Patent Application
20240262831
A number of fatal neurodegenerative diseases, including prion diseases such as Creutzfeldt-Jakob disease (CJD), Alzheimer's (AD), Parkinson's (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), are characterized by toxicity resulting from protein misfolding, and are called protein misfolding neurodegenerative diseases (PMNDs). Proteins involved in these diseases misfold and form aggregates of various sizes. Some of these aggregates are highly toxic for neurons, a phenomenon also referred to as proteotoxicity. Protein aggregates can also exhibit “prion-like” properties, in the sense that they propagate from cell to cell and act as seeds to amplify the misfolding and aggregation process within a cell. 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; SOD1, TDP43, FUS and C9ORF72 in ALS. PD belongs to a broader group of diseases called synucleinopathies, characterized by the accumulation of misfolded α-synuclein aggregates. Lewy body dementia and Multiple System Atrophy are also synucleinopathies. FTD belongs to another group of PMNDs termed 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 mellitus where the proteins IAPP and proinsulin form protein aggregates that are toxic for pancreatic beta-cells, and cardiomyopathy caused by transthyretin (TTR) amyloidosis (ATTR). TTR amyloid deposits predominantly in peripheral nerves cause a polyneuropathy.
Poor knowledge of the mechanisms of neurotoxicity has hampered the development of effective therapies for PMNDs. To study such mechanisms, a model that uses misfolded and toxic prion protein (TPrP) has been developed, and in particular TPrP reproducibly induces neuronal death in cell culture and after intracerebral injection1. TPrP induces death of more than 60% of cultured neurons at nanomolar concentration, whereas the natively folded counterpart of the prion protein, NTPrP, does not. Therefore, this model provides a highly efficient system to study mechanisms of neuronal death linked to proteotoxicity that are broadly applicable to protein misfolding diseases. Thus, as demonstrated herein, TPrP-based studies spurred the development of new neuroprotective approaches for treating devastating neurodegenerative diseases and other diseases involving the death of particular cell types.
Provided herein, inter alia, are novel compounds that may inhibit NAD consumption and/or increase NAD synthesis.
In an aspect, provided is a compound having a structure of Formula (X),
or a pharmaceutically acceptable salt thereof.
Ring A is a substituted or unsubstituted heterocycloalkylene, or substituted or unsubstituted heteroarylene.
L1 is —C(O)—, —C(S)—, or —S(O)2—.
L2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.
Each R1A, R1B, and R1C is independently hydrogen, halogen, —CX13, —CHX12, —CH2X1, —OCX13, —OCH2X1, —OCHX12, —CN, —OR1D, —SR1D, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R1B and R1C together with the nitrogen atom form a substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
R2 is hydrogen, or substituted or unsubstituted alkyl.
Each R3A, R3B, R3C, R3D, and R3E is independently hydrogen, halogen, —CX33, —CHX32, —CH2X3, —OCX33, —OCH2X3, —OCHX32, —CN, —OR3F, —SR3F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; R3A and R3B are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3B and R3C are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R3C and R3D are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R3D and R3E are optionally joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
Each X1 and X3 is independently —F, —Br, —Cl, or —I.
Each R1D and R3F is independently hydrogen, or substituted or unsubstituted alkyl.
In embodiments, the compound has a structure of Formula (I),
In embodiments, the compound has a structure of Formula (II),
the compound has a structure of Formula (III),
In embodiments, the compound has a structure of Formula (IV),
wherein:
In embodiments, the compound has a formula of Formula (V)
wherein:
In embodiments, the compound has a formula of Formula (VI),
wherein:
In embodiments, the compound has the structure of Formula (VII),
In an aspect, provided is a compound having a structure of Formula (VIII),
In an aspect, provided is a pharmaceutical composition including the compound described herein, a pharmaceutically acceptable salt form thereof, an isomer thereof, or a crystal form thereof.
In an aspect, provided is a method of inhibiting NAD consumption and/or increasing NAD synthesis in a patient. The method may include administering to the patient an effective dose of the compound as described herein.
In an aspect, provided is a method of preventing or inhibiting NAD depletion in a patient, or a method of improving a condition linked to alterations of NAD metabolism in a patient. The method may include administering to the patient an effective dose of the compound as described herein.
In an aspect, provided is a method of providing protection from toxicity of misfolded proteins in a patient. The method may include administering to the patient an effective dose of the compound as described herein.
In an aspect, provided is a method of preventing or treating a protein misfolding neurodegenerative disease in a patient. The method may include administering to the patient an effective dose of the compound as described herein.
In an aspect, provided is a method of preventing or treating retinal disease in a patient. The method may include administering to the patient an effective dose of the compound as described herein.
In an aspect, provided is a method of preventing or treating a metabolic disease, ischemic disease, hearing loss or kidney failure in a patient. The method may include administering to the patient an effective dose of the compound as described herein.
Other aspects of the inventions are disclosed infra.
The misfolded toxic prion protein TPrP induces a profound depletion of neuronal NAD that is responsible for cell death, since NAD replenishment leads to full recovery of cells exposed to TPrP injury in vitro and in vivo, despite continued exposure to TPrP2. Intranasal NAD treatment improved motor function and activity in murine prion disease. Further it was discovered that NAD depletion in neurons exposed to TPrP may be due, at least in part, to overconsumption of cellular NAD during metabolic reactions called mono-ADP ribosylations2. Inhibitors of poly-ADP-ribosylations, called PARP inhibitors, have previously been developed as anticancer agents. Available selective PARP inhibitors did not alleviate NAD depletion and neuronal death caused by TPrP, demonstrating the need to identify new compounds capable of interfering with the mechanisms at play in misfolded protein-induced toxicity or capable of preventing NAD depletion irrespective of the mechanism underlying NAD imbalance. Imbalance in NAD metabolism is a pathogenic mechanism of a number of human conditions, as described herein.
NAD, as used here, designates both the oxidized (NAD+) and the reduced (NADH) forms of the cofactor. NAD is critical, inter alia, as a co-enzyme for the regulation of energy metabolism pathways such as glycolysis, TCA cycle and oxidative phosphorylation leading to ATP production. In addition, NAD serves as a substrate for signal transduction and post-translational protein modifications called ADP-ribosylations.
Physiological cellular NAD levels result from the balance of activity of NAD synthesis enzymes and NAD consuming enzymes, which may be reasoned that the NAD imbalance induced by misfolded proteins (and that is assessed in our TPrP assay) could therefore result from either impaired NAD biosynthesis or from increased NAD consumption.
In mammalian cells, NAD is mainly synthesized via the salvage pathway using the precursor nicotinamide (NAM). The rate-limiting enzyme for NAD synthesis in the salvage pathway is nicotinamide phosphoribosyltransferase (NAMPT). Other NAD synthesis pathways are the de novo pathway utilizing the precursor tryptophan and the Preiss-Handler pathway utilizing the precursor nicotinic acid (NA).
On the other hand, NAD is consumed during the following cellular reactions: 1) the production of 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) sirtuin-mediated protein deacetylations, and 3) protein ADP-ribosylations, in which one or several ADP-ribose moiety of NAD is transferred unto proteins by mono/oligo-ADP-ribose transferases (mARTs) or poly-ADP ribose transferases (called PARPs).
NAD deficiency is a feature of prion diseases2 and other PMNDs such as PD3,4, AD5-8 and ALS9,10
NAD dysregulation is now also recognized as being involved in aging11-13, neuronal degeneration associated with multiple sclerosis14, traumatic brain injury15, hearing loss16, axonopathy and axonal degeneration17,18. NAD augmentation such as NAD administration or increased NAD synthesis by enzyme overexpression has been shown to mitigate brain ischemia19 and cardiac ischemia/reperfusion injury20,21
Age-related retinal/macular degeneration (AMD) is associated with the death of photoreceptors and retinal pigment epithelium (RPE) cells of the eye's retina, and causes progressive loss of vision. NAD levels are decreased in RPE cells isolated from patients with AMD22. Healthy NAD levels are required for vision in mice23. Increasing NAD levels by overexpression of cytoplasmic nicotinamide monomucleotide adenyl-transferase-1 (cytNMNAT1) in mice or NAM supplemented diet in rats showed less Zn2+ staining, NAD+×loss and cell death after light-induced retinal damage (LIRD)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 LIRD25.
NAD metabolism has also been shown to be altered in murine models of type 2 diabetes (T2D)26,27. Alterations of NAD metabolism in diabetes can be explained, at least in part, by our findings 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, concomitant with the deposition of aggregated islet amyloid polypeptide (IAPP), a protein co-expressed and secreted with insulin by pancreatic beta-cells28,29. Similarly to proteins involved in other protein misfolding diseases, IAPP forms toxic oligomers28. Moreover, proinsulin, the precursor of insulin, is also prone to misfold in beta-cells. Misfolding of proinsulin has been linked to type 2, type 1 and some monogenic forms of diabetes progression28,30,31. NR supplementation mitigates type 2 diabetes in mice27.
Substantial decreases in NAD levels are found in degenerative renal conditions and NAD augmentation mitigates acute kidney injury triggered by ischaemia-reperfusion, toxic injury and systemic inflammation32
Using TPrP as a prototypic amyloidogenic misfolded protein exhibiting high neurotoxicity, a high-throughput screening (HTS) assay has been developed to identify compounds effective at a) preventing cell death; and b) preventing NAD depletion induced by TPrP.
The HTS campaign was performed at Scripps Florida using a subset of the Scripps Drug Discovery Library (SDDL). Several potent, novel and chemically tractable small molecules are identified that can provide complete neuroprotection and preservation of NAD levels when used at doses ranging from low nanomolar to low micromolar levels, which is also detailed in international patent Publication WO 2020/232255. Its entire content is incorporated herein by reference for all purposes.
