aging comprising administering to a patient an effective dose of a compound described herein. EXAMPLES

[0501] General Chemical Synthesis Protocol. Chemicals and solvents were purchased from commercial sources and used without purification. CH2Cl2, THF, PhMe, and DMF were dried and purified using PureSolv MD 7 (Pure Process Technology). MeCN, NEt3, i-Pr2NEt, and pyridine were distilled over CaH2. 1,4-Dioxane was distilled over Na and benzophenone. Unless otherwise noted, reactions were carried out in flame-dried glassware under a positive pressure of Ar using standard synthetic organic inert atmosphere techniques.

[0502] Analytical thin layer chromatography was performed using precoated silica gel 60F254 plates with a layer thickness of 250 μm (EMD Chemicals). Visualization was performed by UV light and / or staining with ninhydrin. Purification by flash chromatography was performed using prepacked columns of silica gel (40-63 μm, 230-400 mesh) from Biotage and EtOAc / Hexane, MeOH / CH2Cl2 or MeOH / CHCl3 as eluents. LC-MS was performed on an Agilent Technologies 1260 analytical HPLC instrument coupled with an Agilent 500 Ion Trap LC / MS.

[0503] Proton nuclear magnetic resonance ( 1 H NMR spectra were obtained using a Bruker Ultrashield 400 MHz spectrometer. Chemical shifts (δ) are reported in parts per million (ppm) and are calibrated to the residual solvent peak. Coupling constants (J) are reported in Hz. Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet (the range of multiplets is indicated).

[0504] Example 1 General synthetic procedures used in several examples Step 1A: Saponification of Esters To a microwave vial or round bottom flask equipped with a Teflon coated stir bar was added the ester (1 equiv.) and a 1:1 mixture of H2O and EtOH (0.25 or 0.13 or 0.09 M). Lithium hydroxide (1.4 or 3.6 equiv.) was added to the reaction mixture and the vial was sealed or the flask was fitted with a condenser. The reaction mixture was heated to 80° C. and stirred for 16 h before being cooled to room temperature. The mixture was diluted with H2O and acidified to pH 1 with concentrated HCl. The resulting precipitate was collected by vacuum filtration and washed with H2O to give the carboxylic acid without further purification.

[0505] Step 1B: Synthesis of amides using EDC To a flame-dried round-bottom flask equipped with a rubber septum and a Teflon-coated stir bar and flushed with argon was added the carboxylic acid (1 equiv.) followed by DMF (0.16 M). To this mixture was added sequentially N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.2 equiv.), hydroxybenzotriazole hydrate (1.2 equiv.), N,N-diisopropylethylamine (2 equiv.) and amine (1.1 equiv.). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue obtained was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to give the amide.

[0506] Procedure 1C: Addition of substituted imidazoles to tert-butyl (3-bromopropyl)carbamate To a microwave vial equipped with a Teflon coated stir bar was added tert-butyl (3-bromopropyl)carbamate (2 equiv), tetrabutyl ammonium hydrogen sulfate (0.05 equiv), aqueous sodium hydroxide (50 wt%, 12.5 equiv) and substituted imidazole (1 equiv), followed by CHCl or MeCN (0.5M). The reaction mixture was stirred at room temperature or 50° C. for 3 h. The mixture was poured into H0 and extracted with CHCl. ​​The combined organic layers were washed with brine, dried over MgSO, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CHCl) to give the substituted carbamate.

[0507] Step 1D: Deprotection of BOC-protected amines To a round bottom flask equipped with a Teflon coated stir bar was added the carbamate followed by 1,4-dioxane (0.15M). The mixture was cooled to 0° C. and concentrated HCl (0.3M) was added. The reaction mixture was stirred at 0° C. for 2 h and then concentrated in vacuo to give the amine without further purification.

[0508] Step 1E: Suzuki Coupling of Boronic Acids or Esters with Pyrazolopyrimidine Triflates To a microwave vial equipped with a Teflon-coated stir bar was added pyrazolopyrimidine triflate (1 equiv), boronic acid or ester (1.2 equiv), dichlorobis[di-tert-butyl(p-dimethylaminophenyl)phosphino]palladium(II) (7 mol%) and sodium carbonate (1.7 equiv), followed by a 4:1 mixture of 1,4-dioxane and HO (0.03 M). The vial was sealed and the mixture was degassed for 30 min by bubbling argon through it. The mixture was heated to 80 °C and stirred for 1 h. After cooling to room temperature, the reaction mixture was diluted with MeOH and filtered through Celite. The filtrate was concentrated in vacuo. The resulting crude residue was purified by column chromatography (6%-50% or 8%-66% EtOAc in hexanes) to give the arylated pyrazolopyrimidine.

[0509] Step 1F: Chlorination of pyrazolopyrimidones To a flame-dried round-bottom flask equipped with a rubber septum, Teflon-coated stir bar, and condenser, flushed with argon, was added the pyrazolopyrimidone followed by POCI3 (0.08M). The reaction mixture was heated to 100°C and stirred for 16 h. The mixture was cooled to room temperature and then concentrated in vacuo. The crude residue obtained was diluted with a saturated aqueous solution of NaHCO3. The mixture was extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue obtained was purified by column chromatography (8% to 66% EtOAc in hexanes) to give the chloropyrazolopyrimidine.

[0510] Step 1G: Synthesis of β-Ketoesters To a flame-dried round-bottom flask equipped with a rubber septum, Teflon-coated stir bar and condenser, flushed with argon, was added acetophenone (1 eq.) followed by toluene (0.20 M). To the reaction mixture was added sodium hydride (60 wt%, 2 eq.) and diethyl carbonate (3 eq.). The mixture was heated to 120° C. and stirred for 1.5 h. After cooling, the mixture was poured into ice water and acidified to pH 3 with 1.0 M aqueous HCl. The mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude residue obtained was purified by column chromatography (6%-50% or 4%-34% EtOAc in hexanes) to give the β-ketoester.

[0511] Step 1H: Synthesis of Amides Using BPC To a flame-dried round-bottom flask equipped with a rubber septum and a Teflon-coated stir bar and flushed with argon was added the carboxylic acid (1 equiv.) followed by DMF (0.1M). To the mixture was added triethylamine (1 equiv.) and the mixture was stirred at room temperature for 5 min. To the mixture was added bis(perfluorophenyl)carbonate (1 equiv.) and the mixture was stirred at room temperature for 1 h. To the mixture was added 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (1 equiv.) and triethylamine (1 equiv.) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The resulting crude solid was purified by trituration with hot EtOH or by column chromatography (4% to 34% MeOH in CH2Cl2) to give the amide.

[0512] Step 1I: Thionation of chloroheterocycles To a flame-dried microwave vial equipped with a rubber septum and a Teflon-coated stir bar, flushed with argon, was added the chloroheterocycle (1 equiv.) followed by DMF (0.49 M). To the mixture was added sodium hydrosulfide dihydrate (2.7 equiv.). The vial was sealed and the mixture was heated to 120 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and then poured into H2O with vigorous stirring. To the mixture was added a 20% v / v aqueous solution of AcOH and the resulting suspension was stirred at room temperature for 15 min. The precipitate was collected by vacuum filtration, washed with H2O, and either further purified by column chromatography (1% to 8% MeOH in CHCl2) or left without purification to give the thione.

[0513] (Example 2-21) Synthesis of Representative Compounds of the Invention

[0514] Example 2 SR-31105 Process 1.

[0515] [ka]

[0516] The synthesis of 62 was carried out according to general procedure 1G using 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (3.00 g, 18.3 mmol, 1 equiv), NaH (1.46 g, 60 wt%, 36.5 mmol, 2 equiv) and diethyl carbonate (6.48 g, 6.6 mL, 54.8 mmol, 3 equiv) to give 63 (3.24 g, 13.7 mmol, 75%) as a yellow oil.

[0517] R f (3:1 hexane / EtOAc)=0.38, 1 H NMR (400 MHz, CDCl3) δ 7.53 (dd, J = 8.2, 1.8 Hz, 1H), 7.43 (d, J = 1.7 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.06 (s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.92 (s, 2H), 1.26 (t, J = 7.1 Hz, 3H); LC-MS(ESI): m / z 237 [M+H] + Process 2.

[0518] [ka]

[0519] To a tapered microwave vial equipped with a Teflon coated stir bar was added 62 (3.24 g, 13.7 mmol, 1.1 equiv) and ethyl 5-amino-1H-pyrazole-4-carboxylate (1.93 g, 12.5 mmol, 1 equiv), followed by AcOH (1.3 mL, 10 M). The vial was sealed and the reaction mixture was heated to 120° C. and stirred for 12 h. The reaction mixture was cooled to room temperature and solidified. The crude solid was heated in EtOH (10 mL) at 85° C. for 30 min. After allowing the heterogeneous mixture to cool to room temperature, the insoluble material was collected by vacuum filtration and used without further purification to give 63 (1.42 g, 4.34 mmol) as a white solid in 35% yield.

[0520] 11H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.17 (s, 1H), 7.21 (dd, J = 8.1, 2.0 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 6.11 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); LC-MS(ESI): m / z 328 [M+H] + Step 3.

[0521]

Chem.

[0522] Using 63 (884 mg, 2.58 mmol, 1 equiv) and LiOH (222 mg, 9.28 mmol, 3.6 equiv), the synthesis of 64 was carried out according to General Procedure 1A, and 64 (711 mg, 2.38 mmol, 92%) was obtained as a brown solid.

