Isoquinoline derivatives, methods of synthesis and their uses

Abstract

Described herein are compounds, pharmaceutical compositions, and methods of using these compounds and pharmaceutical compositions to treat and / or prevent diseases such as amyotrophic lateral sclerosis. These compounds and pharmaceutical compositions are also useful as antiviral and antibacterial agents.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 046,219, filed June 30, 2020. [Background technology]

[0002] There is a need for compounds that are useful as antiviral agents, antibacterial agents, and for the treatment and prevention of diseases such as amyotrophic lateral sclerosis (ALS).

[0003] It has been discovered that certain compounds described herein are effective against diseases such as ALS, and are also useful as antiviral and antibacterial compounds. These and other uses of these compounds are described herein. Summary of the Invention [Means for solving the problem]

[0004] In one embodiment, a compound represented by Structural Formula (I), (II), (III), or (IV): [ka] wherein X is absent, —CH—, —CHCH—, —CHCHNR 56 R 57 , -C=C-, cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkyl, substituted cycloheteroalkyl or [ka] and R1 is hydrogen, -OR 22 , alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -NR 43 R 44 , -OPh (wherein Ph is optionally substituted phenyl), [ka] and R2 is hydrogen, -OR 23 , -CF3, alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, -NR 45 R 46 , [ka] or R1 and R2 together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; R3 and R4 are independently hydrogen, halo, alkyl, alkenyl, -OR 24 or -NR 25 R 26 R5 is hydrogen, fluoro, alkyl or alkenyl; R6 is hydrogen, fluoro, alkyl, alkenyl, -OR 27 or -NR 28 R 29 and R7 is hydrogen, alkyl, alkenyl, -CO2R 30 , -CONR 31 R 32 -CH2NR 33 R 34 , -CH2R 42 or -CH2OR 35 and R8 is hydrogen, -SO2R 47 , -OR 48 , -SO2NR 69 R 70 , -CONR 71 R 72 , -COR 73 , -CO2R 74, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkyl, or substituted cycloheteroalkenyl; R 10 ~R 14 and R 16 ~R 20 are independently hydrogen, alkyl, alkenyl, halo, -CHOR 36 , -CO2R 37 , -CONR 38 R 39 -NR 40 R 41 , cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkyl or substituted cycloheteroalkenyl; R 15 and R 21 are independently hydrogen, alkyl, or alkenyl; R 22 and R 23 is independently alkyl, alkenyl, halo-substituted alkyl, substituted alkenyl, heteroaryl, or substituted heteroaryl; R 24 , R 27 , R 35 and R 36 is independently alkyl, alkenyl, halo-substituted alkyl, or halo-substituted alkenyl; R 28 , R 29 , R 30 ~R 33 , R 38 ~R 41 , R 63 ~R 74 , R 75 , R 77 and R 79 ~R 83 are independently hydrogen, alkyl, or alkenyl; R 25 and R 26 independently form a hydrogen atom, an alkyl group, an alkenyl group, or an aryl group or a substituted aryl group together with the nitrogen atom to which they are attached; R 34 is hydrogen, -SO2R 63 , -SO2NR 64 R 65, -CONR 66 R 67 or -COR 68 and;R 76 and R 78 are independently hydrogen, -SO2R 79 , -SO2NR 80 R 81 , -CONR 82 R 83 or -COR 84 and;R 42 is cycloheteroalkenyl, substituted cycloheteroalkyl or substituted cycloheteroalkenyl; R 43~46 are independently hydrogen, alkyl, alkenyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R 47 is alkyl, alkenyl, aryl or heteroaryl; R 48 is hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, or aryl; R 55 is heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, -NR 75 R 76 or -CH2R 77 R 78 and;R 56 is hydrogen, alkyl or alkenyl; R 57 is a substituted aryl, heteroaryl, or substituted heteroaryl; provided that R is hydrogen or -OR 22 and R 22 is alkyl and X is -C=C-, R2 is hydrogen, -OR 23 , -CF3 or [ka] (where R 23 is alkyl, n is 1, and R 16 ~R 20 is hydrogen in compounds of formula (I); provided that R1 is not [ka] When R3 to R7 are each hydrogen, at least one of R3 to R7 is not hydrogen in compounds of formula (I) when X is -C=C-, or when each of R3 to R7 are hydrogen, R8 is hydrogen in compounds of formula (I) when X is -C=C-, -CONR 71 R 72 , -COR 73 or -CO2R 74 and provided that R1 and R2 are not both alkyl. Compounds of or a solvate, hydrate or salt thereof is provided.

[0005] Also provided are derivatives, including salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs of the compounds described herein. Additionally, provided are pharmaceutical compositions comprising a compound provided herein and a pharmaceutically acceptable vehicle.

[0006] For example, provided herein are methods for treating, preventing, or ameliorating symptoms of medical disorders such as amyotrophic lateral sclerosis or Alzheimer's disease. Also provided herein are methods for treating viral and microbial infections. [Brief explanation of the drawings]

[0007] [Figure 1] The preparation of compounds of formula (I) and formula (II) (wherein R3 and R4 are not hydrogen) is illustrated. [Figure 2] The preparation of compounds of formula (I) where R3 and R4 are not hydrogen is illustrated. [Figure 3] The preparation of compounds of formula (I) where R3 and R4 are not hydrogen is illustrated. [Figure 4] The preparation of compounds of formula (I) where R3 and R4 are not hydrogen and X is -CH2- is illustrated. [Figure 5] The preparation of compounds of formula (I) where R3 and R4 are not hydrogen and X is absent is illustrated. [Figure 6]The preparation of compounds of formula (I) and (II) where R6 is not hydrogen is illustrated. [Figure 7] The preparation of compounds of formula (I) and (II) where R6 is fluorine is illustrated. [Figure 8] The preparation of compounds of formula (I) and (II) where R6 and R7 are fluorine is illustrated. [Figure 9] The preparation of compounds of formula (I) and (II) where R6 is a hydroxyl or ether derivative is illustrated. [Figure 10] The preparation of compounds of formula (I) and (II) where R8 is alkyl is illustrated. [Figure 11] The preparation of compounds of formula (I) and (II) where R8 is an ester is illustrated. [Figure 12] The preparation of compounds of formula (I) where R9 is a benzyl derivative is illustrated. [Figure 13] The preparation of compounds of formula (I) where R9 is an amine derivative is illustrated. [Figure 14] The preparation of compounds of formula (I) where R3 is an amine derivative is illustrated. DETAILED DESCRIPTION OF THE INVENTION

[0008] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0009] As used herein, and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or a property of a range of values, indicate that the value or range of values ​​may deviate to an extent that would be reasonable to one of ordinary skill in the art while still describing the particular property. Specifically, the terms "about" and "approximately," when used in this context, indicate that the numerical value or range of values ​​may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the recited value or range of values.