Members of each series of compounds described herein are highly potent in neuroprotection assays designed to reflect the potential for the successful treatment of several neurodegenerative diseases as described herein. Several compounds described herein activate the NAD synthetic enzyme NAMPT. Further, many have favorable drug-like properties (e.g., they are PAINS-free33 and compliant with Lipinski and Veber rules for drug-likeness34,35). Since these compounds prevent depletion of cellular NAD levels or increase NAD levels, they have utility in preventing or treating diseases where there is an imbalance in NAD metabolism, such as protein misfolding neurodegenerative diseases, amyloidoses, aging, retinal degeneration, ischemic conditions, traumatic brain injury, kidney failure and metabolic diseases including diabetes and non alcoholic fatty liver disease.
The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., —CH2O— is equivalent to —OCH2—.
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 carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di- and multivalent radicals. The alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl (“Me”), ethyl (“Et”), n-propyl (“Pr”), isopropyl (“iPr”), n-butyl (“Bu”), t-butyl (“t-Bu”), isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds 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 the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (—O—). An alkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynyl moiety. An alkyl moiety may be fully saturated. An alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds. An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited 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 eight 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.
The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (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 an uncyclized 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═CHO—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. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond. A heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds. The term “heteroalkynyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond. A heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, —CH2—CH2—S—CH2—CH2— and —CH2—S—CH2—CH2—NH—CH2—. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). 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)2R′-represents both —C(O)2R′— and —R′C(O)2—. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO2R′. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as —NR′R″ or the like, it will be understood that the terms heteroalkyl and —NR′R″ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as —NR′R″ or the like.
The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, 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, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.
In embodiments, a heterocycloalkyl is a heterocyclyl. The term “heterocyclyl” as used herein, means a monocyclic, bicyclic, or multicyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 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. The 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. The 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, but are not limited to, 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, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclyl bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls 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-1H-indolyl, and octahydrobenzofuranyl. In embodiments, heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. Multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a bicyclic aryl, a monocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. The multicyclic heterocyclyl is attached to the parent molecular moiety through any carbon atom or nitrogen atom contained within the base ring. In embodiments, multicyclic heterocyclyl ring systems are a monocyclic heterocyclyl ring (base ring) fused to either (i) one ring system selected from the group consisting of a bicyclic aryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ring systems independently selected from the group consisting of a phenyl, a monocyclic heteroaryl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclic heterocyclyl groups include, but are not limited to 10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl, 9,10-dihydroacridin-10-yl, 10H-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.
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.
The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. The term “heteroaryl” refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A 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, benzoxazoyl 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, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be —O— bonded to a ring heteroatom nitrogen.
A fused ring heterocyloalkyl-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. Fused ring heterocycloalkyl-aryl, fused ring heterocycloalkyl-heteroaryl, fused ring heterocycloalkyl-cycloalkyl, or fused ring heterocycloalkyl-heterocycloalkyl may each independently be unsubstituted or substituted with one or more of the substitutents described herein.
Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different. Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkyl rings). Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g. all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene). When referring to a spirocyclic ring system, heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
The symbol “” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.
The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.
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 specified number of carbons (e.g., “C1-C4 alkylsulfonyl”).
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.
Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, —OR′, ═O, ═NR′, ═N—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(O)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′, —NR′NR″R′″, —ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO2, —NR′SO2R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. 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 a compound described herein includes more than one R group, for example, each of the R groups is independently selected as are each R′, R″, R′″, and R″″ group when more than one of these groups is present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., —CF3 and —CH2CF3) and acyl (e.g., —C(O)CH3, —C(O)CF3, —C(O)CH2OCH3, and the like).
Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, 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(O)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′, —NR′NR″R′″, —ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO2, —R′, —N3, —CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, —NR′SO2R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where 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. When a compound described herein includes 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.
Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different. Where a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent), the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency. Where a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms. Where the ring heteroatoms are shown bound to one or more hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.
Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)—(CRR′)q—U—, wherein T and U are independently —NR—, —O—, —CRR′—, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r—B—, wherein 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 of from 1 to 4. One of the single bonds of the new ring so 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 of 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.
As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
A “substituent group,” as used herein, means a group selected from the following moieties:
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 group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate. The present disclosure is meant to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-, or (D)- and (L)-isomers may 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 specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
As used herein, the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
The term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit.
The terms “a” or “an,” as used in herein means one or more. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions. For example, a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
A person of ordinary skill in the art will understand when a variable (e.g., moiety or linker) of a compound or of a compound genus (e.g., a genus described herein) is described by a name or formula of a standalone compound with all valencies filled, the unfilled valence(s) of the variable will be dictated by the context in which the variable is used. For example, when a variable of a compound as described herein is connected (e.g., bonded) to the remainder of the compound through a single bond, that variable is understood to represent a monovalent form (i.e., capable of forming a single bond due to an unfilled valence) of a standalone compound (e.g., if the variable is named “methane” in an embodiment but the variable is known to be attached by a single bond to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is actually a monovalent form of methane, i.e., methyl or —CH3). Likewise, for a linker variable (e.g., L1, L2, or L3 as described herein), a person of ordinary skill in the art will understand that the variable is the divalent form of a standalone compound (e.g., if the variable is assigned to “PEG” or “polyethylene glycol” in an embodiment but the variable is connected by two separate bonds to the remainder of the compound, a person of ordinary skill in the art would understand that the variable is a divalent (i.e., capable of forming two bonds through two unfilled valences) form of PEG instead of the standalone compound PEG).
As used herein, the term “salt” refers to acid or base salts of the compounds used in the methods of the present invention. Illustrative examples of acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts.
The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific 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.
Thus, the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids. The present disclosure includes such salts. Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (−)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
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.
In addition to salt forms, the present disclosure provides compounds, which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs of the compounds described herein may be converted in vivo after administration. Additionally, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed 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.
“Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer's, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present disclosure.
The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
As used herein, the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/−10% of the specified value. In embodiments, about includes the specified value.
The term “EC50” or “half maximal effective concentration” as used herein refers to the concentration of a molecule (e.g., small molecule, drug, antibody, chimeric antigen receptor or bispecific antibody) capable of inducing a response which is halfway between the baseline response and the maximum response after a specified exposure time. In embodiments, the EC50 is the concentration of a molecule (e.g., small molecule, drug, antibody, chimeric antigen receptor or bispecific antibody) that produces 50% of the maximal possible effect of that molecule.
As used herein, the term “neurodegenerative disorder” refers to a disease or condition in which the function of a subject's nervous system becomes impaired. Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein include Alexander's disease, Alper's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-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-Sträussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy's disease, Krabbe's disease, Kuru, Lewy body dementia, 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's disease, Sandhoff's disease, Schilder's disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele-Richardson-Olszewski disease, progressive supranuclear palsy, or Tabes dorsalis.
As used herein, the term “retinal degeneration” refers to a disease or condition in which the vision of a subject becomes impaired due to dysfunction and/or damage of the eye's retina. Examples of retinal degeneration include age-related macular degeneration (AMD). Early stage AMD includes abnormalities of the retinal pigment epithelium and drusen. Late-stage AMD can include dry (non-neovascular, atrophic) macular degeneration, wet (neovascular) macular degeneration, proliferative diabetic retinopathy (PDR), diabetic macular edema (DME).
As used herein, the term “axonopathy” refers to functional or structural damage to a neuron or pheripheral nerve.
As used herein, the term “peripheral” refers to the part of the body anatomy located outside of the central nervous system.
As used herein, the term “amyloidosis” refers to a condition linked to the deposition of protein amyloid. An amyloidosis can occur in the central nervous system and is also referred to as a protein misfolding neurodegenerative disease (e.g. prion diseases, AD, PD and other synucleinopathies, ALS, tauopathies). An amyloidosis can occur outside of the central nervous system and can be widespread, i.e. systemic, or located in different organ systems. When amyloid deposits occurs in several organs, it is referred to as “multisystem”. Examples of amyloidoses are cardiomyopathy or polyneuropathy caused by the deposition of the protein TTR in the heart or peripheral nerves, respectively. Other examples of peripheral amyloidoses are AL (Primary) Amyloidosis or AA (Secondary) Amyloidosis.
As used herein, the term “metabolic disorder” refers to a disease or condition in which body metabolism, i.e. the process in which the body gets, makes and stores energy from food, is disrupted. Some metabolic disorders affect the breakdown of amino acids, carbohydrates, or lipids. Other metabolic disorders are known as mitochondrial diseases and affect mitochondria, the cellular organelles that produce energy. Examples of metabolic disorders are diabetes mellitus (sugar metabolism), hypercholesterolemia, Gaucher disease (lipid metabolism), non alcoholic fatty liver disease (NAFLD), metabolic syndrome (dyslipidemia, abdominal obesity, insulin resistance, proinflammatory state).
As used herein, the terms “kidney disease”, “kidney failure”, “renal disease” or “renal failure” refer to a disease or condition in which a subject loses kidney function. The condition can have various etiologies such as infectious, inflammatory, ischemic or traumatic. Kidney failure can be acute, leading to rapid loss of kidney function, or chronic, leading to gradual loss of kidney function. The condition ultimately leads to the accumulation of dangerous levels of fluid, electrolytes and waste products in the body. End-stage kidney failure is fatal without artificial filtering of the blood (dialysis) or kidney transplant.
As used herein, the term “ischemic condition” or “ischemia” refers to a condition in which the blood flow is restricted or reduced in a part of the body, such as the heart or the brain.