[0523] 1 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.20 (s, 1H), 7.40 (d, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.1, 1.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.21 (s, 1H), 6.16 (s, 2H) Step 4.

[0524]

Chem.

[0525] The synthesis of SR-31105 (65) was carried out according to general procedure 1H using 64 (99 mg, 0.33 mmol, 1 equiv), NEt3 (33 mg, 46 μL, 0.33 mmol, 1 equiv), BPC (130 mg, 0.33 mmol, 1 equiv), 3-(2-methyl-1H-imidazol-l-yl)propan-1-amine (46 mg, 45 μL, 0.33 mmol, 1 equiv) and NEt3 (33 mg, 46 μL, 0.33 mmol, 1 equiv) to give SR-31105 (65) (67 mg, 0.16 mmol, 48%) as a pink solid.

[0526] 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (t, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.54 - 7.52 (m, 2H), 7.47 (d, J = 1.9 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H), 6.01 (s, 1H), 4.15 (t, J = 7.0 Hz, 2H), 3.38 (q, J = 7.5 Hz, 2H), 2.07 (p, J = 7.7 Hz, 2H); LC-MS(ESI): m / z 339 [M-2-methylimidazole] +

[0527] Example 3 SR-31107 Process 1.

[0528] [ka]

[0529] To an argon-flushed, flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added ethyl 4-methoxybenzimidate hydrochloride (500 mg, 2.32 mmol, 1 equiv.), followed by pyridine (5.2 mL) and AcO (2.6 mL, 0.3 M total). The reaction mixture was heated to 80° C. and stirred for 48 h before being concentrated in vacuo to give crude 4, which was used directly in the next step. Process 2.

[0530] [ka]

[0531] To an argon-flushed flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added crude 4 and ethyl 5-amino-1H-pyrazole-4-carboxylate (360 mg, 2.32 mmol, 1 equiv.), followed by EtOH (22 ml) and AcOH (1.1 mL, 0.1 M total). The vial was sealed and the reaction mixture was heated to 85° C. and stirred for 48 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was purified by column chromatography (6% to 50% EtOAc in hexanes) to give 5 (111 mg, 0.36 mmol) as a white solid in 15% isolated yield.

[0532] R f (3:1 hexane / EtOAc)=0.26, 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 9.0 Hz, 2H), 8.52 (s, 1H), 7.00 (d, J = 9.0 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.01 (s, 3H), 1.46 (t, J = 7.1 Hz, 3H); LC-MS(ESI): m / z 313 [M+H] + Process 3.

[0533] [ka]

[0534] The synthesis of 5 was carried out following general procedure 1A using 5 (158 mg, 0.51 mmol, 1 equiv) and LiOH (17 mg, 0.71 mmol, 1.4 equiv) to afford 6 (114 mg, 0.40 mmol, 79%) as an off-white solid.

[0535] 1 LC-MS(ESI): m / z 285 [M+H] + Step 4.

[0536] [ka]

[0537] The synthesis of SR-31107 (7) was carried out according to general procedure 1B using 6 (110 mg, 0.39 mmol, 1 equiv), EDC HCl (89 mg, 0.46 mmol, 1.2 equiv), HOBt (71 mg, 0.46 mmol, 1.2 equiv), i-PrNEt (100 mg, 140 μL, 0.77 mmol, 2 equiv) and 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (59 mg, 58 μL, 0.43 mmol, 1.1 equiv) to afford SR-31107 (7) (20 mg, 0.05 mmol, 13%) as a yellow solid.

[0538] R f (10:1 CH2Cl2 / MeOH)=0.27, 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.42 (d, J = 8.9 Hz, 2H), 7.84 (t, J = 5.2 Hz, 1H), 7.03 (d, J = 8.9 Hz, 2H), 6.93 (s, 2H), 4.00 (t, J = 7.0 Hz, 2H), 3.91 (s, 3H), 3.56 (q, J = 6.4 Hz, 2H), 3.03 (s, 3H), 2.39 (s, 3H), 2.14 (p, J = 6.9 Hz, 2H)

[0539] Example 4 SR-31108 Process 1.

[0540] [ka]

[0541] The synthesis of 8 was carried out according to general procedure 1C using tert-butyl (3-bromopropyl)carbamate (348 mg, 1.46 mmol, 2 equiv), TBAHS (12 mg, 0.04 mmol, 0.05 equiv), aqueous NaOH (364 mg, 50 wt%, 728 μL, 9.10 mmol, 12.5 equiv) and 2-isopropyl-1H-imidazole (80 mg, 0.73 mmol, 1 equiv) to afford 8 (53 mg, 0.20 mmol, 27%) as a colorless oil. R f (10:1 CH2Cl2 / MeOH)=0.29. Process 2.

[0542] [ka]

[0543] The synthesis of 9 was carried out following general procedure 1D using 8 (53 mg, 0.20 mmol) to afford 9 (47 mg, 0.20 mmol, 99%) as a brown solid. Process 3.

[0544] [Chemical formula]

[0545] Using 2 (50 mg, 0.15 mmol, 1 equiv), EDC·HCl (34 mg, 0.18 mmol, 1.2 equiv), HOBt (27 mg, 0.18 mmol, 1.2 equiv), i-Pr2NEt (38 mg, 52 μL, 0.30 mmol, 2 equiv) and 9 (39 mg, 0.16 mmol, 1 equiv), the synthesis of SR-31108 (10) was carried out according to General Procedure 1B, and SR-31108 (10) (49 mg, 0.10 mmol, 68%) was obtained as a yellow oil.

[0546] R f (20:1 CH2Cl2 / MeOH) = 0.33, 1 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.04 (t, J = 7.5 Hz, 3H), 7.69 (s, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 1.2 Hz, 1H), 6.87 (d, J = 1.3 Hz, 1H), 4.03 (t, J = 7.3 Hz, 2H), 3.93 (s, 3H), 3.61 (q, J = 6.7 Hz, 2H), 2.99 (p, J = 6.8 Hz, 1H), 2.16 (p, J = 6.9 Hz, 2H), 1.29 (d, J = 6.8 Hz, 6H).

[0547] (Example 6) SR-31109 Step 1.

[0548] [Chemical formula]

[0549] The synthesis of 11 was carried out according to general procedure 1C using tert-butyl (3-bromopropyl)carbamate (697 mg, 2.93 mmol, 2 equiv), TBAHS (25 mg, 0.07 mmol, 0.05 equiv), aqueous NaOH (732 mg, 50 wt%, 1.46 mL, 18.3 mmol, 12.5 equiv) and 2-chloro-1H-imidazole (150 mg, 1.46 mmol, 1 equiv) to afford 11 (378 mg, 1.45 mmol, 99%) as a colorless oil.

[0550] R f (20:1 CH2Cl2 / MeOH)=0.25, 1 H NMR (400 MHz, CDCl3) δ 6.95 (s, 1H), 6.91 (d, J = 1.4 Hz, 1H), 4.83 (s, 1H), 3.94 (t, J = 7.1 Hz, 2H), 3.14 (d, J = 4.4 Hz, 2H), 1.91 (p, J = 6.8 Hz, 2H), 1.41 (s, 9H). Process 2.

[0551] [ka]

[0552] The synthesis of 12 was carried out following general procedure 1D using 11 (378 mg, 1.45 mmol) to afford 12 (285 mg, 1.45 mmol, 99%) as a brown solid. Process 3.

[0553] [ka]

[0554] To a flame-dried 100 mL round-bottom flask equipped with a rubber septum, a Teflon-coated stir bar, and a condenser, flushed with argon, was added ethyl (E)-3-ethoxybut-2-enoate (3.06 g, 19.3 mmol, 1.5 equiv) and ethyl 5-amino-1H-pyrazole-4-carboxylate (2.00 g, 12.9 mmol, 1 equiv), followed by DMF (26 mL, 0.5 M). To the mixture was added Cs2CO3 (7.56 g, 23.2 mmol, 1.8 equiv). The reaction mixture was heated to 100 °C and stirred for 2 h. After the mixture was cooled to room temperature, H2O (10 mL) was added and the mixture was acidified to pH 5 with AcOH. The resulting precipitate was collected by vacuum filtration and washed with H2O without further purification to give intermediate ester 13 (2.45 g, 11.1 mmol) as an off-white solid in 86% yield.

[0555] 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 8.16 (s, 1H), 6.12 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 3.33 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); LC-MS(ESI): m / z 222 [M+H] + Step 4.

[0556] [ka]

[0557] To a flame-dried 100 mL round-bottom flask equipped with a rubber septum and a Teflon-coated stir bar flushed with argon was added 13 (1.00 g, 4.52 mmol, 1 equiv.) followed by CH2Cl2 (34 mL, 0.13 M). To the mixture was added pyridine (1.79 g, 1.8 mL, 22.6 mmol, 5 equiv.) and the mixture was cooled to 0 °C. To the mixture was added Tf2O (6.38 g, 3.82 mL, 22.60 mmol, 5 equiv.) dropwise. The reaction mixture was stirred at room temperature for 2.5 h. The mixture was concentrated in vacuo and the resulting residue was dissolved in EtOAc (75 mL). The mixture was washed with a saturated aqueous solution of NaHCO3 (2 x 50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo without further purification to give intermediate triflate 14 (1.59 g, 4.49 mmol) as a pink solid in 99% yield.