[0010] "Alkyl," by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain, or cyclic monovalent hydrocarbon group derived by removing one hydrogen atom from just one carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl, such as propan-1-yl, propan-2-yl, etc.; butyl, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, etc. In some embodiments, an alkyl group is a group of 1 to 20 carbon atoms (C1-C6). 20 In other embodiments, the alkyl group contains 1 to 10 carbon atoms (C1 to C 10 In yet other embodiments, the alkyl group contains 1 to 6 carbon atoms (C1-C6 alkyl).

[0011] "Alkenyl," by itself or as part of another substituent, refers to an unsaturated, branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of a parent alkene. The group can be in either the cis or trans conformation about the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, and the like.

[0012] "Alkynyl," by itself or as part of another substituent, refers to an unsaturated, branched, straight-chain, or cyclic alkyl group having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, and the like.

[0013] "Aryl," by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon derived by removing one hydrogen atom from only one carbon atom of a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In some embodiments, an aryl group is an aryl group having 6 to 20 carbon atoms (C6-C8). 20 In other embodiments, the aryl group contains 6 to 15 carbon atoms (C 15 In yet another embodiment, the aryl group contains 6 to 15 carbon atoms (C 10 aryl).

[0014] "Arylalkyl" by itself or as part of another substituent means an alkyl group having a carbon atom, typically a terminal or sp 3 It refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. In some embodiments, an arylalkyl group is a (C6-C 30 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C 10 ) alkyl, and the aryl portion is (C6-C 20 In other embodiments, the arylalkyl group is (C6-C 20) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C8) alkyl and the aryl portion is (C6-C 12 In yet another embodiment, the arylalkyl group is (C6-C 15 ) arylalkyl, for example, the alkyl portion of the arylalkyl group is (C1-C5) alkyl and the aryl portion is (C6-C 10 ) aryl.

[0015] "Arylalkenyl," by itself or as part of another substituent, refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein.

[0016] "Cycloalkyl," by itself or as part of another substituent, refers to a saturated cyclic monovalent hydrocarbon group derived by removing one hydrogen atom from just one carbon atom of a parent cycloalkane. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and the like. In some embodiments, cycloalkyl groups have 3 to 20 carbon atoms (C1 to C6). 15 In other embodiments, the cycloalkyl group contains 3 to 10 carbon atoms (C1 to C 10 In yet other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms (C1-C8 alkyl). The term "cyclic monovalent hydrocarbon group" also includes polycyclic hydrocarbon ring systems having only one radical and 3 to 12 carbon atoms. Exemplary polycyclic cycloalkyl rings include, for example, norbornyl, vinyl, and adamantyl.

[0017] "Cycloalkenyl," by itself or as part of another substituent, refers to an unsaturated cyclic monovalent hydrocarbon group obtained by removing one hydrogen atom from just one carbon atom of a parent cycloalkene. Typical cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, and the like. In some embodiments, cycloalkenyl groups have 3 to 20 carbon atoms (C1 to C6). 20 In other embodiments, the cycloalkenyl group contains 3 to 10 carbon atoms (C1 to C2). 10 In yet another embodiment, a cycloalkenyl group contains 3 to 8 carbon atoms (C1-C8 alkenyl). The term "cyclic monovalent hydrocarbon group" also includes polycyclic hydrocarbon ring systems having only one group and 3 to 12 carbon atoms along with alkenyl groups.

[0018] "Cycloheteroalkyl," by itself or as part of another substituent, refers to a cycloalkyl group, as defined herein, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatom groups, as defined below under "heteroalkyl."

[0019] "Cycloheteroalkenyl," by itself or as part of another substituent, refers to a cycloalkenyl group, as defined herein, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatom groups, as defined below under "heteroalkenyl."

[0020] "Compound" refers to a compound encompassed by the structural formulas disclosed herein, including any specific compound within these formulas whose structures are disclosed herein. Compounds may be identified by either their chemical formula and / or chemical name. The chemical structure determines the identity of the compound. The compounds described herein may contain one or more chiral centers and / or double bonds and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Accordingly, chemical structures depicted herein encompass stereomerically pure (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) forms depicted in the structure. Chemical structures depicted herein also encompass enantiomeric and stereoisomeric derivatives of the depicted compounds. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in several tautomeric forms, including the enol form, the keto form, and mixtures thereof. Thus, the chemical structures depicted herein encompass all possible tautomeric forms of the exemplified compounds. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 Examples of suitable physical forms include, but are not limited to, HCl ...

[0021] "Halo," by itself or as part of another substituent, refers to the groups -F, -Cl, -Br, or -I.

[0022] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, etc., and combinations thereof. The heteroatom or heteroatomic group can be located at any interior position of the alkyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, NR 501 R 502 , =NN=, -N=N-,-N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 etc., where R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl.

[0023] "Heteroalkenyl" refers to an alkenyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, etc., and combinations thereof. The heteroatom or heteroatomic group can be located at any interior position of the alkenyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, NR 501 R 502 , =NN=, -N=N-,-N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -O-PO(O)2-, -SO-, -SO2-, -SnR 507 R 508 etc., where R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl.

[0024] "Heteroalkynyl" refers to an alkynyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, etc., and combinations thereof. The heteroatom or heteroatomic group can be located at any interior position of the alkynyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, NR 501 R 502 , =NN=, -N=N-,-N=N-NR 503 R 404 , -PR 505 -, -P(O)2-, -POR 506 -, -O-PO(O)2-, -SO-, -SO2-, -SnR 507 R 508 etc., where R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl.

[0025] "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic group derived by removing one hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In some embodiments, heteroaryl groups contain 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, heteroaryl groups contain 5 to 10 ring atoms (5-10 membered heteroaryl). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0026] "Heteroarylalkyl" by itself or as part of another substituent refers to a heteroaryl group containing a carbon atom, typically a terminal or sp 3" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6- to 21-membered heteroarylalkyl, e.g., the alkyl portion of the heteroarylalkyl is a (C1-C6) alkyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkyl is a 6- to 13-membered heteroarylalkyl, e.g., the alkyl portion is a (C1-C3) alkyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0027] "Heteroarylalkenyl" by itself or as part of another substituent refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group.

[0028] "Heteroarylalkynyl" by itself or as part of another substituent refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group.