The terms “treating”, or “treatment” refers to any indicia of success in the therapy or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation. The term “treating” and conjugations thereof, may include prevention of an injury, pathology, condition, or disease. In embodiments, treating is preventing. In embodiments, treating does not include preventing.
“Treating” or “treatment” as used herein (and as well-understood in the art) also broadly includes any approach for obtaining beneficial or desired results in a subject's condition, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable. In other words, “treatment” as used herein includes any cure, amelioration, or prevention of a disease. Treatment may prevent the disease from occurring; inhibit the disease's spread; relieve the disease's symptoms, fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things.
The term “prevent” refers to a decrease in the occurrence of disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.
“Patient” or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals. In some embodiments, a patient is human.
A “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
Thus, a prophylactically effective amount may be administered in one or more administrations. An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist. A “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).
For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the methods described herein, as measured using the methods described herein or known in the art.
As is well known in the art, therapeutically effective amounts for use in humans can also be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compounds effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
The term “therapeutically effective amount,” as used herein, refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above. For example, for the given parameter, a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%. Therapeutic efficacy can also be expressed as “-fold” increase or decrease. For example, a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
As used herein, the term “administering” means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to 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, e.g., intravenous, intramuscular, intra-arteriole, 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, etc. In embodiments, the administering does not include administration of any active agent other than the recited active agent.
A “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA. A cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring. Cells may include prokaryotic and eukaroytic cells. Prokaryotic cells include but are not limited to bacteria. Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
In an aspect, provided herein are compounds that may provide complete neuroprotection and protection of cell types other than neurons, and preservation of NAD levels. The compounds may be highly potent in a) preventing neuronal and/or cellular death; and b) preventing NAD depletion induced by TPrP, for example, as identified by neuroprotection assays when used at doses ranging from low nanomolar to low micromolar levels.
In an aspect, provided is a compound having a structure of Formula (A),
or a pharmaceutically acceptable salt thereof,
In an aspect, provided is a compound having a structure of Formula (X),
or a pharmaceutically acceptable salt thereof.
L2 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. Ring A, L1, R1A, R1B, R1C, R2, R3A, R3B, R3C, R3D, and R3E are as described herein.
In embodiments, the Ring A is a substituted or unsubstituted 5,6-fused ring heteroarylene. In embodiments, the Ring A may have a core structure of
wherein W1 is —CH2—, —NH—, —O—, or —S—, W2 is independently ═O or ═S, and W3 is ═N— or ═CH—;
wherein W4 is independently —O— or —S—, and these core structures may be substituted or unsubstituted.
In embodiments, the Ring A may have a core structure of
which may be substituted or unsubstituted. In embodiments, the Ring A may have a core structure of
which may be substituted or unsubstituted. In embodiments, the Ring A may have a core structure of
which may be substituted or unsubstituted. In embodiments, the Ring A may have a core structure of
which may be substituted or unsubstituted.
In embodiments, Ring A is a R5-substituted or unsubstituted heterocycloalkylene, or R5-substituted or unsubstituted heteroarylene. In embodiments, R5 is independently hydrogen, —OR5D, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R5D is hydrogen, or substituted or unsubstituted alkyl.
In embodiments, R5D is hydrogen. In embodiments, R5D is methyl. In embodiments, R5D is ethyl. In embodiments, R5D is propyl. In embodiments, R5D is isopropyl. In embodiments, R5D is butyl. In embodiments, R5D is t-butyl. In embodiments, R5D is —CF3, —CH2F, or —CHF2.
In embodiments, R5 is hydrogen, methyl, —OCH3, or —SCH3. In embodiments, R5 is hydrogen. In embodiments, R5 is methyl. In embodiments, R5 is ethyl. In embodiments, R5 is propyl. In embodiments, R5 is isopropyl. In embodiments, R5 is butyl. In embodiments, R5 is t-butyl. In embodiments, R5 is —CF3, —CH2F, or —CHF2.
In embodiments, R1D is independently hydrogen, or substituted or unsubstituted alkyl. In embodiments, R1D is independently hydrogen, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R1D is independently hydrogen. In embodiments, R1D is substituted C1-C4 alkyl. In embodiments, R1D is unsubstituted C1-C4 alkyl. In embodiments, R1D is independently methyl. In embodiments, R1D is independently ethyl. In embodiments, R1D is independently isopropyl.
In embodiments, R3F is independently hydrogen, or substituted or unsubstituted alkyl. In embodiments, R3F is independently hydrogen, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R3F is independently hydrogen. In embodiments, R3F is substituted C1-C4 alkyl. In embodiments, R3F is unsubstituted C1-C4 alkyl. In embodiments, R3F is independently methyl. In embodiments, R3F is independently ethyl. In embodiments, R3F is independently isopropyl.
In embodiments, L2 is a bond. In embodiments, L2 is a substituted or unsubstituted alkylene. In embodiments, L2 is substituted or unsubstituted heteroalkylene.
In embodiments, L2 is independently substituted or unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L2 is independently substituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L2 is independently unsubstituted alkylene (e.g., C1-C20, C1-C12, C1-C8, C1-C6, C1-C4, or C1-C2). In embodiments, L2 is independently substituted or unsubstituted C1-C20 alkylene. In embodiments, L2 is independently substituted C1-C20 alkylene. In embodiments, L2 is independently unsubstituted C1-C20 alkylene. In embodiments, L2 is independently substituted or unsubstituted C1-C12 alkylene. In embodiments, L2 is independently substituted C1-C12 alkylene. In embodiments, L2 is independently unsubstituted C1-C12 alkylene. In embodiments, L2 is independently substituted or unsubstituted C1-C8 alkylene. In embodiments, L2 is independently substituted C1-C8 alkylene. In embodiments, L2 is independently unsubstituted C1-C8 alkylene. In embodiments, L2 is independently substituted or unsubstituted C1-C6 alkylene. In embodiments, L2 is independently substituted C1-C6 alkylene. In embodiments, L2 is independently unsubstituted C1-C6 alkylene. In embodiments, L2 is independently substituted or unsubstituted C1-C4 alkylene. In embodiments, L2 is independently substituted C1-C4 alkylene. In embodiments, L2 is independently unsubstituted C1-C4 alkylene. In embodiments, L2 is independently substituted or unsubstituted ethylene. In embodiments, L2 is independently substituted ethylene. In embodiments, L2 is independently unsubstituted ethylene. In embodiments, L2 is independently substituted or unsubstituted methylene. In embodiments, L2 is independently substituted methylene. In embodiments, L2 is independently unsubstituted methylene.
In embodiments, L2 is independently substituted or unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L2 is independently substituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L2 is independently unsubstituted heteroalkylene (e.g., 2 to 20 membered, 2 to 12 membered, 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered). In embodiments, L2 is independently substituted or unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L2 is independently substituted 2 to 20 membered heteroalkylene. In embodiments, L2 is independently unsubstituted 2 to 20 membered heteroalkylene. In embodiments, L2 is independently substituted or unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L2 is independently substituted 2 to 8 membered heteroalkylene. In embodiments, L2 is independently unsubstituted 2 to 8 membered heteroalkylene. In embodiments, L2 is independently substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L2 is independently substituted 2 to 6 membered heteroalkylene. In embodiments, L2 is independently unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L2 is independently substituted or unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L2 is independently substituted 4 to 6 membered heteroalkylene. In embodiments, L2 is independently unsubstituted 4 to 6 membered heteroalkylene. In embodiments, L2 is independently substituted or unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L2 is independently substituted 2 to 3 membered heteroalkylene. In embodiments, L2 is independently unsubstituted 2 to 3 membered heteroalkylene. In embodiments, L2 is independently substituted or unsubstituted 4 to 5 membered heteroalkylene. In embodiments, L2 is independently substituted 4 to 5 membered heteroalkylene. In embodiments, L2 is independently unsubstituted 4 to 5 membered heteroalkylene.
In embodiments, the compound has a structure of Formula (I),
In embodiments, the compound has the structure of formula (XI),
In embodiments, W3 is —N═ or —CH═. In embodiment, W3 is —N═. In embodiments, W3 is —CH═.
In embodiments, W1 is —NR4C— or —O—. In embodiment, W1 is —NR4C—. In embodiments, W1 is —O—.
In embodiments, R4C is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R4C is hydrogen or methyl. In embodiments, R4C is hydrogen. In embodiments, R4C is methyl. In embodiments, R4C is ethyl.
In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(O)— or —C(S)—.
In embodiments, L1 is —C(S)—.
In embodiments, the compound has a structure of Formula (I-a-1),
In embodiments, the compound has a structure of Formula (I-b-1),
In embodiments, the compound has a structure of Formula (XI-a-1),
In embodiments, the compound has a structure of Formula (XI-b-1),
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, R3B and R3C are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl, substituted or unsubstituted 5 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted 5 to 8 membered heterocycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted phenyl.
In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto, wherein each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto.
In embodiments, R3C and R3D are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3C and R3D are joined to form a substituted or unsubstituted C5-C8 cycloalkyl, substituted or unsubstituted 5 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R3C and R3D are joined to form a substituted or unsubstituted C5-C8 cycloalkyl. In embodiments, R3C and R3D are joined to form substituted or unsubstituted 5 to 8 membered heterocycloalkyl. In embodiments, R3C and R3D are joined to form substituted or unsubstituted phenyl.
In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto, wherein each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto.
In embodiments, R3A is hydrogen. In embodiments, R3B is hydrogen. In embodiments, R3D is hydrogen. In embodiments, R3E is hydrogen. In embodiments, R3AR3B, R3D, and R3E are hydrogen.
In embodiments, the compound has a structure of Formula (I-c), or (I-d),
R1A, R1B, R1C, W2, R3C and n are as described herein.