[0558] 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 6.74 (s, 1H), 4.41 (q, J = 7.1 Hz, 2H), 2.91 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H); LC-MS(ESI): m / z 354 [M+H] + Process 5.

[0559] [ka]

[0560] The synthesis of 15 was carried out according to general procedure 1E using 14 (100 mg, 0.28 mmol, 1 equiv), 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (84 mg, 0.34 mmol, 1.2 equiv), Pd(amphos)Cl2 (14 mg, 0.02 mmol, 7 mol%) and Na2CO3 (51 mg, 0.48 mmol, 1.7 equiv) to give 15 (74 mg, 0.23 mmol) as a yellow solid in 80% isolated yield.

[0561] R f (3:1 EtOAc / ヘキサン)=0.51、 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.76 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 8.2, 1.8 Hz, 1H), 7.20 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.04 (s, 2H), 4.43 (q, J = 7.1 Hz, 2H), 2.83 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H). Project 6.

[0562]

change

[0563] 15 (74 mg, 0.23 mmol, 1 equivalent) and LiOH (8 mg, 0.32 mmol, 1.4 equivalent) were used. The general procedure is to synthesize 1A intermediate acid 16, and 16 (66 mg, 0.22 mmol, 98%) is a yellow solid.

[0564] 1 H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.90 (dd, J = 8.2, 1.8 Hz, 1H), 7.85 - 7.84 (m, 2H), 7.14 (d, J = 8.2 Hz, 1H), 6.16 (s, 2H), 2.80 (s, 3H).; LC-MS(ESI): m / z 298 [M+H] + Project 7

[0565]

change

[0566] Using 16 (50 mg, 0.17 mmol, 1 equiv), EDC·HCl (39 mg, 0.20 mmol, 1.2 equiv), HOBt (31 mg, 0.20 mmol, 1.2 equiv), i-Pr2NEt (43 mg, 59 μL, 0.34 mmol, 2 equiv) and 12 (36 mg, 0.19 mmol, 1 equiv), the synthesis of SR-31109 (17) was carried out according to General Procedure 1B, and SR-31109 (17) (46 mg, 0.10 mmol, 62%) was obtained as an orange solid.

[0567] R f (10:1 CH2Cl2 / MeOH) = 0.7, 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.21 (t, J = 5.3 Hz, 1H), 7.58 - 7.55 (m, 2H), 7.19 (s, 1H), 7.03 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.93 (s, 1H), 6.10 (s, 2H), 4.07 (t, J = 6.9 Hz, 2H), 3.58 (q, J = 6.2 Hz, 2H), 2.88 (s, 3H), 2.16 (p, J = 6.6 Hz, 2H); LC-MS (ESI): m / z 439 [M+H] +

[0568] (Example 7) SR-31110 Step 1.

[0569]

Chem.

[0570] The synthesis of 18 was carried out according to general procedure 1C using tert-butyl (3-bromopropyl)carbamate (652 mg, 2.74 mmol, 2 equiv), TBAHS (23 mg, 0.07 mmol, 0.05 equiv), aqueous NaOH (684 mg, 50 wt%, 1.37 mL, 17.1 mmol, 12.5 equiv) and 2-(methanesulfonyl)-1H-imidazole (200 mg, 1.37 mmol, 1 equiv) to afford 18 (272 mg, 0.90 mmol, 66%) as a colorless oil.

[0571] R f (20:1 CH2Cl2 / MeOH)=0.14, 1 H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 7.10 (d, J = 0.6 Hz, 1H), 4.93 (s, 1H), 4.37 (t, J = 6.8 Hz, 2H), 3.39 (s, 3H), 3.13 (q, J = 6.2 Hz, 2H), 2.03 (p, J = 6.8 Hz, 2H), 1.43 (s, 9H). Process 2.

[0572] [ka]

[0573] The synthesis of 19 was carried out following general procedure 1D using 18 (272 mg, 0.90 mmol) to afford 19 (213 mg, 0.89 mmol, 99%) as a brown solid. Process 3.

[0574] [ka]

[0575] The synthesis of SR-31110 (20) was carried out according to general procedure 1B using 16 (50 mg, 0.17 mmol, 1 equiv), EDC HCl (39 mg, 0.20 mmol, 1.2 equiv), HOBt (31 mg, 0.20 mmol, 1.2 equiv), i-Pr2NEt (43 mg, 59 μL, 0.34 mmol, 2 equiv) and 19 (44 mg, 0.19 mmol, 1 equiv) to afford SR-31110 (20) (2 mg, 0.01 mmol, 3%) as a yellow solid.

[0576] R f (20:1 CH2Cl2 / MeOH)=0.32, 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.21 (s, 1H), 7.61 - 7.60 (m, 2H), 7.28 - 7.24 (m, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.99 (d, J = 8.6 Hz, 1H), 6.10 (s, 2H), 4.49 (t, J = 6.6 Hz, 2H), 3.61 (q, J = 6.2, 5.7 Hz, 2H), 3.37 (s, 3H), 2.88 (s, 3H), 2.29 (p, J = 6.7 Hz, 2H).

[0577] Example 8 SR-32684 Process 1.

[0578] [ka]

[0579] The synthesis of 21 was carried out according to general procedure 1G using 1-(4-ethoxyphenyl)ethan-1-one (5.00 g, 30.5 mmol, 1 equiv), NaH (2.44 g, 60 wt%, 60.9 mmol, 2 equiv) and diethyl carbonate (10.8 g, 11.1 mL, 91.4 mmol, 3 equiv) to give 21 (5.48 g, 23.2 mmol, 76%) as a yellow oil.

[0580] Rf (5:1 hexane / EtOAc)=0.41, 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.10 (q, J = 6.7 Hz, 2H), 3.94 (s, 2H), 1.44 (t, J = 7.0 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H); LC-MS(ESI): m / z 237 [M+H] + Process 2.

[0581] [ka]

[0582] To a round-bottom microwave vial equipped with a Teflon-coated stir bar was added 21 (5.48 g, 23.2 mmol, 1.2 equiv), ethyl 5-amino-1H-pyrazole-4-carboxylate (3.00 g, 19.3 mmol, 1 equiv) and TsOH (184 mg, 0.97 mmol, 0.05 equiv), followed by n-butanol (3.6 mL, 6.5 M). The vial was sealed and the reaction mixture was heated to 130° C. and stirred for 20 h. After the reaction mixture was cooled to room temperature, acetone (5 mL) was added. The mixture was partially concentrated in vacuo. The resulting precipitate was collected by vacuum filtration and washed with acetone to give 22 (4.57 g, 14.0 mmol) as a white solid in 72% yield without further purification.

[0583] R f (3:1 EtOAc / Hexane)=0.13, 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 8.24 (s, 1H), 7.75 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 8.9 Hz, 2H), 6.23 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.35 (q, J = 6.9 Hz, 6H); LC-MS(ESI): m / z 328 [M+H] + Process 3.

[0584] [ka]

[0585] The synthesis of 23 was carried out following general procedure 1A using 22 (2.86 g, 8.74 mmol, 1 equiv) and LiOH (753 mg, 31.5 mmol, 3.6 equiv) to afford 23 (2.51 g, 8.39 mmol, 96%) as an off-white solid.

[0586] 1 H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 11.32 (s, 1H), 8.20 (s, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 8.9 Hz, 2H), 6.22 (s, 1H), 4.13 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); LC-MS(ESI): m / z 300 [M+H] + Step 4.

[0587] [ka]

[0588] The synthesis of SR-32684 (24) was carried out according to general procedure 1H using 23 (100 mg, 0.33 mmol, 1 equiv), NEt3 (34 mg, 47 μL, 0.33 mmol, 1 equiv), BPC (132 mg, 0.33 mmol, 1 equiv), 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (47 mg, 45 μL, 0.33 mmol, 1 equiv) and NEt3 (34 mg, 47 μL, 0.33 mmol, 1 equiv) to give SR-32684 (24) (67 mg, 0.16 mmol, 48%) as a white solid.

[0589] 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (t, J = 5.3 Hz, 1H), 7.96 (s, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.64 (s, 1H), 7.43 (s, 1H), 6.99 (d, J = 8.5 Hz, 2H), 6.02 (s, 1H), 4.14 (t, J = 6.9 Hz, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.38 (q, J = 6.7 Hz, 2H), 2.07 (p, J = 7.1 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).

[0590] Example 9 SR-32685 Process 1.

[0591] [ka] The synthesis of 25 was carried out following general procedure 1F using 22 (1.00 g, 3.05 mmol) to afford 25 (630 mg, 1.81 mmol, 60%) as a white solid.

[0592] R f (2:1 hexane / EtOAc)=0.50, 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.18 (d, J = 9.0 Hz, 2H), 7.54 (s, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.48 - 1.45 (m, 6H); LC-MS(ESI): m / z 346 [M+H] + Process 2.

[0593] [ka]

[0594] The synthesis of 26 was carried out according to general procedure 1I using 25 (630 mg, 1.82 mmol, 1 equiv) and NaSH 2H2O (453 mg, 4.92 mmol, 2.7 equiv) to afford 26 (575 mg, 1.67 mmol, 92%) as a yellow solid.

[0595] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.20 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 1.38 - 1.34 (m, 6H). Process 3.

[0596] [ka]

[0597] The synthesis of 27 was carried out following general procedure 1A using 26 (626 mg, 1.82 mmol, 1 equiv) and LiOH (157 mg, 6.56 mmol, 3.6 equiv) to afford 27 (570 mg, 1.81 mmol, 99%) as a yellow solid.