[0029] "Hydrate" refers to the incorporation of water into the crystal lattice of a compound described herein in a stoichiometric proportion, resulting in the formation of an adduct. Methods for producing hydrates include, but are not limited to, storage in an atmosphere containing water vapor, dosage forms containing water, or routine formulation processes such as crystallization (i.e., from water or mixed aqueous solvents), lyophilization, wet granulation, aqueous film coating, or spray drying. Hydrates can also form, under certain circumstances, from crystalline solvates upon exposure to water vapor or upon suspension of anhydrous materials in water. Hydrates can also crystallize in more than one form, resulting in hydrate polymorphs. See, for example, Guillory, K., Chapter 5, pp. 202205, in Polymorphism in Pharmaceutical Solids, (ed. Brittain, H.), Marcel Dekker, Inc., New York, NY, 1999. The above-described methods for preparing hydrates are well within the scope of those skilled in the art and are completely conventional, requiring no experimentation beyond that typical in the art. Hydrates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single crystal X-ray diffraction, X-ray powder diffraction, polarized light microscopy, thermal microscopy, thermogravimetric analysis, scanning calorimetry, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Chapter 6, pp. 205-208, in "Polymorphism in Pharmaceutical Solids," edited by Brittain, H.), Marcel Dekker, Inc., New York, 1999). In addition, many commercial routine companies offer services that include the preparation and / or characterization of hydrates, such as HOLODIAC, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com).

[0030] "Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated π-electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Exemplary parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like.

[0031] "Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatom. Typical heteroatoms for replacing carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more of the rings is aromatic and one or more of the rings is saturated or unsaturated, such as, for example, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Exemplary parent heteroaromatic ring systems include, but are not limited to, alcidol, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like.

[0032] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic ... or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordination compounds with organic bases such as ethanolamine, diethanolamine, triethylamine, N-methylglucamine, and the like.

[0033] "Preventing" or "prevention" refers to reducing the risk of acquiring a disease or disorder (i.e., not developing at least one clinical symptom of the disease in a patient who may be exposed to or susceptible to the disease, but who has not yet experienced or exhibited symptoms of the disease). In some embodiments, the compounds provided herein provide superior prevention due to lower long-term side effects over the long term.

[0034] A "protecting group" refers to a grouping of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group during chemical synthesis. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry," (Wiley, 2nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods," Vols. 1-8 (John Wiley and Sons, 1971-1996). Representative amine protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups are those in which the hydroxy group is either acylated or alkylated, such as benzyl, and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0035] "Solvate" refers to the incorporation of a solvent into the crystal lattice of a compound described herein in a stoichiometric proportion, resulting in the formation of an adduct. Methods for producing solvates include, but are not limited to, storage in a solvent-containing atmosphere, solvent-containing dosage forms, or routine formulation processes such as, for example, crystallization (i.e., from a solvent or mixture of solvents), vapor diffusion, etc. Solvates may also, under certain circumstances, form from other crystalline solvates or hydrates upon exposure to a solvent, or upon suspension of a material in a solvent. Solvates may crystallize in more than one form, resulting in solvate polymorphs. For example, see Guillory, K., Chapter 5, pp. 205-208, in Polymorphism in Pharmaceutical Solids, (ed. Brittain, H.), Marcel Dekker, Inc., New York, NY, 1999. The above methods for preparing solvates are well within the skill of those skilled in the art and are completely conventional, requiring no experimentation beyond that which is typical in the art. Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as, for example, single crystal X-ray diffraction, X-ray powder diffraction, polarized light microscopy, thermal microscopy, thermogravimetry, scanning calorimetry, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Chapter 6, pp. 205-208, in "Polymorphism in Pharmaceutical Solids," (Brittain, H., ed.), Marcel Dekker, Inc., New York, NY, 1999). In addition, many commercial routine companies offer services that include the preparation and / or characterization of solvates, such as, for example, HOLODIAC, Pharmaparc II, Voie de lInnovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com).

[0036] "Substituted," when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s). Substituents useful for replacing saturated carbon atoms in a specified group or radical include -R a , halo, -O - , =O, -OR b , -SR b , -S - , =S, -NR c R c , =NR b , =N-OR b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b , -N-NR c R c , -NR b S(O)2R b , =N2, -N3, -S(O)2R b , -S(O)NR b R b , -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2O - , -OS(O)2OR b , -OS(O)2NR c NR c , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(O)NR b -OR b -C(S)R b , -C(NR b )R b , -C(O)O - , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)Rb , -OC(S)R b , -OC(O)O - , -OC(O)OR b , -OC(O)NR c R c , -OC(NCN)NR c R c -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O - , -NR b C(O)OR b , -NR b C(NCN)OR b , -NR b S(O)NR c R c , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(S)NR c R c , -NR b C(S)NR b C(O)R a , -NR b S(O)2OR b , -NR b S(O)2R b , -NR b C(NCN)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c where each R a is independently a substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, or substituted heteroaryl; each R bis independently hydrogen, alkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, or substituted heteroarylalkyl; each R c are independently b or alternatively, two R c taken together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl, or cycloheteroalkyl fused to an aryl group, which may optionally contain 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N, and S. Specific examples include -NR c R c is meant to include -NH, -NH-alkyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, substituents useful for replacing saturated carbon atoms in certain groups or radicals include R a , halo, -OR b , -NR c R c , trihalomethyl, -CN, -NR b S(O)2R b , -C(O)R b , -C(O)NR b -OR b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -OC(O)NR c R c , and -NR b C(O)OR b where each R a are independently alkyl, aryl, or heteroalkyl, and each R b are independently hydrogen, R a , heteroalkyl, arylalkyl, and heteroarylalkyl; each R c are independently b or alternatively, two R ctogether with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl ring.

[0037] Substituents useful for replacing unsaturated carbon atoms in certain groups or radicals include -R a , halo, -O - , -OR b , -SR b , -S - , -NR c R c , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2OR b , -OS(O)2O - , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(S)R b , -C(NR b )R b , -C(O)O - , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)O - , -OC(O)OR b , -OC(S)OR b , -OC(O)NR c R c , -OS(O)2NR c NR c , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O -, -NR b C(O)OR b , -NR b S(O)2OR a , -NR b S(O)2R a , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c where R a , R b and R c is as defined above. In other embodiments, substituents useful for replacing unsaturated carbon atoms in certain groups or radicals include -R a , halo, -OR b , -SR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R c is as previously defined.

[0038] Useful substituents for replacing nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include -R a , -O - , -OR b , -SR b , -S- , -NR c R c , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R b , -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2O - , -OS(O)2OR b , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(S)R b , -C(NR b )R b , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)OR b , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)OR b , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c These include, but are not limited to, where R a , R b and R cis as defined above. In some embodiments, useful substituents for substituting a nitrogen atom in heteroalkyl and cycloheteroalkyl groups include R a , halo, -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -OS(O)2OR b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R c is as previously defined.

[0039] Substituents from the above list that are useful to replace other particular groups or atoms will be apparent to those skilled in the art.

[0040] The substituents used to substituted a particular group may be further substituted with one or more of the same or different groups, typically selected from the various groups specified above.

[0041] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals, and pets.