In embodiments, n is 2, 3, or 4. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
In embodiments, the compound has a structure of Formula (XI-c), or (XI-d),
wherein Ring B is
each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. L2, R1A, R1B, R1C, W2, are as described herein.
In embodiments, Ring B is
In embodiments, Ring B is
In embodiments, Ring B is
In embodiments, Ring B is
In embodiments, Ring B is
In embodiments, Ring B is
In embodiments, R4C is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R4C is hydrogen or methyl. In embodiments, R4C is hydrogen. In embodiments, R4C is methyl. In embodiments, R4C is ethyl.
In embodiments, R3A is hydrogen. In embodiments, R3B is hydrogen. In embodiments, R3D is hydrogen. In embodiments, R3E is hydrogen. In embodiments, R3AR3B, R3D, and R3E are hydrogen. In embodiments, R3A, R3B, R3D, and R3E are hydrogen; and R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, R1B and R1C are hydrogen. In embodiments, R1A is hydrogen, halogen, —CH3, —CH2CH3, —OCH2CH3, —CF3, or —OCF3. In embodiments, R1A is methyl.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
Exemplary compounds of Formula (I) are shown in Table 1.
In embodiments, the compound has a structure of Formula (III),
or a pharmaceutically acceptable salt thereof,
wherein:
In embodiments, the compound has a structure of Formula (XIII),
or a pharmaceutically acceptable salt thereof.
L1, L2, R1A, R1B, R1C, R2, R3A, R3B, R3C, R3D, R3E, R5A and R5B are as disclosed herein.
In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(S)—.
In embodiments, R3A is hydrogen. In embodiments, R3B is hydrogen. In embodiments, R3D is hydrogen. In embodiments, R3E is hydrogen. In embodiments, R3AR3B, R3D, and R3E are hydrogen. In embodiments, R3A, R3B, R3D, and R3E are hydrogen; and R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, R5A is substituted or unsubstituted cycloalkylene or substituted or unsubstituted heterocycloalkylene; and R5B is —NH—(CO)—R5C or —C(O)—NH—R5C. In embodiments, R5A is substituted or unsubstituted C5-C6 cycloalkylene or substituted or unsubstituted 5 to 6 membered heterocycloalkylene; and R5B is —NH—(CO)—R5C or —C(O)—NH—R5C. In embodiments, R5A is substituted or unsubstituted C5-C6 cycloalkylene or substituted; and R5B is —NH—(CO)—R5C or —C(O)—NH—R5C. In embodiments, R5A is substituted or unsubstituted C5-C6 cycloalkylene or substituted; and R5B is —NH—(CO)—R5C. In embodiments, R5A is substituted or unsubstituted C5-C6 cycloalkylene or substituted; and R5B is —C(O)—NH—R5C. In embodiments, R5A is substituted or unsubstituted 5 to 6 membered heterocycloalkylene; and R5B is —NH—(CO)—R5C or —C(O)—NH—R5C. In embodiments, R5A is substituted or unsubstituted 5 to 6 membered heterocycloalkylene; and R5B is —NH—(CO)—R c. In embodiments, R5A is substituted or unsubstituted 5 to 6 membered heterocycloalkylene; and R5B is —C(O)—NH—R5C.
In embodiments, the compound has a structure of Formula (III-a) or (III-b),
R1A, R1B, R1C, R3C, R5C and n are as described herein.
In embodiments, the compound has a structure of Formula (XIII-a) or (XIII-b),
L2, R1A, R1B, R1C, R3C, and R5C are as described herein.
In embodiments, the compound has a structure of Formula (III-a-1), (III-a-2), (III-b-1), or (III-b-2)
R1A, R1B, R1C, R3C, R5C and n are as described herein.
In embodiments, the compound has a structure of Formula (XIII-a-1), (XIII-a-2), (XIII-b-1), or (XIII-b-2)
L2, R1A, R1B, R1C, R3C, and R5C are as described herein.
In embodiments, R5C is hydrogen, or substituted or unsubstituted alkyl. In embodiments, R5C is hydrogen, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R5C is hydrogen.
In embodiments, R5C is unsubstituted C1-C4 alkyl. In embodiments, R5C is methyl. In embodiments, R5C is ethyl.
In embodiments, R3B and R3C are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl, substituted or unsubstituted 5 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted 5 to 8 membered heterocycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted phenyl.
In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto, wherein each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto.
In embodiments, R3C and R3D are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3C and R3D are joined to form a substituted or unsubstituted C5-C8 cycloalkyl, substituted or unsubstituted 5 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R3C and R3D are joined to form a substituted or unsubstituted C5-C8 cycloalkyl. In embodiments, R3C and R3D are joined to form substituted or unsubstituted 5 to 8 membered heterocycloalkyl. In embodiments, R3C and R3D are joined to form substituted or unsubstituted phenyl.
In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto, wherein each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto.
In embodiments, R5A is —S—; and R5B 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. In embodiments, R5A is —S—; and R5B is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 4 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R5A is —S—; and R5B is hydrogen. In embodiments, R5A is —S—; and R5B is substituted or unsubstituted C1-C4 alkyl. In embodiments, R5A is —S—; and R5B is unsubstituted alkyl. In embodiments, R5A is —S—; and R5B is methyl. In embodiments, R5A is —S—; and R5B is ethyl.
In embodiments, the compound has a structure of Formula (III-c),
R1A, R1B, R1C and n are as described herein. R5B is halogen.
In embodiments, n is 2, 3, or 4. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
In embodiments, the compound has a structure of Formula (XIII-c),
L2, R1A, R1B, R1C, and R5B are as described herein.
In embodiments, R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is SCH3, or —SCH2CH3.
In embodiments, R1B and R1C are hydrogen. In embodiments, R1A is hydrogen, halogen, —CH3, —CH2CH3, —OCH2CH3, —CF3, or —OCF3. In embodiments, R1A is methyl.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, the compound has a structure of Formula (IV),
wherein:
In embodiments, the compound has a structure of Formula (XIV),
In embodiments, R3B and R3C are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl, substituted or unsubstituted 5 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted 5 to 8 membered heterocycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted phenyl.
In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto, wherein each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto.
In embodiments, the compound has a structure of Formula (IV-a) or (IV-b),
R1A, R1B, R1C, R5 and n are as described herein.
In embodiments, the compound has a structure of Formula (IV-c) or (IV-d),
R1A, R1B, R1C, R3C, R5 and n are as described herein.
In embodiments, n is 2, 3, or 4. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
In embodiments, the compound has a structure of Formula (XIV-a) or (XIV-b),
L2, R1A, R1B, R1C, R3C, and R5 are as described herein.
In embodiments, the compound has a structure of Formula (XIV-c) or (XIV-d),
L2, R1A, R1B, R1C, R3C, and R5 are as described herein.
In embodiments, R5 is hydrogen, or substituted or unsubstituted alkyl. In embodiments, R5 is hydrogen, or substituted or unsubstituted C1-C4 alkyl. In embodiments, R5 is hydrogen.
In embodiments, R5 is unsubstituted C1-C4 alkyl. In embodiments, R5 is methyl. In embodiments, R5 is ethyl.
In embodiments, R1B and R1C are hydrogen. In embodiments, R1A is hydrogen, halogen, —CH3, —CH2CH3, —OCH2CH3, —CF3, or —OCF3. In embodiments, R1A is methyl.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
Exemplary compounds of Formulae (III) and (IV) are shown in Table 2.
In embodiments, the compound has a formula of Formula (V)
or a pharmaceutically acceptable salt thereof,
wherein:
In embodiments, the compound has a formula of Formula (XV)
or a pharmaceutically acceptable salt thereof.
W5, W6, L1, L2, R1A, R1B, R1C, R2, R3A, R3B, R3C, R3D, R3E, and R5 are as disclosed herein.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(O)— or —C(S)—.
In embodiments, L1 is —C(S)—.
In embodiments, R3A is hydrogen. In embodiments, R3B is hydrogen. In embodiments, R3D is hydrogen. In embodiments, R3E is hydrogen. In embodiments, R3AR3B, R3D, and R3E are hydrogen. In embodiments, R3A, R3B, R3D, and R3E are hydrogen; and R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, R5 is hydrogen, methyl, —OCH3, or —SCH3. In embodiments, R5 is hydrogen. In embodiments, R5 is methyl. In embodiments, R5 is ethyl. In embodiments, R5 is propyl. In embodiments, R5 is isopropyl. In embodiments, R5 is butyl. In embodiments, R5 is t-butyl. In embodiments, R5 is —CF3, —CH2F, or —CHF2.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, the compound has the Formula (V-a), (V-b), (V-c) or (V-d),
R1A, R1B, R1C, R2, R3C, R5 and n are as disclosed herein.
In embodiments, the compound has the Formula (XV-a), (XV-b), (XV-c) or (XV-d),
L2, R1A, R1B, R1C, R2, R3C, and R5 are as disclosed herein.
In embodiments, R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, n is 2, 3, or 4. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
In embodiments, R5 is hydrogen, methyl, —OCH3, or —SCH3. In embodiments, R5 is hydrogen. In embodiments, R5 is methyl. In embodiments, R5 is ethyl. In embodiments, R5 is propyl. In embodiments, R5 is isopropyl. In embodiments, R5 is butyl. In embodiments, R5 is t-butyl. In embodiments, R5 is —CF3, —CH2F, or —CHF2.
In embodiments, R1B and R1C are hydrogen. In embodiments, R1A is hydrogen, halogen, —CH3, —CH2CH3, —OCH2CH3, —CF3, or —OCF3. In embodiments, R1A is methyl.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, the compound has a formula of Formula (VI),
or a pharmaceutically acceptable salt thereof,
wherein:
In embodiments, the compound has a formula of Formula (XVI),
or a pharmaceutically acceptable salt thereof.