[0598] 1 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.86 (d, J = 8.9 Hz, 2H), 7.20 (s, 1H), 7.11 (d, J = 8.7 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H) Project 4.

[0599] [Chem.]

[0600] Using 27 (570 mg, 1.81 mmol, 1 equiv), NEt3 (183 mg, 252 μL, 1.81 mmol, 1 equiv), BPC (712 mg, 1.81 mmol, 1 equiv), 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (252 mg, 245 μL, 1.81 mmol, 1 equiv) and NEt3 (183 mg, 252 μL, 1.81 mmol, 1 equiv), the synthesis of SR-32685 (28) was carried out according to General Procedure 1H, and SR-32685 (28) (234 mg, 0.54 mmol, 30%) was obtained as a yellow solid.

[0601] R f (5:1 CH2Cl2 / MeOH) = 0.57, 1 1H NMR (400 MHz, DMSO-d6) δ 8.54 (t, J = 6.2 Hz, 1H), 8.15 (s, 1H), 8.04 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.22 (s, 1H), 7.02 (d, J = 8.9 Hz, 2H), 4.17 (t, J = 7.1 Hz, 2H), 4.09 (t, J = 7.0 Hz, 2H), 3.43 (q, J = 6.5 Hz, 2H), 2.52 (s, 3H), 2.12 (p, J = 6.7 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H).

[0602] Example 10 SR-32686 Process 1.

[0603] [ka]

[0604] To a flame-dried 10 mL round-bottom flask equipped with a rubber septum and a Teflon-coated stir bar flushed with argon was added 22 (400 mg, 1.22 mmol, 1 equiv.) followed by DMF (6.1 mL, 0.2 M). To the mixture was added Cs2CO3 (796 mg, 2.44 mmol, 2 equiv.) and Mel (347 mg, 153 μL, 2.44 mmol, 2 equiv.). The reaction mixture was stirred at room temperature for 20 h and then diluted with EtOAc (10 mL). The mixture was washed with H2O (3x15 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (18% to 100% EtOAc in hexanes) to give 29 (103 mg, 0.30 mmol) as an off-white solid in 25% isolated yield.

[0605] R f (3:1 EtOAc / Hexane)=0.34, 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.37 (d, J = 8.7 Hz, 2H), 6.99 (d, J = 8.7 Hz, 2H), 5.98 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.77 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H) LC-MS(ESI): m / z 342 [M+H] + Process 2.

[0606] [ka]

[0607] The synthesis of 30 was carried out following general procedure 1A using 29 (100 mg, 0.29 mmol, 1 equiv) and LiOH (25 mg, 1.05 mmol, 3.6 equiv) to afford 30 (52 mg, 0.17 mmol, 57%) as an off-white solid.

[0608] LC-MS(ESI):m / z314[M+H] + Process 3.

[0609] [ka]

[0610] The synthesis of SR-32686 (31) was carried out according to general procedure 1H using 30 (52 mg, 0.17 mmol, 1 equiv), NEt3 (17 mg, 23 μL, 0.17 mmol, 1 equiv), BPC (65 mg, 0.17 mmol, 1 equiv), 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (23 mg, 22 μL, 0.17 mmol, 1 equiv) and NEt3 (17 mg, 23 μL, 0.17 mmol, 1 equiv) to give SR-32686 (31) (27 mg, 0.06 mmol, 37%) as a white solid.

[0611] R f (5:1 CH2Cl2 / MeOH)=0.57, 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 8.03 - 8.01 (m, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 6.96 (s, 1H), 6.90 (s, 1H), 5.88 (s, 1H), 4.10 (q, J = 6.9 Hz, 2H), 4.01 (t, J = 7.1 Hz, 2H), 3.69 (s, 3H), 3.52 - 3.47 (m, 2H), 2.38 (s, 3H), 2.11 (p, J = 6.8 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H); LC-MS(ESI): m / z 434 [M+H] +

[0612] Example 11 SR-32689 Process 1.

[0613] [ka]

[0614] To an argon-flushed flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added 23 (500 mg, 1.67 mmol, 1 equiv.) followed by POCl3 (16 mL, 0.1 M). The vial was sealed and the reaction mixture was heated to 70 °C and stirred for 16 h. The mixture was cooled to room temperature before cold (0 °C) MTBE (112 mL, 7 x POCl3 vol.) was added. The mixture was concentrated in vacuo. The resulting crude residue was dissolved in CHCl (50 mL) and washed with H0 (50 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting crude solid was triturated with hexanes and collected by vacuum filtration to give 32 (560 mg, 1.67 mmol) as a yellow solid in 100% yield without further purification.

[0615] 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.31 (d, J = 8.9 Hz, 2H), 8.23 ​​(s, 1H), 7.13 (d, J = 9.0 Hz, 2H), 4.15 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). Process 2.

[0616] [ka]

[0617] To an argon-flushed flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added 32 (560 mg, 1.67 mmol, 1 equiv.) followed by CHCl (7.3 mL, 0.23 M). The reaction mixture was cooled to 0° C. and i-PrNEt (646 mg, 871 μL, 5.00 mmol, 3 equiv.) and 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (232 mg, 225 μL, 1.67 mmol, 1 equiv.) were added sequentially. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was poured onto H0 (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to give SR-32689 (33) (70 mg. 0.16 mmol) as a red solid in 10% isolated yield.

[0618] R f (10:1 CH2Cl2 / MeOH)=0.62, 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.11 (t, J = 5.8 Hz, 1H), 7.98 (d, J = 8.9 Hz, 2H), 7.49 (s, 1H), 7.05 (d, J = 8.9 Hz, 2H), 6.93 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 4.00 (t, J = 7.1 Hz, 2H), 3.57 (q, J = 6.5 Hz, 2H), 2.38 (s, 3H), 2.14 (p, J = 6.8 Hz, 2H), 1.47 (d, J = 7.0Hz, 3H); LC-MS(ESI): m / z357[M-2-methylimidazole] +

[0619] Example 12 SR-32687

[0620] [ka]

[0621] To an argon-flushed flame-dried tapered microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added SR-32689 (33) from the previous example (55 mg, 0.13 mmol, 1 equiv.), followed by i-PrOH (760 μL, 0.3 M). To the mixture was added i-Pr2NEt (32 mg, 44 μL, 0.25 mmol, 2 equiv.) and (R)-N-(pyrrolidin-3-yl)acetamide (16 mg, 0.13 mmol, 1 equiv.). The vial was sealed and the mixture was heated to 80° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was dissolved in CHCl (10 mL) and washed with H0 (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to give SR-32687 (34) (22 mg, 0.04 mmol) as a white solid in 33% isolated yield.

[0622] R f (10:1 CH2Cl2 / MeOH)=0.14, 1 H NMR (400 MHz, CD3OD) δ 8.63 (t, J = 5.4 Hz, 1H), 8.20 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.15 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.93 (s, 1H), 6.24 (s, 1H), 4.50 (p, J = 5.1 Hz, 1H), 4.24 (dd, J = 11.6, 6.0 Hz, 1H), 4.15 - 4.10 (m, 2H), 4.07 - 3.94 (m, 5H), 3.41 (q, J = 6.3 Hz, 2H), 2.35 (s, 3H), 2.26 (dd, J = 13.4, 7.4 Hz, 1H), 2.11 - 2.04 (m, 4H), 2.01 (s, 3H), 1.46 (t, J = 6.9 Hz, 3H); LC-MS(ESI): m / z 531 [M+H] +

[0623] (Example 13) SR-32688

[0624]

change

[0625] To an argon-flushed flame-dried tapered microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added SR-32689 (33) from the previous example (55 mg, 0.13 mmol, 1 equiv.), followed by i-PrOH (760 μL, 0.3 M). To the mixture was added i-Pr2NEt (32 mg, 44 μL, 0.25 mmol, 2 equiv.) and (S)-N-(pyrrolidin-3-yl)acetamide (16 mg, 0.13 mmol, 1 equiv.). The vial was sealed and the mixture was heated to 80° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was dissolved in CHCl (10 mL) and washed with H0 (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to give SR-32688 (35) (25 mg, 0.05 mmol) as a white solid in 38% isolated yield.

[0626] The characterization data for SR-32688 (35) were consistent with those for the enantiomer SR-32687 (34).

[0627] Example 14 SR-34831 Process 1.

[0628] [ka]

[0629] The synthesis of 36 was carried out following general procedure 1G using 1-(4-(ethylthio)phenyl)ethan-1-one (1.00 g, 5.55 mmol, 1 equiv), NaH (444 mg, 60 wt%, 11.1 mmol, 2 equiv) and diethyl carbonate (1.97 g, 2.02 mL, 16.6 mmol, 3 equiv) to afford 36 (711 mg, 2.82 mmol, 51%) as a yellow oil.

[0630] R f (5:1 hexane / EtOAc)=0.35, 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 4.21 (q, J = 7.1, 5.6 Hz, 2H), 3.94 (s, 2H), 3.03 (q, J = 7.3 Hz, 2H), 1.38 (t, J = 8.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). Process 2.