[0042] "Treating" or "treatment" of any disease or disorder, in some embodiments, refers to ameliorating the disease or disorder (i.e., arresting or reducing the progression of the disease or at least one of its clinical symptoms). Treatment may also be considered to include preemptive or prophylactic administration to ameliorate, arrest, or prevent the progression of the disease or at least one of its clinical symptoms. In a further aspect, the treatment administered has a lower likelihood of long-term side effects over a period of years. In other embodiments, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible by the patient. In yet other embodiments, "treating" or "treatment" refers to preventing the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder.

[0043] "Therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism, excretion, etc., of the patient being treated.

[0044] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a subject. In some embodiments, the vehicle is pharmaceutically acceptable.

[0045] compound Structural Formula (I), (II), (III) or (IV): [ka] [Wherein: X is absent, —CH—, —CHCH—, —CHCHNR 56 R 57 , -C=C-, cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkyl, substituted cycloheteroalkyl or [ka] and R1 is hydrogen, -OR 22 , alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, -NR 43 R 44 , -OPh (wherein Ph is optionally substituted phenyl), [ka] and R2 is hydrogen, -OR 23 , -CF3, alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, heteroaryl, substituted heteroaryl, -NR 45 R 46 , [ka] or R1 and R2 together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring; n is 0, 1, 2, or 3; o is 0, 1, 2, or 3; R3 and R4 are independently hydrogen, halo, alkyl, alkenyl, -OR 24 or -NR 25 R 26 R5 is hydrogen, fluoro, alkyl or alkenyl; R6 is hydrogen, fluoro, alkyl, alkenyl, -OR 27 or -NR 28 R 29 and R7 is hydrogen, alkyl, alkenyl, -CO2R 30 , -CONR 31 R 32 , -CH2NR 33 R 34 , -CH2R 42 or -CH2OR 35 and R8 is hydrogen, -SO2R 47 , -OR 48 , -SO2NR 69 R 70 , -CONR 71 R72 , -COR 73 , -CO2R 74 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkyl, or substituted cycloheteroalkenyl; R 10 ~R 14 and R 16 ~R 20 are independently hydrogen, alkyl, alkenyl, halo, -CHOR 36 , -CO2R 37 , -CONR 38 R 39 -NR 40 R 41 , cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkyl or substituted cycloheteroalkenyl; R 15 and R 21 are independently hydrogen, alkyl, or alkenyl; R 22 and R 23 is independently alkyl, alkenyl, halo-substituted alkyl, substituted alkenyl, heteroaryl, or substituted heteroaryl; R 24 , R 27 , R 35 and R 36 are independently alkyl, alkenyl, halo-substituted alkyl, or halo-substituted alkenyl; R 28 , R 29 , R 30 ~R 33 , R 38 ~R 41 , R 63 ~R 74 , R 75 , R 77 and R 79 ~R 83 are independently hydrogen, alkyl, or alkenyl; R 25 and R 26 are independently hydrogen, alkyl, alkenyl, or together with the nitrogen atom to which they are attached form an aryl or substituted aryl group; R 34 is hydrogen, -SO2R63 , -SO2NR 64 R 65 , -CONR 66 R 67 or -COR 68 and;R 76 and R 78 are independently hydrogen, -SO2R 79 , -SO2NR 80 R 81 , -CONR 82 R 83 or -COR 84 and;R 42 is cycloheteroalkenyl, substituted cycloheteroalkyl or substituted cycloheteroalkenyl; R 43 ~ 46 are independently hydrogen, alkyl, alkenyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R 47 is alkyl, alkenyl, aryl or heteroaryl; R 48 is hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, or aryl; R 55 is heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, -NR 75 R 76 , -CH2R 77 R 78 and;R 56 is hydrogen, alkyl or alkenyl; R 57 is a substituted aryl, heteroaryl, or substituted heteroaryl; provided that R is hydrogen or -OR 22 and R 22 is alkyl and X is -C=C-, R2 is hydrogen, -OR 23 , -CF3 or [ka] (where R 23 is alkyl, n is 1, and R 16 ~R 20 is hydrogen in compounds of formula (I); provided that R1 is not [ka] when X is -C=C-, then at least one of R3 to R7 is not hydrogen in compounds of formula (I) when X is -C=C-, or when each of C3 to C7 is hydrogen, R8 is hydrogen in compounds of formula (I) when X is -C=C-, -CONR 71 R 72 , -COR 73 or -CO2R 74 and provided that R1 and R2 are not both alkyl. Compounds of or a solvate, hydrate or salt thereof is provided herein.

[0046] In some embodiments, R1 is hydrogen or -OR 22 and R 22 is alkyl, R2 is hydrogen, -OR 23 , -CF3 or [ka] (where R 23 is alkyl, or n is 1, and R 16 ~R 20 is hydrogen); [ka] then at least one of R3 to R8 is not hydrogen in the compounds of formulae (II) to (IV) and both R1 and R2 are not both alkyl.

[0047] In some embodiments, R is hydrogen, -OR 22 , [ka] arylalkyl, substituted arylalkyl or [ka] In other embodiments, R2 is hydrogen, -OR23 , -CF3, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, [ka] In still other embodiments, R is hydrogen, -OR 22 , [ka] Aryl alkyl, substituted aryl alkyl, aryl alkenyl, substituted aryl alkenyl [ka] and R2 is hydrogen, -OR 23 , -CF3, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, [ka] In still other embodiments, R1 and R2 together with the carbon atoms to which they are attached form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring.

[0048] In some embodiments, R3 and R4 are hydrogen. In other embodiments, R3, R4, and R8 are hydrogen. In still other embodiments, R5-R7 are hydrogen. In still other embodiments, R5-R8 are hydrogen. In still other embodiments, R3-R8 are hydrogen.

[0049] In some embodiments, R 22 and R 23 is pyridyl or substituted pyridyl.

[0050] In some embodiments, R9 is phenyl, substituted phenyl, imidazopyridine, substituted imidazopyridine, imidazopyrimidine, substituted imidazopyrimidine, imidazopyrazine, substituted imidazopyrazine, imidazopyridazine, substituted imidazopyridazine, indole, substituted indole, azaindole, substituted azaindole, pyrrolopyrazine, substituted pyrrolopyrazine, benzofuran, substituted benzofuran, benzothiophene, substituted benzothiophene, furopyrimidine, substituted furopyrimidine, thienopyrimidine, substituted thienopyrimidine, pyrazolopyrindine, substituted pyrazolopyrindine, pyrazolopyrimidine, substituted pyrazolopyrimidine, pyrazolopyrazine, substituted pyrazolopyrazine, pyrazolopyradazine, substituted pyrazolopyradazine or [ka] In some of the above embodiments, R1 is hydrogen, -OR 22 , [ka] Aryl alkyl, substituted aryl alkyl, aryl alkenyl, substituted aryl alkenyl [ka] In still other of the above embodiments, R2 is hydrogen, -OR 23 , -CF3, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, [ka] In still other of the above embodiments, R1 is hydrogen, -OR 22 , [ka] arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, [ka] and R2 is hydrogen, -OR 23 , -CF3, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, [ka] In still other of the above embodiments, R1 and R2, together with the carbon atoms to which they are attached, form an aryl, substituted aryl, heteroaryl, or substituted heteroaryl ring. In still other of the above embodiments, R3 and R4 are hydrogen. In still other of the above embodiments, R3, R4, and R8 are hydrogen. In still other of the above embodiments, R5-R7 are hydrogen. In still other of the above embodiments, R5-R8 are hydrogen. In still other of the above embodiments, R3-R8 are hydrogen. In still other of the above embodiments, R 22 and R 23 is pyridyl or substituted pyridyl.