L1, L2, W5, W6, R1A, R1B, R1C, R2, R3A, R3B, R3C, R3D, R3E, and R5 are as disclosed herein.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(S)—.
In embodiments, R3A is hydrogen. In embodiments, R3B is hydrogen. In embodiments, R3D is hydrogen. In embodiments, R3E is hydrogen. In embodiments, R3AR3B, R3D, and R3E are hydrogen. In embodiments, R3A, R3B, R3D, and R3E are hydrogen; and R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, R5 is hydrogen, methyl, —OCH3, or —SCH3. In embodiments, R5 is hydrogen. In embodiments, R5 is methyl. In embodiments, R5 is ethyl. In embodiments, R5 is propyl. In embodiments, R5 is isopropyl. In embodiments, R5 is butyl. In embodiments, R5 is t-butyl. In embodiments, R5 is —CF3, —CH2F, or —CHF2.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, the compound has a formula of Formula (VI-a), (VI-b), (VI-c), (VI-d), (VI-e), or (VI-f),
R1A, R1B, R1C, R2, R3C C, R5 and n are as disclosed herein.
In embodiments, the compound has a formula of Formula (XVI-a), (XVI-b), (XVI-c), (XVI-d), (XVI-e), or (XVI-f),
L2, R1A, R1B, R1C, R2, R3C, and R5 are as disclosed herein.
In embodiments, R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, n is 2, 3, or 4. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
In embodiments, R5 is hydrogen, methyl, —OCH3, or —SCH3. In embodiments, R5 is hydrogen. In embodiments, R5 is methyl. In embodiments, R5 is ethyl. In embodiments, R5 is propyl. In embodiments, R5 is isopropyl. In embodiments, R5 is butyl. In embodiments, R5 is t-butyl. In embodiments, R5 is —CF3, —CH2F, or —CHF2.
In embodiments, R1B and R1C are hydrogen. In embodiments, R1A is hydrogen, halogen, —CH3, —CH2CH3, —OCH2CH3, —CF3, or —OCF3. In embodiments, R1A is methyl.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, the compound has the structure of Formula (VII),
or a pharmaceutically acceptable salt thereof,
wherein:
In embodiments, the compound has the structure of Formula (XVII),
or a pharmaceutically acceptable salt thereof. L1, L2, R1A, R1B, R1C, R2, R3A, R3B, R3C, R3D, R3E, and R5 are as disclosed herein.
In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(S)—.
In embodiments, R3A is hydrogen. In embodiments, R3B is hydrogen. In embodiments, R3D is hydrogen. In embodiments, R3E is hydrogen. In embodiments, R3AR3B, R3D, and R3E are hydrogen. In embodiments, R3A, R3B, R3D, and R3E are hydrogen; and R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, R5 is hydrogen, methyl, —OCH3, or —SCH3. In embodiments, R5 is hydrogen. In embodiments, R5 is methyl. In embodiments, R5 is ethyl. In embodiments, R5 is propyl. In embodiments, R5 is isopropyl. In embodiments, R5 is butyl. In embodiments, R5 is t-butyl. In embodiments, R5 is —CF3, —CH2F, or —CHF2.
In embodiments, the compound has a structure of Formula (VII-a),
R1A, R1B, R1C, R5 and n are as described herein.
In embodiments, n is 2, 3, or 4. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
In embodiments, the compound has a structure of Formula (XVII-a),
L2, R1A, R1B, R1C and R5 are as described herein.
In embodiments, R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, R1B and R1C are hydrogen. In embodiments, R1A is hydrogen, halogen, —CH3, —CH2CH3, —OCH2CH3, —CF3, or —OCF3. In embodiments, R1A is methyl.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In an aspect, provided is a compound having a structure of Formula (XVIII),
or a pharmaceutically acceptable salt thereof,
wherein z is an integer of 0 to 5.
L2, R1A, R1B, R1C, R2, R3A, R3B, R3C, R3D, R3E, and R5 are as disclosed herein.
In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(O)— or —C(S)—. In embodiments, L1 is —C(S)—.
In embodiments, Ring A is a R5-substituted or unsubstituted heterocycloalkylene, or R5-substituted or unsubstituted heteroarylene. In embodiments, R5 is independently hydrogen, —OR5D, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; and R5D is hydrogen, or substituted or unsubstituted alkyl.
In embodiments, R5D is hydrogen. In embodiments, R5D is methyl. In embodiments, R5D is ethyl. In embodiments, R5D is propyl. In embodiments, R5D is isopropyl. In embodiments, R5D is butyl. In embodiments, R5D is t-butyl. In embodiments, R5D is —CF3, —CH2F, or —CHF2.
In embodiments, R5 is hydrogen, methyl, —OCH3, or —SCH3. In embodiments, R5 is hydrogen. In embodiments, R5 is methyl. In embodiments, R5 is ethyl. In embodiments, R5 is propyl. In embodiments, R5 is isopropyl. In embodiments, R5 is butyl. In embodiments, R5 is t-butyl. In embodiments, R5 is —CF3, —CH2F, or —CHF2.
In embodiments, R3A is hydrogen. In embodiments, R3B is hydrogen. In embodiments, R3D is hydrogen. In embodiments, R3E is hydrogen. In embodiments, R3AR3B, R3D, and R3E are hydrogen. In embodiments, R3A, R3B, R3D, and R3E are hydrogen; and R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, the compound has the Formula (VIII),
wherein z is an integer of 0 to 4. R1A, R1B, R1C, R3A, R3B, R3C, R3D, R3E, R5, and n are as described herein.
In embodiments, the compound has the Formula (VIII-a),
R1A, R1B, R1C, R3C, R5, z, and n are as described herein.
In embodiments, the compound has the Formula (VIII-b),
R1A, R1B, R1C, R3C, and n are as described herein.
In embodiments, R3C is hydrogen, halogen, —CH3, —CH2CH3, —OCH3, —OCH2CH3, —SCH3, —SCH2CH3, —CF3, or —OCF3. In embodiments, R3C is hydrogen, —CH3, —CH2CH3, —OCH3, or —OCH2CH3. In embodiments, R3C is hydrogen. In embodiments, R3C is —CH3, or —CH2CH3. In embodiments, R3C is —OCH3, or —OCH2CH3. In embodiments, R3C is —SCH3, or —SCH2CH3.
In embodiments, n is 2, 3, or 4. In embodiments, n is 2. In embodiments, n is 3. In embodiments, n is 4.
In embodiments, R1B and R1C are hydrogen. In embodiments, R1A is hydrogen, halogen, —CH3, —CH2CH3, —OCH2CH3, —CF3, or —OCF3. In embodiments, R1A is methyl.
In embodiments, R2 is hydrogen or C1-C4 unsubstituted alkyl. In embodiments, R2 is hydrogen or methyl. In embodiments, R2 is hydrogen. In embodiments, R2 is methyl. In embodiments, R2 is ethyl.
In embodiments, in Formula (B), R3B and R3C are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl, substituted or unsubstituted 5 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R3B and R3C are joined to form a substituted or unsubstituted C5-C8 cycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted 5 to 8 membered heterocycloalkyl. In embodiments, R3B and R3C are joined to form substituted or unsubstituted phenyl.
In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto, wherein each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto. In embodiments, R3B and R3C are joined to form
together with the phenyl ring attached thereto.
In embodiments, R3C and R3D are joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R3C and R3D are joined to form a substituted or unsubstituted C5-C8 cycloalkyl, substituted or unsubstituted 5 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 8 membered heteroaryl. In embodiments, R3C and R3D are joined to form a substituted or unsubstituted C5-C8 cycloalkyl. In embodiments, R3C and R3D are joined to form substituted or unsubstituted 5 to 8 membered heterocycloalkyl. In embodiments, R3C and R3D are joined to form substituted or unsubstituted phenyl.
In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto, wherein each Y1 and Y2 is independently —CH2— or —O—, and m is 1 or 2. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto. In embodiments, R3C and R3D are joined to form
together with the phenyl ring attached thereto.
In an aspect, provided is a pharmaceutical composition including the compound described herein, a pharmaceutically acceptable salt form thereof, an isomer thereof, or a crystal form thereof. Also provided herein are pharmaceutical formulations. In embodiments, the pharmaceutical formulation includes a compound (e.g. formulae (X), (I), (III), (IV), (V), (VI), (VII), and (VIII) including all embodiments thereof, or compounds in Tables 1-3 described above) and a pharmaceutically acceptable excipient.
The pharmaceutical composition may contain a dosage of the compound in a therapeutically effective amount.
In embodiments, the pharmaceutical composition includes any compound described above.
The pharmaceutical composition may be prepared and administered in a wide variety of dosage formulations. Compounds described may be administered orally, rectally, or by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally).
For preparing pharmaceutical compositions from compounds described herein, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substance that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
In powders, the carrier may be a finely divided solid in a mixture with the finely divided active component. In tablets, the active component may be mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
The powders and tablets preferably contain from 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, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
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.
Aqueous solutions suitable for oral use can be prepared by dissolving the active component 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 component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
Also included are solid form 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 component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 10000 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate 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 employed at a level between about 0.01% and about 2% by weight. Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.
The pharmaceutical compositions may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides, and finely-divided drug carrier substrates. These components are discussed in greater detail in U.S. Pat. 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.
The pharmaceutical composition may be intended for intravenous use. The pharmaceutically acceptable excipient can include buffers to adjust the pH to a desirable range for intravenous use. Many buffers including salts of inorganic acids such as phosphate, borate, and sulfate are known.
The pharmaceutical composition may include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in 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.
The dosage and frequency (single or multiple doses) of compounds administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent 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.