[0631] [ka]

[0632] To a round-bottom microwave vial equipped with a Teflon-coated stir bar was added 36 (711 mg, 2.82 mmol, 1.2 equiv), ethyl 5-amino-1H-pyrazole-4-carboxylate (364 mg, 2.35 mmol, 1 equiv) and TsOH (22 mg, 0.12 mmol, 0.05 equiv), followed by n-butanol (360 μL, 6.5 M). The vial was sealed and the reaction mixture was heated to 130 °C and stirred for 20 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CHCl) to give 37 (409 mg, 1.19 mmol) as a yellow oil in 51% isolated yield.

[0633] R f (10:1 CH2Cl2 / MeOH)=0.50, 1 H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.18 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.42 (d, J = 8.7 Hz, 2H), 6.25 (d, J = 2.3 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.05 (q, J = 7.4 Hz, 2H), 1.41 (q, J = 7.2 Hz, 6H). Process 3.

[0634] [ka]

[0635] The synthesis of 38 was carried out following general procedure 1F using 37 (409 mg, 1.19 mmol) to afford 38 (225 mg, 0.62 mmol, 52%) as a brown solid.

[0636] R f (3:1 hexane / EtOAc)=0.33, 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.13 (d, J = 8.5 Hz, 2H), 7.56 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 3.05 (q, J = 7.4 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H), 1.39 (t, J = 7.4 Hz, 3H). Step 4.

[0637] [ka]

[0638] The synthesis of 39 was carried out according to general procedure 1I using 38 (225 mg, 0.62 mmol, 1 equiv) and NaSH 2H2O (155 mg, 1.68 mmol, 2.7 equiv) to afford 39 (205 mg, 0.57 mmol, 92%) as a green solid.

[0639] R f (20:1 CH2Cl2 / MeOH)=0.31, 1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.29 (s, 1H), 7.60 (d, J = 5.4 Hz, 2H), 7.39 (d, J = 5.4 Hz, 2H), 7.23 (s, 1H), 4.39 (d, J = 6.4 Hz, 2H), 3.04 (q, J = 6.6 Hz, 2H), 1.43 - 1.37 (m, 6H). Process 5.

[0640] [ka]

[0641] The synthesis of 40 was carried out following general procedure 1A using 39 (205 mg, 0.57 mmol, 1 equiv) and LiOH (49 mg, 2.05 mmol, 3.6 equiv) to give crude 40, which was used directly in the next step. Process 6.

[0642] [ka]

[0643] The synthesis of SR-34831 (41) was carried out according to general procedure 1H using crude 40, NEt3 (58 mg, 79 μL, 0.57 mmol, 1 equiv), BPC (224 mg, 0.57 mmol, 1 equiv), 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (79 mg, 77 μL, 0.57 mmol, 1 equiv) and NEt3 (58 mg, 79 μL, 0.57 mmol, 1 equiv) to afford SR-34831 (41) (105 mg, 0.23 mmol, 40%) as a yellow solid.

[0644] R f (5:1 CH2Cl2 / MeOH)=0.5, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (t, J = 5.9 Hz, 1H), 8.19 (s, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 1.5 Hz, 1H), 7.26 (s, 1H), 4.11 (t, J = 7.0 Hz, 2H), 3.42 (q, J = 6.7 Hz, 2H), 3.06 (q, J = 7.3 Hz, 2H), 2.44 (s, 3H), 2.08 (p, J = 6.9 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H); LC-MS(ESI): m / z 453 [M+H] +

[0645] Example 15 SR-34953 Process 1.

[0646] [ka]

[0647] To a round-bottom microwave vial equipped with a Teflon-coated stir bar was added methyl 4-oxotetrahydrothiophene-3-carboxylate (3.00 g, 18.7 mmol, 1 equiv.) followed by MeCN (13.4 mL, 1.4 M). To the mixture was added hydroxylamine hydrochloride (1.30 g, 18.7 mmol, 1 equiv.) and the vial was sealed. The reaction mixture was heated to 85° C. and stirred for 1 h. After the mixture was cooled to room temperature, the resulting precipitate was collected by vacuum filtration and washed with Et2O to give 42 (2.81 g, 17.9 mmol) as a brown solid in 96% yield without further purification.

[0648] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.08 (s, 1H), 3.81 (s, 3H); LC-MS(ESI): m / z 158 [M+H] + Process 2.

[0649] [ka]

[0650] To a flame-dried 250 mL round-bottom flask equipped with a rubber septum, Teflon-coated stir bar, and condenser flushed with argon was added 42 (2.59 g, 16.5 mmol, 1 equiv.) and malonic acid (1.71 g, 16.5 mmol, 1 equiv.), followed by POCl3 (50 mL, 0.33 M). The reaction mixture was heated to 90 °C and stirred for 16 h. The mixture was cooled to room temperature and then poured onto crushed ice. Once the ice had melted, the mixture was neutralized with solid NaHCO3. The mixture was extracted with CH2Cl2 (3x100 mL). The combined organic layers were washed with H2O (150 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by column chromatography (12% to 100% EtOAc in hexanes) to give 43 (930 mg, 3.55 mmol) as a white solid in 22% isolated yield.

[0651] R f (1:1 hexane / EtOAc)=0.69, 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.44 (s, 1H), 4.00 (s, 3H). Process 3.

[0652] [ka]

[0653] To a round-bottom microwave vial equipped with a Teflon-coated stir bar was added 43 (530 mg, 2.02 mmol, 1 equiv), (4-ethoxyphenyl)boronic acid (369 mg, 2.22 mmol, 1.1 equiv), Na2CO3 (643 mg, 6.07 mmol, 3 equiv) and Pd(PPh3)4 (234 mg, 0.20 mmol, 10 mol%) followed by PhMe (17 mL), EtOH (11 mL) and H2O (5.3 mL, total 0.06 M). The mixture was degassed for 15 min by bubbling argon through it. The vial was sealed and the mixture was heated to 120 °C and stirred for 1 h. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was purified by column chromatography (4% to 34% EtOAc in hexanes) to give 44 (677 mg, 1.95 mmol) as a yellow solid in 96% isolated yield.

[0654] R f (5:1 hexane / EtOAc)=0.37, 1 H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.12 (d, J = 8.8 Hz, 2H), 7.78 (s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 4.11 (q, J = 6.9 Hz, 2H), 4.02 (s, 3H), 1.45 (t, J = 7.0 Hz, 3H). Step 4.

[0655] [ka]

[0656] The synthesis of 45 was carried out according to general procedure 1I using 44 (677 mg, 1.95 mmol, 1 equiv) and NaSH 2H2O (484 mg, 5.27 mmol, 2.7 equiv) to afford 45 (469 mg, 1.42 mmol, 73%) as a yellow solid.

[0657] R f (10:1 CH2Cl2 / MeOH)=0.05, 1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 6.72 (d, J = 8.1 Hz, 2H), 3.98 (q, J = 6.9 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H); LC-MS(ESI): m / z 332 [M+H] + Process 5.

[0658] [ka]

[0659] To an argon flushed flame dried round bottom microwave vial equipped with a rubber septum and a Teflon coated stir bar was added 45 (56 mg, 0.17 mmol, 1 equiv.) followed by POCI3 (1.7 mL, 0.1 M). The vial was sealed and the reaction mixture was heated to 70° C. and stirred for 16 h. The mixture was concentrated in vacuo in the microwave vial to give crude 46 which was used directly in the next step. Process 6.

[0660] [ka]

[0661] The vial containing crude 46 was fitted with a rubber septum and a Teflon coated stir bar and flushed with argon. The residue was dissolved in CHCl (3.5 mL, 0.04 M). The mixture was cooled to 0° C. and NEt (34 mg, 47 μL, 2 Eq, 0.34 mmol) and 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (26 mg, 25 μL, 1.1 Eq, 0.19 mmol) were added dropwise as a solution in CHCl (3.5 mL, 0.04 M). The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was concentrated in vacuo and the resulting crude residue was dissolved in a saturated aqueous solution of NaHCO (15 mL). The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried over MgSO, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to give SR-34953 (47) (37 mg, 0.08 mmol) as a brown solid in 48% isolated yield.

[0662] R f (10:1 CH2Cl2 / MeOH)=0.43, 1 H NMR (400 MHz, CDCl3+ 1% TMS) δ 10.01 (t, J = 5.5 Hz, 1H), 8.74 (s, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.74 (s, 1H), 7.02 (d, J = 8.9 Hz, 2H), 6.87 (d, J = 1.1 Hz, 1H), 6.85 (d, J = 1.2 Hz, 1H), 4.12 (q, J = 7.0 Hz, 2H), 3.97 (t, J = 7.2 Hz, 2H), 3.61 (q, J = 6.6 Hz, 2H), 2.32 (s, 3H), 2.15 (p, J = 6.8 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); LC-MS(ESI): m / z 453 [M+H] +

[0663] (Example 16) SR-34954 Process 1.

[0664] [ka]

[0665] To an argon flushed flame dried round bottom microwave vial equipped with a rubber septum and a Teflon coated stir bar was added 21 (2.11 g, 1.85 mL, 8.93 mmol, 1 equiv.) followed by benzene (8.0 mL) and MsOH (80 μL, 1.1 M total). To the mixture was added ethyl 2-aminobenzoate (1.47 g, 1.32 mL, 8.93 mmol, 1 equiv.). The vial was sealed and the mixture was heated to 80° C. and stirred for 40 h. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was dissolved in PhOPh (16 mL).