[0051] In some embodiments, structural formula (V): [ka] (In the formula, R 49 is hydrogen or alkyl; Y is -CR 50 - or -N-; Z is -CR 51 - or -N-; R 50 and R 51 are independently hydrogen, halo, alkyl, -OR 52 or NR 53 R 54 and;R 52 is alkyl; R 53 and R 54 are independently hydrogen or alkyl. In other embodiments, R9 is [ka] is.

[0052] In some embodiments, structural formula (VI): [ka] In another embodiment, a compound of structural formula (VII): [ka] In yet another embodiment, a compound of structural formula (VIII): [ka] The compound of formula (I) is provided.

[0053] In some embodiments, structural formula (IX): [ka] (Wherein, R3 is F, Cl, Br, -CH3, alkyl, alkenyl, -CF3, -OCR 24 or -NR 25 R 26 is) The compound of formula (I) is provided.

[0054] In some embodiments, structural formula (X): [ka] The compound of formula (I) is provided.

[0055] In some embodiments, structural formula (XI): [ka] (Wherein, R4 is F, Cl, Br, -CH3, alkyl, alkenyl, -CF3-OCR 24 or -NR 25 R 26 is) The compound of formula (I) is provided.

[0056] In some embodiments, structural formula (XII): [ka] The compound of formula (I) is provided.

[0057] In some embodiments, structural formula (XIII): [ka] (Wherein, R5 is hydrogen or fluorine, and R6 is alkyl, methyl, alkenyl, fluorine, -OR 27 or -NR 28 R 29 is) The compound of formula (I) is provided.

[0058] In some embodiments, structural formula (XIV): [ka] The compound of formula (I) is provided.

[0059] In some embodiments, structural formula (XV): [ka] (Wherein, R7 is alkyl, alkenyl, -CO2R 30 , -CONR 31 R 32 , -CH2NR 33 R 34 , -CH2R 42 or -CH2OR 35 is) The compound of formula (I) is provided.

[0060] In some embodiments, structural formula (XVI): [ka] The compound of formula (I) is provided.

[0061] In some embodiments, structural formula (XVII): [ka] (Wherein, R7 is alkyl, alkenyl, -CO2R 30 , -CONR 31 R 32 , -CH2NR 33 R 34 , -CH2R 42 or -CH2OR 35 is) The compound of formula (I) is provided.

[0062] In some embodiments, structural formula (XVIII): [ka] The compound of formula (I) is provided.

[0063] In some embodiments, structural formula (XIX): [ka] The compound of formula (I) is provided.

[0064] In some embodiments, structural formula (XX): [ka] The compound of formula (I) is provided.

[0065] In some embodiments, structural formula (XXI): [ka] The compound of formula (I) is provided.

[0066] In some embodiments, structural formula (XXII): [ka] (In the formula, R 58 is hydrogen, alkyl, alkenyl, -CO2R 59 , -CONR 60 R 61 , or -CH2OR 62 and R 59is hydrogen, alkyl or alkenyl, and R 60 and R 61 are independently hydrogen, alkyl, or alkenyl; R 62 is alkyl or alkenyl) The compound of formula (I) is provided.

[0067] In some embodiments, structural formula (XXIII): [ka] (Wherein, R7 is alkyl, alkenyl, -CO2R 30 , -CONR 31 R 32 , -CH2NR 33 R 34 , -CH2R 42 or -CH2OR 35 is) The compound of formula (I) is provided.

[0068] In some embodiments, structural formula (XXIV): [ka] The compound of formula (I) is provided.

[0069] In some embodiments, structural formula (XXV): [ka] The compound of formula (I) is provided.

[0070] In some embodiments, structural formula (XXVI): [ka] The compound of formula (I) is provided.

[0071] In some embodiments, Structural Formula (XXVII): [ka] (R8 is hydrogen, -SO2R47 , -OR 48 , -SO2NR 69 R 70 , -CONR 71 R 72 or -COR 73 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl) The compound of formula (I) is provided.

[0072] In some embodiments, a compound of structural formula (XXVIII): [ka] The compound of formula (I) is provided.

[0073] In some embodiments, structural formula (XXIX): [ka] (Wherein, R3 is F, Cl, Br, -CH3, alkyl, -CF3-OCR 24 or -NR 25 R 26 and R8 is hydrogen, -SO2R 47 , -OR 48 , -SO2NR 69 R 70 , -CONR 71 R 72 or -COR 73 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl) The compound of formula (I) is provided.

[0074] In some embodiments, structural formula (XXX): [ka] The compound of formula (I) is provided.

[0075] In some embodiments, structural formula (XXXI): [ka] The compound of formula (I) is provided.

[0076] In some embodiments, R3 is -CH3, R4 is -CH3, and R6 is H, -CH3, -C2H5, -OR 27 ,-NR 28 R 29 and R7 is H, -CH3, or -C2H5. In other embodiments, R3 is -OCH3, R4 is -OCH3, and R6 is H, -CH3, -C2H5, -OR 27 ,-NR 28 R 29 and R7 is H, -CH3, or -C2H5. In yet other embodiments, R3 is -F3, R4 is -F, and R6 is H, -CH3, -C2H5, -OR 27 ,-NR 28 R 29 and R7 is H, -CH3, or -C2H5. In yet other embodiments, R3 is -Cl, R4 is -Cl, and R6 is H, -CH3, -C2H5, -OR 27 ,-NR 28 R 29 and R7 is H, -CH3, or -C2H5. In other embodiments, R3 is -Br, R4 is -Br, and R6 is H, -CH3, -C2H5, -OR 27 , -NR 28 R 29 and R7 is H, —CH3 or —C2H5.

[0077] Specific compounds are disclosed in Table 1 below.