Therapeutically effective amounts for use in humans may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring response of the constipation or dry eye to the treatment and adjusting the dosage upwards or downwards, as described above.
Dosages may be varied depending upon the requirements of the subject and the compound being employed. The dose administered to a subject, in the context of the pharmaceutical compositions presented herein, should be sufficient to effect a beneficial therapeutic response in the subject over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
Dosage amounts and intervals can be adjusted individually to provide levels of the administered compounds effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's disease state.
Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is entirely effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.
The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal in 50% of the population) and ED50 (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 preferably lies within a range of plasma concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, p. 1, 1975. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition and the particular method in which the compound is used.
When parenteral application is needed or desired, particularly suitable admixtures for the compounds included in the pharmaceutical composition may be injectable, sterile solutions, oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. 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, and the like. Ampoules are convenient unit dosages. Pharmaceutical admixtures suitable for use in the pharmaceutical compositions presented herein may include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both of which are hereby incorporated by reference.
In an aspect, provided is a method for inhibiting NAD consumption and/or increasing NAD synthesis in a patient, and the method includes administering to the patient an effective dose of a compound (e.g. (X), (I), (III), (IV), (V), (VI), (VII), and (VIII) including all embodiments thereof, or compounds in Tables 1-3 described above) described above.
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 of the NAD synthetic pathways such as the rate-limiting enzyme for NAD synthesis in the salvage pathway called NAMPT. The patient is afflicted with, or at risk for, a protein misfolding neurodegenerative disease or another protein misfolding disease.
The protein misfolding neurodegenerative disease includes a prion disease, Parkinson's disease, dementia with Lewy Bodies, multiple system atrophy or other synucleinopathies, Alzheimer's disease, amyotrophic lateral sclerosis, fronto-temporal dementia or other tauopathy, chronic traumatic encephalopathy, and the protein misfolding disease includes diabetes mellitus and amyloidoses.
In an aspect, provided is a method for preventing or inhibiting NAD depletion in a patient. In another aspect, provided is a method for increasing NAD levels to improve cellular function. In another aspect, provided is a method for improving a condition linked to alterations of NAD metabolism in a patient. The method includes administering to the patient an effective dose of the compound described herein.
The condition includes a metabolic disorder, a liver disorder, aging, a degenerative disease, a neurodegenerative disease, neuronal degeneration associated with multiple sclerosis, hearing loss, retinal damage, macular degeneration, brain or cardiac ischemia, kidney failure, kidney disease, traumatic brain injury, or an axonopathy.
In an aspect, provided is a method for providing protection from toxicity of misfolded proteins in a patient. The method includes administering to the patient an effective dose of the compound described herein. The patient is afflicted with a prion disease, Parkinson's disease or other synucleinopathy, Alzheimer's disease, amyotrophic lateral sclerosis, a tauopathy, an amyloidosis or diabetes mellitus.
In an aspect, provided is a method for preventing or treating a protein misfolding neurodegenerative disease in a patient. The method includes administering to the patient an effective dose of the compound described herein.
In embodiments, the protein misfolding neurodegenerative disease is a disorder associated with protein aggregate-induced neurodegeneration and NAD depletion. In embodiments, the protein misfolding neurodegenerative disease includes a prion disease, Parkinson's disease, dementia with Lewy Bodies, multiple system atrophy or other synucleinopathy, Alzheimer's disease, amyotrophic lateral sclerosis, fronto-temporal dementia or other tauopathy, chronic traumatic encephalopathy. In embodiments, the neurodegenerative disease is multiple sclerosis, brain ischemia or an axonopathy.
In embodiments, the metabolic disorder includes diabetes or a liver disorder.
In embodiments, the condition linked to alterations of NAD metabolism includes aging, a retinal disease or a kidney disease.
In an aspect, provided is a method of preventing or treating a retinal disease in a patient. The method includes administering to the patient an effective dose of the compound described herein.
In an aspect, provided is 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 the compound described herein.
In an aspect, provided is a method of preventing or treating a kidney disease in a patient, comprising administering to the patient an effective dose of the compound described herein.
In an aspect, provided is a method of mitigating health effects of aging, comprising administering to the patient an effective dose of the compound described herein.
General Chemical Synthesis Protocols. Chemicals and solvents were purchased from commercial sources and used without purification. CH2Cl2, THF, PhMe, and DMF were dried and purified using a PureSolv MD 7 (from 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 performed in flame-dried glassware under a positive pressure of Ar using standard synthetic organic, inert atmosphere techniques.
Analytical thin-layer chromatography was performed on pre-coated 250 μm layer thickness silica gel 60 F254 plates (EMD Chemicals Inc.). Visualization was performed by ultraviolet light and/or by staining with ninhydrin. Purifications by flash chromatography were performed using pre-packed columns of silica gel (40-63 m, 230-400 mesh) by Biotage with EtOAc/hexanes, MeOH/CH2Cl2, or MeOH/CHCl3 as eluents. LC-MS was performed on an Agilent Technologies 1260 analytical HPLC instrument paired with an Agilent 500 Ion Trap LC/MS.
Proton nuclear magnetic resonance (1H NMR) spectra were acquired 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 (range of multiplet is given).
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). To the reaction mixture was added lithium hydroxide (1.4 or 3.6 equiv) 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 hours before being allowed to cool 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 afford the carboxylic acid without further purification.
To a flame-dried round bottom flask, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added the carboxylic acid (1 equiv), followed by DMF (0.16 M). To the mixture was added sequentially N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.2 equiv), hydroxybenzotriazole hydrate (1.2 equiv), N,N-diisopropylethylamine (2 equiv), and the amine (1.1 equiv). The mixture was stirred for 16 hours at room temperature. 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 resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to afford the amide.
To a microwave vial, equipped with a Teflon-coated stir bar, was added tert-butyl (3-bromopropyl)carbamate (2 equiv), tetrabutylammonium hydrogen sulfate (0.05 equiv), aqueous sodium hydroxide (50 wt %, 12.5 equiv) and the substituted imidazole (1 equiv), followed by CH2Cl2 or MeCN (0.5 M). The reaction mixture was stirred for 3 hours at room temperature or 50° C. The mixture was poured into H2O and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to afford the substituted carbamate.
To a round bottom flask, equipped with a Teflon-coated stir bar, was added the carbamate, followed by 1,4-dioxane (0.15 M). The mixture was cooled to 0° C. and concentrated HCl (0.3 M) was added. The reaction mixture was stirred for 2 hours at 0° C. before being concentrated in vacuo to afford the amine without further purification.
To a microwave vial, equipped with a Teflon-coated stir bar, was added the pyrazolopyrimidine triflate (1 equiv), the 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 H2O (0.03 M). The vial was sealed, and the mixture was degassed with bubbling argon for 30 minutes. The mixture was heated to 80° C. and stirred for 1 hour. After being allowed to cool 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% to 50% or 8% to 66% EtOAc in hexanes) to afford the arylated pyrazolopyrimidine.
To a flame-dried round bottom flask, equipped with a rubber septum, Teflon-coated stir bar, and condenser and flushed with argon, was added the pyrazolopyrimidone, followed by POCl3 (0.08 M). The reaction mixture was heated to 100° C. and stirred for 16 hours. The mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue 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 resulting crude residue was purified by column chromatography (8% to 66% EtOAc in hexanes) to afford the chloropyrazolopyrimidine.
To a flame-dried round bottom flask, equipped with a rubber septum, Teflon-coated stir bar, and condenser and flushed with argon, was added the acetophenone (1 equiv), followed by toluene (0.20 M). To the reaction mixture was added sodium hydride (60 wt %, 2 equiv) and diethyl carbonate (3 equiv). The mixture was heated to 120° C. and stirred for 1.5 hours. The mixture was allowed to cool temperature before being poured into ice water and acidified to pH 3 with a 1.0 M aqueous solution of HCl. The mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by column chromatography (6% to 50% or 4% to 34% EtOAc in hexanes) to afford the P-keto ester.
To a flame-dried round-bottom flask, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added the carboxylic acid (1 equiv), followed by DMF (0.1 M). To the mixture was added triethylamine (1 equiv) and the mixture was stirred for 5 minutes at room temperature. To the mixture was added bis(perfluorophenyl) carbonate (1 equiv) and the mixture was stirred for 1 hour at room temperature. 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 for 16 hours at room temperature. The mixture was concentrated in vacuo. The resulting crude solid was purified by trituration with hot EtOH or column chromatography (4% to 34% MeOH in CH2Cl2) to afford the amide.
To a flame-dried microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added the chloro-heterocycle (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 hours. The reaction mixture was allowed to cool to room temperature before being 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 for 15 minutes at room temperature. The precipitate was collected by vacuum filtration and washed with H2O to afford the thione with or without further purification by column chromatography (1% to 8% MeOH in CH2C12).
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 afford 63 (3.24 g, 13.7 mmol, 75%) as a yellow oil.
Rf (3:1 hexanes/EtOAc)=0.38; 1H 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]+
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 hours. The reaction mixture was allowed to cool to room temperature and solidify. The crude solid was heated in EtOH (10 mL) at 85° C. for 30 minutes. After allowing the heterogeneous mixture to cool to room temperature, the insoluble material was collected by vacuum filtration to afford 63 (1.42 g, 4.34 mmol) as a white solid in 35% yield without further purification.
1H 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]+
Synthesis of 64 was carried out according to general procedure 1A using 63 (884 mg, 2.58 mmol, 1 equiv) and LiOH (222 mg, 9.28 mmol, 3.6 equiv) to afford 64 (711 mg, 2.38 mmol, 92%) as a brown solid.