[0666] PhOPh (40 mL) was added to a 100 mL round bottom flask equipped with a Teflon coated stir bar. PhOPh was heated to 255 °C and the PhOPh solution from the first step was added dropwise. The mixture was stirred at 255 °C for 4 h. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was purified by column chromatography (12% to 100% EtOAc in hexanes) to give 48 (177 mg, 0.53 mmol) as a yellow solid in 6% isolated yield.

[0667] R f (1:1 hexane / EtOAc)=0.16, 1 H NMR (400 MHz, CDCl3+ 1% TMS) δ 12.21 (s, 1H), 8.65 (dd, J = 7.9, 1.2 Hz, 1H), 8.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 8.9 Hz, 2H), 6.66 (d, J = 2.0 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 4.12 (q, J = 7.0 Hz, 2H), 1.49 - 1.45 (m, 6H); LC-MS(ESI): m / z 338 [M+H]+ Process 2.

[0668] [ka]

[0669] To an argon-flushed flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added 48 (100 mg, 0.30 mmol, 1 equiv.) followed by PhMe (4.9 mL, 0.06 M). Lawesson's reagent (180 mg, 0.45 mmol, 1.5 equiv.) was added to the mixture and the vial was sealed. The mixture was heated to 115 °C and stirred for 24 h. After the mixture was cooled to room temperature, H2O (15 mL) was added and the mixture was extracted with CHCl2 (3x15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (0%-20% MeOH in CHCl2) to give 49 (77 mg, 0.22 mmol) as a red solid in 74% isolated yield.

[0670] R f (CH2Cl2)=0.52, 1 H NMR (400 MHz, CDCl3+ 1% TMS) δ 13.07 (s, 1H), 9.23 (d, J = 9.0 Hz, 1H), 8.47 (d, J = 7.0 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.9 Hz, 2H), 4.51 (q, J = 6.9 Hz, 2H), 4.13 (q, J = 6.8 Hz, 2H), 1.52 - 1.46 (m, 6H). Process 3.

[0671] [ka]

[0672] To a tapered microwave vial equipped with a Teflon coated stir bar was added 49 (77 mg, 0.22 mmol, 1 equiv.), followed by EtOH (380 μL) and HO (380 μL, 0.29 M total). To the mixture was added KOH (40 mg, 0.72 mmol, 3.3 equiv.). The vial was sealed and the mixture was heated to 80° C. and stirred for 2 h. The mixture was cooled to room temperature and then acidified to pH 2 with 1.0 M aqueous HCl. The resulting precipitate was collected by vacuum filtration and washed with HO to give 50 (54 mg, 0.17 mmol) as a red solid in 76% yield without further purification.

[0673] 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 8.93 (d, J = 9.3 Hz, 1H), 8.46 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.76 (s, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 9.3 Hz, 2H), 4.16 (q, J = 6.9 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H). Step 4.

[0674] [ka]

[0675] To an argon-flushed flame-dried tapered microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added 50 (54 mg, 0.17 mmol, 1 equiv.), followed by DMF (880 μL, 0.15 M). To the mixture was added i-Pr2NEt (64 mg, 87 μL, 0.50 mmol, 3 equiv.), HATU (95 mg, 0.25 mmol, 1.5 equiv.) and 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (25 mg, 25 μL, 0.18 mmol, 1.1 equiv.). The reaction mixture was heated to 75° C. and stirred for 16 h. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was purified by column chromatography (1% to 12% MeOH in CHCl) to give SR-34954 (51) (4 mg, 0.09 mmol) as a white solid in 5% isolated yield.

[0676] R f (15:1 CHCl3 / MeOH)=0.15, 1 H NMR (400 MHz, CDCl3+ 1% TMS) δ 11.61 (t, J = 5.6 Hz, 1H), 8.93 (dd, J = 7.4, 1.4 Hz, 1H), 8.47 (dd, J = 8.3, 1.4 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.70 - 7.66 (m, 3H), 6.94 (d, J = 8.8 Hz, 2H), 6.90 (s, 1H), 6.87 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 3.99 (t, J = 7.2 Hz, 2H), 3.70 (q, J = 6.6 Hz, 2H), 2.34 (s, 3H), 2.19 (p, J = 6.7 Hz, 2H), 1.44 (t, J = 7.0 Hz, 3H)

[0677] (Example 17) SR-35435 Process 1.

[0678] [ka]

[0679] To a 50 mL round bottom flask equipped with a Teflon coated stir bar was added methyl 3-acetyl-2-hydroxybenzoate (1.00 g, 5.15 mmol, 1 equiv) and 4-ethoxybenzaldehyde (773 mg, 716 μL, 5.15 mmol, 1 equiv), followed by EtOH (10.3 mL, 0.5 M). The mixture was heated to 50 °C and aqueous NaOH (2.68 g, 50 wt%, 5.4 mL, 66.9 mmol, 13 equiv) was added dropwise. The mixture was cooled to room temperature and stirred for 48 h. The mixture was poured onto ice and neutralized with 1.0 M aqueous HCl (5 mL). The resulting precipitate was collected by vacuum filtration, rinsed with HO, and used without further purification to give 52 (1.48 g, 4.74 mmol) as a yellow solid in 92% yield.

[0680] 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (dd, J = 7.7, 1.7 Hz, 1H), 7.94 (dd, J = 7.7, 1.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 15.8 Hz, 1H), 7.54 (d, J = 15.8 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 4.09 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H) Process 2.

[0681] [ka]

[0682] To an argon-flushed flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added 52 (225 mg, 0.72 mmol, 1 equiv.), followed by DMSO (7.2 mL, 0.1 M). To the mixture was added iodine (18 mg, 0.07 mmol, 0.1 equiv.). The mixture was heated to 110° C. and stirred for 1.5 h. The mixture was cooled to room temperature and then neutralized with 1.0 M aqueous HCl. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude 53, which was used directly in the next step. A suitable variation of the general method used to prepare intermediates such as compound 53 employs acid chloride acylation of a phenol followed by ring formation. 36 Process 3.

[0683] [ka]

[0684] The synthesis of SR-35434 (54) was carried out according to general procedure 1H using crude 53, NEt3 (73 mg, 101 μL, 0.72 mmol, 1 equiv), BPC (284 mg, 0.72 mmol, 1 equiv), 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (100 mg, 98 μL, 0.72 mmol, 1 equiv) and NEt3 (73 mg, 101 μL, 0.72 mmol, 1 equiv) to give SR-35434 (54) (164 mg, 0.38 mmol, 53%) as a yellow solid.

[0685] R f (10:1 CH2Cl2 / MeOH)=0.36, 1H NMR (400 MHz, CDCl3+ 1% TMS) δ 8.07 - 8.00 (m, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.55 (t, J = 5.4 Hz, 1H), 7.33 - 7.28 (m, 1H), 6.94 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 1.2 Hz, 1H), 6.85 (s, 1H), 6.50 (s, 1H), 4.09 (q, J = 6.9 Hz, 2H), 4.01 (t, J = 7.1 Hz, 2H), 3.63 (q, J = 6.7 Hz, 2H), 2.34 (s, 3H), 2.17 (p, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H)

[0686] (Example 18) SR-35435 Process 1.

[0687] [ka]

[0688] To an argon-flushed flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added SR-35434 (54) from the previous example (100 mg, 0.22 mmol, 1 equiv.), followed by pyridine (5.6 mL, 0.04 M). To the mixture was added Lawesson's reagent (90 mg, 0.22 mmol, 1 equiv.). The vial was sealed and the reaction mixture was heated to 130 °C and stirred for 2 h. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude residue was immediately purified by column chromatography (2% to 18% MeOH in CHCl) to give SR-35435 (55) (80 mg, 0.17 mmol) as a red solid in 77% isolated yield.

[0689] R f (10:1 CH2Cl2 / MeOH)=0.30, 1H NMR (400 MHz, CDCl3) δ 8.71 (dd, J = 8.1, 1.7 Hz, 1H), 8.14 (dd, J = 7.4, 1.7 Hz, 1H), 7.84 (d, J = 8.9 Hz, 2H), 7.69 (s, 1H), 7.46 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 6.91 (dd, J = 8.5, 1.3 Hz, 2H), 6.84 (t, J = 6.4 Hz, 1H), 4.11 (q, J = 7.0 Hz, 2H), 4.01 (t, J = 7.1 Hz, 2H), 3.62 (q, J = 6.7 Hz, 2H), 2.39 (s, 3H), 2.14 (p, J = 7.1 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H).

[0690] (Example 19) SR-34784 Project 1.

[0691]

change

[0692] To a flame-dried 100 mL round-bottom flask equipped with a rubber septum and a Teflon-coated stir bar flushed with argon was added ethyl 2-amino-1H-pyrrole-3-carboxylate (3.00 g, 19.5 mmol, 1 equiv.), followed by DMF (32.5 mL, 0.6 M). The mixture was cooled to 0° C. and NaH (934 mg, 60 wt%, 23.4 mmol, 1.2 equiv.) was added. The mixture was stirred at 0° C. for 30 min. To the mixture was added ethyl (E)-3-ethoxyacrylate (3.37 g, 3.37 mL, 23.4 mmol, 1.2 equiv.) and the mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was diluted with EtOAc (20 mL) and acidified to pH 7 with 1.0 M aqueous HCl. The mixture was separated and the organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc) to give 56 (2.77 g, 13.4 mmol) as a purple solid in 69% isolated yield.