[0078] [Table 1] TIFF0007828905000057.tif229170 TIFF0007828905000058.tif234170TIFF0007828905000059.tif188170TIFF0007828905000060.tif234170TIFF00078289050 00061.tif183170TIFF0007828905000062.tif188170TIFF0007828905000063.tif229170TIFF0007828905000064.tif234170

[0079] Synthesis method Referring now to Figure 1, aldehyde 100 undergoes aldol condensation with nitromethane and is reduced with lithium aluminum hydride to give amine 101. Reaction with carboxylic acid 102 provides amide 103, which cyclizes to give imine 104, a compound of formula (II). Reduction of imine 104 gives compound 105, a compound of formula (I). It should be pointed out that the use of polycyclic aryl and heteroaryl aldehydes allows for the preparation of polycyclic aryl and heteroaryl derivatives of compounds of formulas (I) and (II).

[0080] Figure 2 illustrates the preparation of compounds of formula (I) where R3 and R4 are not hydrogen. Reaction of amine 100 with thiol 106 provides protected amine 107, which is condensed with unsaturated aldehyde 109 to give tetrahydroisoquinoline 110, which is then deprotected to provide amine 105.

[0081] Figure 3 illustrates the preparation of compounds of formula (I) where R3 and R4 are not hydrogen. Amine 100 reacts with acid 102 to provide 112, which then cyclizes to imine 113 and is then reduced to give alkene 114. Protection of the amine provides 115, and a Heck reaction with an aryl bromide gives functionalized compound 117, which is then deprotected to provide amine salt 118.

[0082] 4 illustrates the preparation of compounds of formula (I) where R3 and R4 are not hydrogen and X is -CH2-. Protected amine 107 is condensed with aldehyde 119 to provide protected tetrahydroisoquinoline 120, which is deprotected to yield amine salt 121.

[0083] 5 illustrates the preparation of compounds of formula (I) where R3 and R4 are not hydrogen and X is absent. Protected amine 107 is condensed with aldehyde 122 to provide protected tetrahydroisoquinoline 123, which is deprotected to yield amine salt 124.

[0084] Figure 6 illustrates the preparation of compounds of formula (I) and (II) where R6 is not hydrogen. Aldehyde 100 reacts with an alkyl Grignard reagent to provide an alcohol, which is then oxidized to ketone 125. Aldol condensation with nitromethane, followed by reduction of the nitro group, provides amine 126, which then reacts with acid 102 to form an amide, which then cyclizes to provide an imine (i.e., a compound of formula (II)), which is then reduced to provide tetrahydroisoquinoline 127 of formula (I).

[0085] 7 illustrates the preparation of compounds of formula (I) and (II) where R6 is fluorine. Condensation of aldehyde 100 with trimethylsilyl chloride in the presence of zinc iodide and diethylaminosulfur trifluoride provides cyanofluoride 128, which is reduced to give fluoroamine 129. Fluoroamine 129 reacts with acid 102 to form an amide, which then cyclizes to give the imine (i.e., the compound of formula (II)), which is then reduced to give tetrahydroisoquinoline 130 of formula (I).

[0086] Figure 8 illustrates the preparation of compounds of formula (I) and (II) where R6 and R7 are fluorine. Bromination of ketone 131 provides bromoketone 132, which is converted to difluoroazide 133. Reduction of the azide provides difluoroamine 134, which then reacts with acid 102 to form an amide, which then cyclizes to provide the imine (i.e., compound of formula (II)), which is then reduced to afford tetrahydroisoquinoline 135 of formula (I).

[0087] Figure 9 illustrates the preparation of compounds of Formulas (I) and (II) (where R6 is a hydroxyl or ether derivative). Reduction of ketoazide 136 to an alcohol and protection of the alcohol provides protected azide 137, which is then reduced to amine 138. Amine 138 then reacts with acid 102 to form an amide, which then cyclizes to provide an imine (i.e., a compound of Formula (II)), which is then reduced to provide tetrahydroisoquinoline 139 of Formula (I). Deprotection can readily provide the alcohol. Dihydroisoquinolines (i.e., compounds of Formula (III)) can be prepared by dehydration of the alcohol. Alternatively, amino derivatives can be prepared from alcohols by oxidation and reductive amination. Ether derivatives can be prepared by protection of the free nitrogen and deprotection of the alcohol to provide 140, which is then alkylated and deprotected to provide tetrahydroisoquinoline 141 of Formula (I).

[0088] 10 illustrates the preparation of compounds of formula (I) and (II) where R8 is an alkyl group. Aldol condensation of aldehyde 100 with an alkyl nitro compound, followed by reduction of the nitro group, affords amine 142. Amine 142 reacts with acid 102 to form an amide, which then cyclizes to provide an imine (i.e., a compound of formula (II)), which is then reduced to afford tetrahydroisoquinoline 143 of formula (I).

[0089] 11 illustrates the preparation of compounds of formula (I) and (II) where R8 is an ester. Conversion of aldehyde 100 to bromide 144 is accomplished by conventional means. The bromide is converted to a protected amino acid 145 by standard procedures, which, after deprotection of the amino group, reacts with acid 102 to form an amide, which then cyclizes to provide the imine (i.e., a compound of formula (II)), which is then reduced to afford tetrahydroisoquinoline 146 of formula (I). Those skilled in the art will appreciate that the ester group can be converted to a wide variety of functionalized derivatives that fall within the scope of compounds of formula (I).

[0090] Figure 12 illustrates the preparation of compounds of formula (I) where R is a benzyl derivative. Aryl bromide 116 is converted to aldehyde 147 by Suzuki coupling, alcohol deprotection, and oxidation. Condensation with amine 148 and deprotection affords tetrahydroisoquinoline 149 of formula (I).

[0091] Figure 13 illustrates the preparation of compounds of formula (I) where R is an amine derivative. Alkyl bromide 150 is converted to aldehyde 151 by conventional procedures. Condensation with amine 107 and deprotection of 152 provides tetrahydroisoquinoline 153 of formula (I).

[0092] Figure 14 illustrates the preparation of compounds of formula (I) where R3 is an amine derivative. Condensation of amine 239 with unsaturated aldehyde 242 provided key intermediate 154. Unsaturated imine 154 is converted to sulfonamide 155, sulfamide 156, urea 157, or carbamate 158 by treatment with the appropriate chloro derivative.

[0093] Although functionalization of the tetrahydroisoquinoline nitrogen has not previously been described, many such procedures are conventional and well known to those skilled in the art.

[0094] Compositions and Methods of Administration The compositions provided herein contain a therapeutically effective amount of one or more compounds provided herein and a vehicle that is useful for preventing, treating, or ameliorating one or more symptoms of the diseases or disorders described herein. Vehicles suitable for administering the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the compounds can be formulated as the sole active ingredient in the composition or can be combined with other active ingredients.