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)
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-1-yl)propan-1-amine (46 mg, L, 0.33 mmol, 1 equiv), and NEt3 (33 mg, 46 μL, 0.33 mmol, 1 equiv) to afford SR-31105 (65) (67 mg, 0.16 mmol, 48%) as a pink solid.
1H 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]+
To a flame-dried round-bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added ethyl 4-methoxybenzimidate hydrochloride (500 mg, 2.32 mmol, 1 equiv), followed by pyridine (5.2 mL) and Ac2O (2.6 mL, 0.3 M in total). The reaction mixture was heated to 80° C. and stirred for 48 hours before being concentrated in vacuo to afford crude 4, which was used directly in the next step.
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 in total). The vial was sealed, and the reaction mixture was heated to 85° C. and stirred for 48 hours. The reaction mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was purified by column chromatography (6% to 50% EtOAc in hexanes) to afford 5 (111 mg, 0.36 mmol) as a white solid in 15% isolated yield.
Rf (3:1 hexanes/EtOAc)=0.26; 1H 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]+
Synthesis of 5 was carried out according to 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.
1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.45 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz, 2H), 3.87 (s, 3H), 2.95 (s, 3H); LC-MS(ESI): m/z 285 [M+H]+
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-Pr2NEt (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.
Rf (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)
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.
Rf (10:1 CH2Cl2/MeOH)=0.29.
Synthesis of 9 was carried out according to general procedure 1D using 8 (53 mg, 0.20 mmol) to afford 9 (47 mg, 0.20 mmol, 99%) as a brown solid.
Synthesis of SR-31108 (10) was carried out according to general procedure 1B 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, 1.1 equiv) to afford SR-31108 (10) (49 mg, 0.10 mmol, 68%) as a yellow oil.
Rf (20:1 CH2Cl2/MeOH)=0.33; 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).
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.
Rf (20:1 CH2Cl2/MeOH)=0.25; 1H 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).
Synthesis of 12 was carried out according to general procedure 1D using 11 (378 mg, 1.45 mmol) to afford 12 (285 mg, 1.45 mmol, 99%) as a brown solid.
To a flame-dried 100 mL round bottom flask, equipped with a rubber septum, Teflon-coated stir bar, and condenser and 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 hours. After allowing the mixture to cool 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 to afford intermediate ester 13 (2.45 g, 11.1 mmol) as an off-white solid in 86% yield without further purification.
1H 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]+
To a flame-dried 100 mL round bottom flask, equipped with a rubber septum and Teflon-coated stir bar and 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 dropwise Tf2O (6.38 g, 3.82 mL, 22.60 mmol, 5 equiv). The reaction mixture was stirred for 2.5 hours at room temperature. The mixture was concentrated in vacuo and the resulting residue was taken up in EtOAc (75 mL). The mixture was washed a saturated aqueous solution of NaHCO3 (2×50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford intermediate triflate 14 (1.59 g, 4.49 mmol) as a pink solid in 99% yield without further purification.
1H 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]+
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 afford 15 (74 mg, 0.23 mmol) as a yellow solid in 80% isolated yield.
Rf (3:1 EtOAc/hexanes)=0.51; 1H 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).
Synthesis of intermediate acid 16 was carried out according to general procedure 1A using 15 (74 mg, 0.23 mmol, 1 equiv) and LiOH (8 mg, 0.32 mmol, 1.4 equiv) to afford 16 (66 mg, 0.22 mmol, 98%) as a yellow solid.
1H 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]+
Synthesis of SR-31109 (17) 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 12 (36 mg, 0.19 mmol, 1.1 equiv) to afford SR-31109 (17) (46 mg, 0.10 mmol, 62%) as an orange solid.
Rf (10:1 CH2Cl2/MeOH)=0.7; 1H 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]+
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.
Rf (20:1 CH2Cl2/MeOH)=0.14; 1H 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).
Synthesis of 19 was carried out according to general procedure 1D using 18 (272 mg, 0.90 mmol) to afford 19 (213 mg, 0.89 mmol, 99%) as a brown solid.
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, 1.1 equiv) to afford SR-31110 (20) (2 mg, 0.01 mmol, 3%) as a yellow solid.
Rf (20:1 CH2Cl2/MeOH)=0.32; 1H 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).
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 afford 21 (5.48 g, 23.2 mmol, 76%) as a yellow oil.
Rf (5:1 hexanes/EtOAc)=0.41; 1H 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]+
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 hours. After allowing the reaction mixture to cool 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 afford 22 (4.57 g, 14.0 mmol) as a white solid in 72% yield without further purification.
Rf (3:1 EtOAc/hexanes)=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]+
Synthesis of 23 was carried out according to 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.
1H 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]+
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, L, 0.33 mmol, 1 equiv), and NEt3 (34 mg, 47 μL, 0.33 mmol, 1 equiv) to afford SR-32684 (24) (67 mg, 0.16 mmol, 48%) as a white solid.
1H 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).
Synthesis of 25 was carried out according to general procedure 1F using 22 (1.00 g, 3.05 mmol) to afford 25 (630 mg, 1.81 mmol, 60%) as a white solid.
Rf (2:1 hexanes/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]+
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.
1H 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).
Synthesis of 27 was carried out according to 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.
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)
Synthesis of SR-32685 (28) was carried out according to general procedure 1H 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) to afford SR-32685 (28) (234 mg, 0.54 mmol, 30%) as a yellow solid.
Rf (5:1 CH2Cl2/MeOH)=0.57; 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).
To a flame-dried 10 mL round bottom flask, equipped with a rubber septum and Teflon-coated stir bar and 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 for 20 hours at room temperature before being diluted with EtOAc (10 mL). The mixture was washed with H2O (3×15 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 afford 29 (103 mg, 0.30 mmol) as an off-white solid in 25% isolated yield
Rf (3:1 EtOAc/hexanes)=0.34; 1H 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]+
Synthesis of 30 was carried out according to 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.
LC-MS(ESI): m/z 314 [M+H]+
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 afford SR-32686 (31) (27 mg, 0.06 mmol, 37%) as a white solid.
Rf (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]+
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 hours. After allowing the mixture to cool to room temperature, cold (0° C.) MTBE (112 mL, 7×POCl3 volume) was added. The mixture was concentrated in vacuo. The resulting crude residue was taken up in CH2Cl2 (50 mL) and washed with H2O (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 afford 32 (560 mg, 1.67 mmol) as a yellow solid in 100% yield without further purification.
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).
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added 32 (560 mg, 1.67 mmol, 1 equiv), followed by CH2Cl2 (7.3 mL, 0.23 M). The reaction mixture was cooled to 0° C. and i-Pr2NEt (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 stir for 16 hours. The mixture was poured onto H2O (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to afford SR-32689 (33) (70 mg. 0.16 mmol) as a red solid in 10% isolated yield.
Rf (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=7.0 Hz, 3H);
LC-MS(ESI): m/z 357 [M-2-methylimidazole]+
To a flame-dried tapered microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 hours. The reaction mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was taken up in CH2Cl2 (10 mL) and washed with H2O (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 afford SR-32687 (34) (22 mg, 0.04 mmol) as a white solid in 33% isolated yield.
Rf (10:1 CH2Cl2/MeOH)=0.14; 1H 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]+
To a flame-dried tapered microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 hours. The reaction mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was taken up in CH2Cl2 (10 mL) and washed with H2O (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 afford SR-32688 (35) (25 mg, 0.05 mmol) as a white solid in 38% isolated yield.
Characterization data for SR-32688 (35) was consistent with data for enantiomer SR-32687 (34).
Synthesis of 36 was carried out according to 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.
Rf (5:1 hexanes/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).
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 hours. The reaction mixture allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to afford 37 (409 mg, 1.19 mmol) as a yellow oil in 51% isolated yield.
Rf (10:1 CH2Cl2/MeOH)=0.50; 1H 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).
Synthesis of 38 was carried out according to general procedure 1F using 37 (409 mg, 1.19 mmol) to afford 38 (225 mg, 0.62 mmol, 52%) as a brown solid.
Rf (3:1 hexanes/EtOAc)=0.33; 1H 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).
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.
Rf (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).
Synthesis of 40 was carried out according to general procedure 1A using 39 (205 mg, 0.57 mmol, 1 equiv) and LiOH (49 mg, 2.05 mmol, 3.6 equiv) to afford crude 40, which was used directly in the next step.
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.
Rf (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]+
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 hour. After allowing the mixture to cool to room temperature, the resulting precipitate was collected by vacuum filtration and washed with Et2O to afford 42 (2.81 g, 17.9 mmol) as a brown solid in 96% yield without further purification.
1H 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]+
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 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 hours. The mixture was allowed to cool to room temperature before being poured onto crushed ice. When the ice had melted, the mixture was neutralized solid NaHCO3. The mixture was extracted with CH2Cl2 (3×100 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), affording 43 (930 mg, 3.55 mmol) as a white solid in 22% isolated yield.
Rf (1:1 hexanes/EtOAc)=0.69; 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.44 (s, 1H), 4.00 (s, 3H).
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, 0.06 M in total). The mixture was degassed with bubbling argon for 15 minutes. The vial was sealed, and the mixture was heated to 120° C. and stirred for 1 hour. The reaction mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was purified by column chromatography (4% to 34% EtOAc in hexanes) to afford 44 (677 mg, 1.95 mmol) as a yellow solid in 96% isolated yield.
Rf (5:1 hexanes/EtOAc)=0.37; 1H 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).
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.
Rf (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]+
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added 45 (56 mg, 0.17 mmol, 1 equiv), followed by POCl3 (1.7 mL, 0.1 M). The vial was sealed, and the reaction mixture was heated to 70° C. and stirred for 16 hours. The mixture was concentrated in vacuo in the microwave vial to afford crude 46, which was used directly in the next step.