[0693] R f (Et0Ac)=0.50, 1 H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 6.74 (d, J = 3.4 Hz, 1H), 6.62 (d, J = 3.4 Hz, 1H), 6.05 (d, J = 7.8 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H). Process 2.

[0694] [ka]

[0695] To an argon-flushed, flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added 56 (400 mg, 1.93 mmol, 1 equiv.) followed by CHCl (4.8 mL, 0.4 M). To the mixture was added NEt (781 mg, 1.08 mL, 7.72 mmol, 4 equiv.) and the mixture was cooled to 0° C. To the mixture was added TsCl (383 mg, 2.01 mmol, 1.04 equiv.). The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The mixture was diluted with EtOAc (10 mL) and washed with HO (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO, filtered and concentrated in vacuo. The resulting crude residue was purified by column chromatography (20% to 100% EtOAc in hexanes) to give 57 (533 mg, 1.47 mmol) as a brown solid in 76% isolated yield.

[0696] R f (1:1 hexane / EtOAc)=0.46, 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz, 2H), 8.23 ​​(d, J = 7.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 3.3 Hz, 1H), 7.08 (d, J = LC-MS(ESI): m / z 383 [M+Na] + Process 3.

[0697] [ka]

[0698] To an argon-flushed flame-dried round-bottom microwave vial equipped with a rubber septum and a Teflon-coated stir bar was added 57 (150 mg, 0.42 mmol, 1 equiv), (4-ethoxyphenyl)boronic acid (104 mg, 0.62 mmol, 1.5 equiv), K3PO4 (177 mg, 0.83 mmol, 2 equiv), Pd(OAc)2 (9 mg, 0.04 mmol, 10 mol%) and 2-(dicyclohexylphosphino)biphenyl (29 mg, 0.08 mmol, 20 mol%) followed by 1,4-dioxane (5.2 mL, 0.08 M). The vial was sealed and the mixture was degassed for 30 min while bubbling argon through it. The mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and then filtered through Celite rinsing with acetone. The filtrate was concentrated in vacuo. The resulting crude residue was purified by column chromatography (8% to 66% EtOAc in hexanes) to give 58 (127 mg, 0.41 mmol) as a white solid in 98% isolated yield.

[0699] R f (2:1 hexane / EtOAc)=0.27, 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.3 Hz, 1H), 8.15 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 3.2 Hz, 1H), 7.18 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 3.2 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 4.43 (q, J = 7.0 Hz, 2H), 4.10 (q, J = 6.9 Hz, 2H), 1.49 - 1.43 (m, 6H). Step 4.

[0700] [ka]

[0701] The synthesis of 59 was carried out following general procedure 1A using 58 (114 mg, 0.37 mmol, 1 equiv) and LiOH (32 mg, 1.32 mmol, 3.6 equiv) to afford 59 (85 mg, 0.30 mmol, 82%) as a yellow solid.

[0702] 1 H NMR (400 MHz, DMSO-d6) δ 8.86 (d, J = 7.4 Hz, 1H), 8.19 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 7.4 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.25 (d, J = 3.2 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 4.12 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H) LC-MS(ESI): m / z 283 [M+H] + Process 5.

[0703] [ka]

[0704] The synthesis of SR-35784 (60) was carried out according to general procedure 1B using 59 (40 mg, 0.14 mmol, 1 equiv), EDC HCl (33 mg, 0.17 mmol, 1.2 equiv), HOBt (26 mg, 0.17 mmol, 1.2 equiv), i-PrNEt (37 mg, 49 μL, 0.28 mmol, 2 equiv) and 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (22 mg, 21 μL, 0.16 mmol, 1.1 equiv) to afford SR-35784 (60) (34 mg, 0.08 mmol, 59%) as a yellow solid.

[0705] R f (10:1 CH2Cl2 / MeOH)=0.27, 11H NMR (400 MHz, CDCl3) δ 8.65 (t, J = 5.9 Hz, 1H), 8.29 (d, J = 7.4 Hz, 1H), 7.94 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 3.2 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 7.03 (d, J = 8.9 Hz, 2H), 6.97 (d, J = 1.3 Hz, 1H), 6.92 (d, J = 1.3 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 4.02 (t, J = 7.2 Hz, 2H), 3.61 (q, J = 6.3 Hz, 2H), 2.40 (s, 3H), 2.14 (p, J = 6.7 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H) LC-MS(ESI): m / z 404 [M+H] +

[0706] (Example 20) SR-35785

[0707] [Chemical Structure]

[0708] To a flame-dried 15 mL round-bottom flask equipped with a rubber septum and a Teflon-coated stir bar and flushed with argon was added 53 (100 mg, 0.32 mmol, 1 equiv.), followed by CHCl (3 mL) and DMF (3 mL, 0.05 M total). To the mixture was added EDC·HCl (68 mg, 0.35 mmol, 1.1 equiv.), HOBt (62 mg, 0.32 mmol, 1 equiv.), NEt3 (78 mg, 108 μL, 0.77 mmol, 2.4 equiv.) and 3-(2-methyl-1H-imidazol-1-yl)propan-1-ol hydrochloride (57 mg, 0.32 mmol, 1 equiv.). The mixture was stirred at room temperature for 24 h and then concentrated in vacuo. The resulting crude residue was purified by column chromatography (0% to 6% MeOH in CH2Cl2) to give SR-35785 (61) (34 mg, 0.08 mmol) as a yellow solid in 24% isolated yield.

[0709] R f (30:1 CH2Cl2 / MeOH)=0.12, 1 H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 7.9 Hz, 1H), 8.23 ​​(d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.46 (t, J = 7.7 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 6.93 (s, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 4.45 (t, J = 6.0 Hz, 2H), 4.11 (q, J = 6.9 Hz, 2H), 4.03 (t, J = 6.9 Hz, 2H), 2.38 (d, J = 1.6 Hz, 3H), 2.27 (p, J = 6.4 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H)

[0710] Example 21 SR-33781 Process 1.

[0711] [ka]

[0712] To a 100 mL round-bottom flask equipped with a Teflon-coated stir bar was added 42 (2.81 g, 17.9 mmol, 1 equiv.) followed by ethyl acetoacetate (30 mL, 0.6 M). An air condenser was fitted to the flask and the reaction mixture was heated to 180 °C and stirred for 2 h. The mixture was cooled to room temperature and allowed to stand for 16 h. The resulting precipitate was collected by vacuum filtration and rinsed with Et2O to give 66 (2.30 g, 10.3 mmol) as a grey solid in 58% yield without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.71 (s, 1H), 6.34 (s, 1H), 3.90 (s, 3H), 2.37 (s, 3H). Process 2.

[0713] [ka]

[0714] To a flame-dried round-bottom microwave vial equipped with a rubber septum, a Teflon-coated stir bar and flushed with argon was added 66 (1.16 g, 5.20 mmol, 1 equiv.) followed by POCl3 (19 mL, 0.27 M). The vial was sealed and the mixture was heated to 110 °C and stirred for 2 h. The mixture was cooled to room temperature and then poured onto ice. The mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (30 mL) and brine (30 mL). The organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude solid was triturated with Et2O to give 67 (987 mg, 4.08 mmol) as an off-white solid in 79% yield without further purification. 1 H NMR (400 MHz, CDCl3) δ (8.79, 1H), 7.43 (s, 1H), 4.02 (s, 3H), 2.75 (s, 3H). Process 3.

[0715] [ka]

[0716] To a flame-dried 250 mL round bottom flask equipped with a rubber septum, Teflon coated stir bar and condenser and flushed with argon was added 67 (500 mg, 2.07 mmol, 1 equiv), benzo[d][1,3]dioxyl-5-ylboronic acid (412 mg, 2.48 mmol, 1.2 equiv), K3PO4 (1.32 g, 6.21 mmol, 3 equiv) and Pd(dppf)Cl2·CH2Cl2 (76 mg, 0.10 mmol, 5 mol%) followed by DME (82 mL, 0.025 M). The mixture was heated to 90 °C and stirred for 6 h before being cooled to room temperature. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were washed with H2O (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a crude residue which was purified by column chromatography (6% to 50% EtOAc in hexanes) to give 68 (368 mg, 1.12 mmol) as a white solid in 54% isolated yield. R f (3:1 hexane / EtOAc)=0.45, 1 H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.69 (dd, J = 8.2, 1.8 Hz, 1H), 7.56 (s, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.03 (s, 2H), 4.03 (s 3H), 2.65 (s, 3H). Step 4.

[0717] [ka]

[0718] To a round-bottom microwave vial equipped with a Teflon-coated stir bar was added 68 (368 mg, 1.12 mmol, 1 equiv), followed by EtOH (5 mL) and HO (3 mL, 0.13 M total). To the mixture was added NaOH (180 mg, 4.50 mmol, 4 equiv) and the vial was sealed. The mixture was heated to 80 °C and stirred for 2 h. The mixture was cooled to room temperature and then concentrated in vacuo. The resulting crude solid was dissolved in HO (10 mL) and acidified to pH 2 with concentrated HCl. The mixture was stirred for 10 min and the resulting precipitate was collected by vacuum filtration and washed with HO to give 69 (320 mg, 1.02 mmol) as a yellow solid in 91% yield without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 7.98 (s, 1H), 7.73 - 7.71 (m, 2H), 7.11 (d, J = 8.7 Hz, 1H), 6.13 (s, 2H), 2.67 (s, 3H). Process 5.