[0095] The composition contains one or more compounds provided herein. In some embodiments, the compound is formulated into a suitable preparation, such as a solution, suspension, tablet, dispersible tablet, pill, capsule, powder, sustained-release preparation or elixir for oral administration, or into a sterile solution or suspension for parenteral administration, topical administration, transdermal administration, and oral inhalation by nebulizer, pressurized metered-dose inhaler and dry powder inhaler. In some embodiments, the compound is formulated into a composition using techniques and procedures well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0096] In the composition, an effective concentration of one or more compounds or their derivatives is mixed with a suitable vehicle. The compound may be derivatized as the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate, or prodrug before formulation, as described above. The concentration of the compound in the composition is effective for delivery of an amount that, upon administration, will treat, treat one or more symptoms of the disease or disorder described herein, prevent one or more symptoms, or improve one or more symptoms. In some embodiments, the composition is formulated for single-dose administration. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at an effective concentration such that the disease being treated is alleviated, prevented, or one or more symptoms are improved.

[0097] The active compound is contained in the vehicle in an amount sufficient to exert a therapeutically useful effect without causing undesirable side effects to the treated patient.The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then extrapolated to human dosages.The human dosage is then typically fine-tuned in clinical trials and increased depending on the response.

[0098] The concentration of active compound in the composition will depend on absorption, inactivation, and excretion rates of the active compound, the physicochemical properties of the compound, the dosing schedule, and the amount administered, as well as other factors known to those skilled in the art. For example, the amount delivered will be sufficient to ameliorate one or more of the symptoms of a disease or disorder as described herein.

[0099] If a compound exhibits insufficient solubility, methods for solubilizing the compound can be used, such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles, or emulsions or tertiary templating. Such methods are known to those skilled in the art and include, but are not limited to, the use of cosolvents such as dimethyl sulfoxide (DMSO), surfactants or surface modifiers such as TWEEN®, complexing agents such as cyclodextrins, and dissolution by enhanced ionization (i.e., dissolution in aqueous sodium bicarbonate). Derivatives of the compound, such as prodrugs of the compound, can also be used to formulate effective compositions.

[0100] Upon mixing or adding the compounds, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends upon numerous factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder, or condition being treated and may be empirically determined.

[0101] The compositions are provided for administration to humans and animals in appropriate dosage forms, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / bioerodible strips, tablets or capsules, powders, granules, lozenges, lotions, ointments, suppositories, fast melts, transdermal patches or other transdermal application devices / preparations, sterile parenteral solutions or suspensions, and oral solutions or suspensions, as well as oil-water emulsions containing an appropriate amount of the compounds and their derivatives. The therapeutically active compounds and their derivatives are, in some embodiments, formulated and administered in unit dosage forms or multi-dosage forms. As used herein, unit dosage form refers to physically discrete units suitable for human and animal subjects, individually packaged as known in the art. Each unit dosage contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect in association with the required vehicle. Examples of unit dosage forms include ampoules and syringes and individually packaged tablets or capsules. A unit-dose form can be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit-dose forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple-dose form is a multiple of unit doses that are not segregated in packaging.

[0102] Liquid compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active compound as defined above and optional auxiliary agents in a vehicle such as, for example, water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a solution or suspension, colloidal dispersion, emulsion, or liposomal preparation. If necessary, the composition to be administered may also contain small amounts of nontoxic auxiliary substances, such as wetting agents, emulsifiers, solubilizing agents, pH buffering agents, and the like, for example, acetate salts, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.

[0103] Actual methods for preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mach Publishing Company, Easton, Pa., 15 th Edition, 1975 or more recent editions thereof.

[0104] Dosage forms or compositions may be prepared containing active ingredient in the range of 0.005% to 100%, with the remainder consisting of a vehicle or carrier. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001% to 100%, in one embodiment 0.1 to 95%, and in another embodiment 0.4 to 10% active ingredient.

[0105] In certain embodiments, the composition is a lactose-free composition containing excipients known in the art, e.g., listed in US Pharmacopeia (USP) 25-NF20 (2002). Generally, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in compatible amounts. A particular lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0106] Because water can facilitate the decomposition of some compounds, anhydrous compositions and dosage forms containing active ingredients are also provided.For example, the addition of water (e.g., 5%) is widely accepted as a means of simulating long-term storage to determine properties such as the shelf life or stability of formulations over time.See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d.Ed., Marcel Dekker, NY, NY, 1995, pp.379-80.In fact, water and heat accelerate the decomposition of some compounds.Therefore, the effect of water on formulations can be very important, since moisture and / or humidity are commonly encountered during the production, handling, packaging, storage, shipping, and use of formulations.

[0107] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0108] Anhydrous compositions should be prepared and stored so that their anhydrous nature is maintained.Therefore, anhydrous compositions are generally packaged using materials known to prevent exposure to water, so that they can be included in suitable prescribed kits.Suitable packaging examples include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0109] Oral dosage forms are either solid, gel, or liquid. Solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets, which may be enteric-coated, sugar-coated, or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form in combination with other ingredients known to those skilled in the art.

[0110] In certain embodiments, the formulation is in a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, troches, etc. may contain one or more of the following ingredients, or compounds of a similar nature: binders; lubricants; diluents; glidants; disintegrants; colorants; sweeteners; flavorings; wetting agents; enteric coatings; film coatings; and modified release agents. Examples of binders include amorphous cellulose, methylparaben, polyalkylene oxides, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, molasses, polyvinylpyrrolidone, povidone, crospovidone, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol, and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, approved, certified, water-soluble FD and C dyes, mixtures thereof, and water-insoluble FD and C dyes suspended on alumina hydrate, as well as advanced coloring or non-counterfeit color / opalescent additives known to those skilled in the art. Sweetening agents include sucrose, lactose, mannitol, and artificial sweeteners, such as saccharin, as well as any number of spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that create a pleasant sensation or mask unpleasant tastes, such as, but not limited to, peppermint and methyl salicylate. Humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalate.Film coatings include hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Modified release agents include polymers such as the Eudragit® series and cellulose esters.

[0111] The compound, or a derivative thereof, can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated with an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an antacid or other such ingredient.

[0112] When the dosage unit form is a capsule, it can contain a liquid carrier such as fatty oil in addition to the above-mentioned materials.In addition, the dosage unit form can contain various other materials that modify the physical form of the dosage unit, such as sugar and other enteric coatings.The compound can also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc.Syrups can contain sucrose as a sweetener and certain preservatives, dyes and colorings, and flavorings in addition to the active compounds.

[0113] The active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound as described herein or a derivative thereof. Higher concentrations, up to about 98% by weight of the active ingredient, can be included.

[0114] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with conventional enteric digestible coatings such as phenyl salicylate, waxes, and cellulose acetate phthalate.

[0115] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

[0116] Elixirs are clear, colorless, sweetened, hydroalcoholic preparations. Vehicles used in elixirs include solvents; syrups are concentrated aqueous solutions of sugars, such as sucrose, and may contain preservatives. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. The carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules, to be reconstituted into liquid oral dosage forms, include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules, to be reconstituted into liquid oral dosage forms, include organic acids and carbon dioxide sources. Coloring and flavoring agents are used in all of the above dosage forms.