The vial containing crude 46 was equipped with a rubber septum and Teflon-coated stir bar and flushed with argon. The residue was taken up in CH2Cl2 (3.5 mL, 0.04 M). The mixture was cooled to 0° C. and NEt3 (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 CH2Cl2 (3.5 mL, 0.04 M). The mixture was allowed to warm to room temperature and stir for 2 hours. The mixture was concentrated in vacuo and the resulting crude residue was taken up in a saturated aqueous solution of NaHCO3 (15 mL). The mixture was extracted with EtOAc (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by column chromatography (2% to 18% MeOH in CH2Cl2) to afford SR-34953 (47) (37 mg, 0.08 mmol) as a brown solid in 48% isolated yield.
Rf (10:1 CH2Cl2/MeOH)=0.43; 1H 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]+
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 in 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 hours. The mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was taken up in PhOPh (16 mL).
To a 100 mL round bottom flask, equipped with a Teflon-coated stir bar, was added PhOPh (40 mL). The PhOPh was heated to 255° C. and the PhOPh solution from the first step was added dropwise. The mixture was stirred for 4 hours at 255° C. The mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was purified by column chromatography (12% to 100% EtOAc in hexanes) to afford 48 (177 mg, 0.53 mmol) as a yellow solid in 6% isolated yield.
Rf (1:1 hexanes/EtOAc)=0.16; 1H 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]+
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added 48 (100 mg, 0.30 mmol, 1 equiv), followed by PhMe (4.9 mL, 0.06 M). To the mixture was added Lawesson's reagent (180 mg, 0.45 mmol, 1.5 equiv) and the vial was sealed. The mixture was heated to 115° C. and stirred for 24 hours. After allowing the mixture to cool to room temperature, H2O (15 mL) was added, and the mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by column chromatography (0% to 20% MeOH in CH2Cl2) to afford 49 (77 mg, 0.22 mmol) as a red solid in 74% isolated yield.
Rf (CH2Cl2)=0.52; 1H 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).
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 H2O (380 μL, 0.29 M in 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 hours. The mixture was allowed to cool to room temperature before being acidified to pH 2 with a 1.0 M aqueous solution of HCl. The resulting precipitate was collected by vacuum filtration and washed with H2O to afford 50 (54 mg, 0.17 mmol) as a red solid in 76% yield without further purification.
1H 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).
To a flame-dried tapered microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 hours. The mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was purified by column chromatography (1% to 12% MeOH in CHCl3) to afford SR-34954 (51) (4 mg, 0.09 mmol) as a white solid in 5% isolated yield.
Rf (15:1 CHCl3/MeOH)=0.15; 1H 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)
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 allowed to cool to room temperature and stir for 48 hours. The mixture was poured onto ice and neutralized with a 1.0 M aqueous solution of HCl (5 mL). The resulting precipitate was collected by vacuum filtration, rinsing with H2O, to afford 52 (1.48 g, 4.74 mmol) as a yellow solid in 92% yield without further purification.
1H 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)
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 hours. The mixture was allowed to cool to room temperature before being neutralized with a 1.0 M aqueous solution of 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 afford crude 53, which was used directly in the next step. A suitable variation in the general method used to prepare intermediates such as compound 53 uses an acid chloride acylation of a phenol, followed by ring formation.36.
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 afford SR-35434 (54) (164 mg, 0.38 mmol, 53%) as a yellow solid.
Rf (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)
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 hours. The mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude residue was purified immediately by column chromatography (2% to 18% MeOH in CH2Cl2) to afford SR-35435 (55) (80 mg, 0.17 mmol) as a red solid in 77% isolated yield.
Rf (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).
To a flame-dried 100 mL round bottom flask, equipped with a rubber septum and Teflon-coated stir bar and 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 allowed to stir for 30 minutes at 0° C. 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 stir for 3 hours. The mixture was diluted with EtOAc (20 mL) and acidified to pH 7 with a 1.0 M aqueous solution of HCl. The mixture was separated, and the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by column chromatography (EtOAc) to afford 56 (2.77 g, 13.4 mmol) as a purple solid in 69% isolated yield.
Rf (EtOAc)=0.50; 1H 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).
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added 56 (400 mg, 1.93 mmol, 1 equiv), followed by CH2Cl2 (4.8 mL, 0.4 M). To the mixture was added NEt3 (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 stir for 16 hours. The mixture was diluted with EtOAc (10 mL) and washed with H2O (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 (20% to 100% EtOAc in hexanes) to afford 57 (533 mg, 1.47 mmol) as a brown solid in 76% isolated yield.
Rf (1:1 Hexanes/EtOAc)=0.46; 1H 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=3.3 Hz, 1H), 6.48 (d, J=7.3 Hz, 1H), 4.40 (q, J=7.1 Hz, 2H), 2.42 (s, 3H), 1.41 (t, J=7.1 Hz, 3H); LC-MS(ESI): m/z 383 [M+Na]+
To a flame-dried round bottom microwave vial, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, 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 with bubbling argon for 30 minutes. The mixture was heated to 80° C. and stirred for 3 hours. The reaction mixture was allowed to cool to room temperature before being 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 afford 58 (127 mg, 0.41 mmol) as a white solid in 98% isolated yield.
Rf (2:1 hexanes/EtOAc)=0.27; 1H 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).
Synthesis of 59 was carried out according to 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.
1H 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)
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-Pr2NEt (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.
Rf (10:1 CH2Cl2/MeOH)=0.27; 1H 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)
To a flame-dried 15 mL round bottom flask, equipped with a rubber septum and Teflon-coated stir bar and flushed with argon, was added 53 (100 mg, 0.32 mmol, 1 equiv), followed by CH2Cl2 (3 mL) and DMF (3 mL, 0.05 M in total). To the mixture was added sequentially 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 for 24 hours at room temperature before being concentrated in vacuo. The resulting crude residue was purified by column chromatography (0% to 6% MeOH in CH2Cl2) to afford SR-35785 (61) (34 mg, 0.08 mmol) as a yellow solid in 24% isolated yield.
Rf (30:1 CH2Cl2/MeOH)=0.12; 1H 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)
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 hours. The mixture was allowed to cool to room temperature and sit for 16 hours. The resulting precipitate was collected by vacuum filtration, rinsing with Et2O, to afford 66 (2.30 g, 10.3 mmol) as a grey solid in 58% yield without further purification. 1H 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).
To a flame-dried round bottom microwave vial, equipped with a rubber septum, Teflon-coated stir bar and flushed 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 hours. The mixture was allowed to cool to room temperature before being poured onto ice. The mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude solid was triturated with Et2O to afford 67 (987 mg, 4.08 mmol) as an off-white solid in 79% yield without further purification.
1H NMR (400 MHz, CDCl3) δ (8.79, 1H), 7.43 (s, 1H), 4.02 (s, 3H), 2.75 (s, 3H).
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 hours before being allowed to cool to room temperature. The mixture was quenched with H2O (100 mL) and extracted with EtOAc (3×100 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, The resulting crude residue was purified by column chromatography (6% to 50% EtOAc in hexanes) to afford 68 (368 mg, 1.12 mmol) as a white solid in 54% isolated yield.
Rf (3:1 hexanes/EtOAc)=0.45; 1H 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).
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 H2O (3 mL, 0.13 M in 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 hours. The mixture was allowed to cool to room temperature before being concentrated in vacuo. The resulting crude solid was taken up in H2O (10 mL) and acidified to pH 2 with concentrated HCl. The mixture was stirred for 10 minutes and the resulting precipitate was collected by vacuum filtration and washed with H2O to afford 69 (320 mg, 1.02 mmol) as a yellow solid in 91% yield without further purification.
1H 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).
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-Pr2NEt (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).
The tables below show the structures of specific examples of compounds useful for practice of methods of the invention, associated with corresponding data such as compound identifier, and biological results.
The biological activity of test compounds was quantified in a cell viability assay (CellTiter-Glo®) assessing the ability of compounds to prevent neuronal death due to NAD deprivation induced by the misfolded protein TPrP. Dose-response profiles were established in the TPrP neuroprotection assay for each compound. PK1 neuroblastoma cells (˜1000 cells/well, 96-well plates) were exposed to TPrP at 5 μg/ml and to compounds at doses ranging 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 doses indicated in 0.5% DMSO final concentration. Cell viability was measured using CellTiter-Glo® (Promega). Efficacious concentrations (EC50 values) were determined. TPrP EC50 for the compounds described herein are shown in Table 4. Dose-response activity curves are shown in
The metabolic stability of some test compounds was determined in hepatic human and mouse microsomes. The compound was incubated with 1 mg/ml human or mouse hepatic microsomes at 37° C. with continuous shaking. Aliquots were removed at various time points between 5 minutes and 2 hours and acetonitrile was added to quench the reactions and precipitate the proteins. Samples were then centrifuged through 0.45 μm filter plates and half-lives were determined by LC-MS/MS. Microsomal stability ≥15 minutes for tested compounds is shown in Table 4.
The ability of some test compounds to activate human NAMPT was tested in 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 by mouse NAMPT (Fisher Scientific AG-40B0179-C050). Enzymatic activity rate was calculated by the formula: ((A at T2)-(A at T1))/(T2-T1) where A is the OD450 at each time point T (min). Examples of activation curves are shown in
This application claims the benefit of priority of U.S. Provisional Application No. 63/127,859 filed on Dec. 18, 2020, which is incorporated herein by reference in its entirety and for all purposes.
This invention was made with government support under Grant Number 5R01NS103195 awarded by the National Institutes of Health. The government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US21/64189 | 12/17/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63127859 | Dec 2020 | US |