[0719] [ka]

[0720] The synthesis of SR-33781 (70) was carried out according to general procedure 1B using 69 (200 mg, 0.64 mmol, 1 equiv), EDC HCl (147 mg, 0.77 mmol, 1.2 equiv), HOBt (117 mg, 0.77 mmol, 1.2 equiv), i-PrNEt (165 mg, 220 μL, 1.28 mmol, 2 equiv) and 3-(2-methyl-1H-imidazol-1-yl)propan-1-amine (98 mg, 95 μL, 0.70 mmol, 1.1 equiv) to afford SR-33781 (70) (40 mg, 0.09 mmol, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.88 (t, J = 5.7 Hz, 1H), 8.82 (s, 1H), 7.93 (s, 1H), 7.70 - 7.66 (m, 2H), 7.08 - 7.06 (m, 2H), 6.72 (s, 1H), 6.12 (s, 2H), 3.99 (t, J = 7.0 Hz, 2H), 3.46 (q, J = 6.7 Hz, 2H), 2.67 (s, 3H), 2.20 (s, 3H), 2.05 (p, J = 8.2 Hz, 2H).

[0721] Example 22 Cell viability assay The following table shows structures of illustrative compounds useful in practicing the methods of the invention, associated with corresponding data, such as compound identifiers, and biological results.

[0722] Biological activity of test compounds was quantified in a cell viability assay (CellTiter-Glo®) that evaluates the ability of compounds to prevent neuronal cell death due to NAD depletion induced by the misfolded protein TPrP. A dose-response profile was established for each compound in the TPrP neuroprotection assay. PK1 neuroblastoma cells (approximately 1000 cells / well, 96-well plate) were exposed to 5 μg / ml TPrP and doses of compounds ranging from 2 nM to 2.7 μM 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 curves are shown in FIG.

[0723] (Example 23) 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 min and 2 h 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 >15 min is shown in Table 4.

[0724] (Example 24) NAMPT activation assay The ability of some test compounds to activate human NAMPT was tested with a colorimetric NAMPT activity assay (AbCam ab221819). The assay was performed according to the manufacturer's instructions. For compound SR229, mouse NAMPT activity was measured by replacing human NAMPT with mouse NAMPT (Fisher Scientific AG-40B0179-C050). The enzyme activity rate was calculated by the formula: ((A at T2)-(A at Tl)) / (T2-Tl), 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 the baseline (CTRL, no compound) is also shown in Figure 2. For the test compounds, ≧10% NAMPT activation at 1 μM compound is shown in Table 4.

[0725] [Table 4A]

[0726] [Table 4B]

[0727] [Table 4C]

[0728]

Table 4D

[0729] (References) TIFF2024508761000189.tif215170TIFF2024508761000190.tif223170TIFF2024508761000191.tif226170TIFF2024508761000192.tif200170

Claims

1. Structure of formula (X) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof. (In the formula, Ring A is a substituted or unsubstituted heterocycloalkylene or a substituted or unsubstituted heteroarylene; L 1 is -C(O)-, -C(S)- or -S(O) 2 - and L 2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; Each R 1A , R 1B and R 1C are independently hydrogen, halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2 , -CN, -OR 1D , -SR 1D , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or R 1B and R 1C together with the nitrogen atom form a substituted or unsubstituted heterocycloalkyl, or a substituted or unsubstituted heteroaryl; R 2 is hydrogen or substituted or unsubstituted alkyl; Each R 3A , R 3B , R 3C , R 3D and R 3E are independently hydrogen, halogen, -CX 3 3 , -CHX 3 2 , -CH 2 X 3 , -OCX 3 3 , -OCH 2 X 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, or R 3A and R 3B are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3B and R 3C are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3C and R 3D are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3D and R 3E are optionally linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each X 1 and X 3 are independently -F, -Br, -Cl, or -I; Each R 1D and R 3F are independently hydrogen or substituted or unsubstituted alkyl.

2. Structure of Formula (I) 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof. (In the formula, n is an integer from 1 to 5, W 1 -CR 4A R 4B -, -NR 4C -, -O- or -S-; W 2 is =O or =S, W 3 is =N- or =CH-, Each R 4A , R 4B and R 5 are independently hydrogen, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; Each R 4C and R 5D are independently hydrogen or substituted or unsubstituted alkyl.

3. W 1 Ga-NR 4C 3. The compound according to claim 2, wherein - or -O- and / or L 1 is -C(O)- or -C(S)-, or a pharma- ceutically acceptable salt thereof.

4. Structure of formula (Ia-1) or (Ib-1) 【Chemistry 3】 4. The compound of claim 2 or 3, having the formula:

5. Structure of formula (Ic) or (Id) 【Chemistry 4】 4. The compound of claim 2 or 3, having the formula:

6. R 4C 6. The compound according to any one of claims 2 to 5, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or methyl.

7. Structure of formula (III) 【Chemistry 5】 or a pharma- ceutically acceptable salt thereof. (In the formula, n is an integer from 1 to 5, however, (i)R 5A is a substituted or unsubstituted cycloalkylene or a substituted or unsubstituted heterocycloalkylene; R 5B is -NH-(CO)-R 5C or -C(O)-NH-R 5C and R 5C is hydrogen or substituted or unsubstituted alkyl, or (ii)R 5A is a bond, and R 5B is a halogen).

8. Structure of formula (Ill-a) or (Ill-b) 【Chemistry 6】 8. The compound of claim 7, having the formula:

9. Structure of formula (III-a-1), (III-a-2), (III-b-1) or (III-b-2) 【Chemistry 7】 9. The compound of claim 7 or 8, or a pharma- ceutically acceptable salt thereof, having the formula:

10. Structure of formula (III-c) 【Chemistry 8】 (In the formula, R 5B or a pharma- ceutically acceptable salt thereof.

11. Structure of formula (IV) 【Chemistry 9】 or a pharma- ceutically acceptable salt thereof. (In the formula, n is an integer from 1 to 5, W 4 is -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl).

12. R 3B and R 3C are linked to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R 3C and R 3D or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 2 to 11, wherein:

13. Structure of formula (IV-a) or (IV-b) 【Chemistry 10】 13. The compound of claim 11 or 12, having the formula:

14. Structure of formula (V) 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof. (In the formula, W 5 is =O or =S, W 6 is -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl).

15. Structure of Formula (Va), (Vb), (Vc) or (Vd) 【Chemistry 12】 15. The compound of claim 14, having the formula:

16. Structure of formula (VI) 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof. (In the formula, n is an integer from 1 to 5, W 5 is =O or =S, W 6 is -NH-, -O- or -S-; R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl).

17. Structure of formula (VI-a), (VI-b), (VI-c), (VI-d), (VI-e) or (VI-f) 【Chemistry 14】 【Chemistry 15】 17. The compound of claim 16, having the formula:

18. Structure of formula (VII) 【Chemistry 16】 or a pharma- ceutically acceptable salt thereof. (In the formula, n is an integer from 1 to 5, R 5 are independently hydrogen, -OR 5D , halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R 5D is hydrogen or substituted or unsubstituted alkyl).

19. Having a structure of formula (VII), and having a structure of formula (VII-a) 【Chemistry 17】 19. The compound of claim 18, having the formula:

20. R 5 20. The compound according to any one of claims 14 to 19, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or methyl.

21. R 1A is hydrogen, halogen, -CH 3 , -CH 2 CH 3 , -OCH 2 CH 3 , -CF 3 Or -OCF 3 and R 1B and R 1C 21. The compound according to any one of claims 2 to 20, wherein is hydrogen.

22. Formula (VIII) 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof. (wherein n is an integer from 1 to 5).

23. Formula (VIII-a) 【Chemistry 19】 23. The compound of claim 22, having the formula:

24. Formula (VIII-b) 【Chemistry 20】 24. The compound of claim 22 or 23, having the formula:

25. 25. The compound according to any one of claims 2 to 24, wherein n is 2, 3 or 4.

26. R 3C is hydrogen, halogen, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -SCH 3 , -SCH 2 CH 3 , -CF 3 Or -OCF 3 26. The compound according to any one of claims 2 to 25, wherein:

27. Each R 1A , R 1B and R 1C are independently hydrogen, halogen, -CH 3 , -CH 2 CH 3 , -OCH 2 CH 3 , -CF 3 Or -OCF 3 27. The compound of any one of claims 22 to 26, wherein:

28. 28. A compound according to any one of claims 1 to 27, which is any compound in the following table, or a pharma- ceutically acceptable salt thereof: 【Table 1】 【Table 2】 【Table 3】 。

29. 29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, a pharma- ceutically acceptable salt form thereof, an isomer thereof or a crystalline form thereof and a pharma- ceutically acceptable carrier.

30. 29. A medicament comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof for inhibiting NAD consumption, preventing or inhibiting NAD depletion, ameliorating a condition associated with altered NAD metabolism, providing protection from misfolded protein toxicity, and / or increasing NAD synthesis in a subject.

31. A pharmaceutical comprising a compound according to any one of claims 1 to 28 or a pharma- ceutically acceptable salt thereof for treating a disease or condition selected from degenerative diseases, retinal diseases, hearing loss, renal diseases, diabetes, non-alcoholic fatty liver disease or other metabolic diseases and the effects of aging.

32. The pharmaceutical composition of claim 31, wherein the degenerative disease is peripheral amyloidosis, or a neurodegenerative disorder associated with misfolded protein-induced neurodegeneration and / or NAD depletion, 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.

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