[0117] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and acacia. Sweetening agents include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include approved, certified, water-soluble FD and C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from fruits and other plants, and synthetic blends of compounds producing a pleasant taste sensation.

[0118] For solid dosage forms, the solution or suspension, for example, in propylene carbonate, vegetable oils, or triglycerides, is in some embodiments encapsulated in a gelatin capsule. Such solutions, and their preparation and encapsulation, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. For liquid dosage forms, the solution, for example, in polyethylene glycol, can be diluted with a sufficient quantity of a liquid vehicle, for example, water, to be easily measured for administration.

[0119] Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include those shown in Reissue U.S. Patent No. RE28,819 and U.S. Patent No. 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein and a dialkylated mono- or polyalkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0120] Other formulations include, but are not limited to, aqueous alcoholic solutions containing acetals. The alcohols used in these formulations are any water-miscible solvents containing one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0121] Parenteral administration, characterized by either subcutaneous, intramuscular, or intravenous injection, is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Injectables, solutions, and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol, or ethanol. In addition, if necessary, the administered composition may also contain small amounts of nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0122] Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Pat. No. 3,710,795), is also contemplated herein. Briefly, the compounds provided herein are administered through a bolus of ... The solid internal matrix is ​​dispersed in a matrix of epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate. The compound diffuses through the outer polymer membrane in a release rate-controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on its specific properties, the activity of the compound, and the needs of the patient.

[0123] Parenteral administration of the composition includes intravenous administration, subcutaneous administration, and intramuscular administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as subcutaneous tablets, sterile suspensions ready for injection, sterile dry insoluble products and sterile emulsions ready to be combined with a vehicle immediately before use, freeze-dried powders ready to be combined with a solvent immediately before use, etc. The solution may be either aqueous or non-aqueous.

[0124] If administered intravenously, suitable carriers include saline or phosphate buffered saline (PBS), as well as solutions containing thickening agents and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[0125] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antibacterial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other substances.

[0126] Examples of aqueous vehicles include sodium chloride injection, Ringer's solution, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antibacterial agents in bacteriostatic or fungistatic concentrates should be added to parenteral preparations in multidose containers, including phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphates and citrates. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween® 80). Sequestering or chelating agents of metal ions include EDTA. Carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0127] The concentration of the compound is adjusted so that injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, body surface area, and physical condition of the patient or animal, as is known in the art.

[0128] Unit dose parenteral preparations are packaged in an ampoule, vial or syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[0129] Illustratively, intravenous or intraarterial injection of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution containing the active material injected as necessary to produce the desired pharmacological effect.

[0130] Injectables are designed for local and systemic administration. In some embodiments, therapeutically effective dosages are formulated to contain a concentration of at least about 0.01% w / w, up to about 90% w / w or more, and in certain embodiments, greater than 0.1% w / w, of the active compound in the tissue to be treated.

[0131] The compound may be suspended in micronized or other suitable form, or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture will depend on a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the disease and can be empirically determined.

[0132] The active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; These include, but are not limited to, those described in US Pat. Nos. 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634. Such dosage forms can be used to provide a sustained or controlled release of one or more active ingredients using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide a desired release profile at various rates. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0133] All controlled-release products share a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of optimally designed controlled-release formulations in medical treatment is characterized by the minimum amount of drug substance used to cure or control a disease in the minimum amount of time. Advantages of controlled-release formulations include extended drug activity, reduced dosing frequency, and increased patient compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other properties, such as blood levels of the drug, and therefore can affect the occurrence of side effects (adverse effects).

[0134] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and then gradually and continuously release another amount of drug to maintain this level of the desired therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of the active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0135] In certain embodiments, the agent may be administered using intravenous injection, an implanted osmotic pump, a skin patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials may be used. In other embodiments, the controlled release system may be placed near the therapeutic target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-138 (1984)). In some embodiments, the controlled release device is introduced into the subject near the site of inappropriate immune activation or tumor. Other controlled-release systems are discussed in the review by Langer (Science 249:1527-1533 (1990)).The active ingredient is insoluble in body fluids and is enclosed within an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride and vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber. The solid internal matrix may be dispersed in a matrix of epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.The active ingredient then diffuses through the outer polymer membrane in a release rate-controlling step.The percentage of the active compound contained in such parenteral compositions is highly dependent on its specific properties and the needs of the patient.

[0136] Also of interest herein are lyophilized powders that can be reconstituted for administration as solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0137] Sterile, lyophilized powders are prepared by dissolving a compound provided herein, or a derivative thereof, in a suitable solvent. The solvent may contain excipients to improve stability or other pharmacological components of the powder or a reconstituted solution prepared from the powder. Excipients that can be used include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the excipient is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable agents. The solvent may contain a buffer, such as citrate, sodium or potassium phosphate, or other such buffers at about neutral pH known to those of skill in the art. Subsequent sterile filtration of the solution, followed by lyophilization under standard conditions known to those of skill in the art, provides the desired formulation. In some embodiments, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.

[0138] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount depends on the compound selected. Such amounts can be determined empirically.

[0139] Topical mixtures are prepared as described for local and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and may be a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, douche, spray, suppository, bandage, skin patch, or any other formulation suitable for topical administration.

[0140] The compounds or their derivatives can be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for the delivery of steroids useful in the treatment of inflammatory conditions, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for nebulizers, alone or in combination with an inert carrier such as lactose, or as ultrafine powders for insufflation. In such cases, the particles of the formulation will have a mass median geometric diameter of less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0141] Oral inhalation formulations of the compound or derivative suitable for inhalation include metered dose inhalers, dry powder inhalers, and liquid formulations for administration from a nebulizer or metered dose liquid dispensing device. For both metered dose inhalers and dry powder inhalers, a crystalline form of the compound or derivative is the preferred physical form of the drug to provide longer product stability.

[0142] In addition to particle size reduction methods known to those skilled in the art, crystalline particles of a compound or derivative can be produced using supercritical fluid processing, which offers a significant advantage in the preparation of such particles for inhalation delivery by producing inhalable particles of a desired size in a single step (e.g., WO 2005 / 025506). Controlled particle size for the crystallites can be selected to ensure that a significant proportion of the compound or derivative is deposited in the lungs. In some embodiments, these particles have a mass median aerodynamic diameter of about 0.1 to about 10 microns, in other embodiments, about 1 to about 5 microns, and in yet other embodiments, about 1.2 to about 3 microns.

[0143] The inert and non-flammable HFA propellants are selected from HFA 134a (1,1,1,2-tetrafluoroethane) and HFA 227e (1,1,1,2,3,3,3-heptafluoropropane), provided either alone or in ratios to match the density of the crystalline particles of the compound or derivative. The ratios are also selected to ensure that the product suspension avoids harmful settling or creaming (which can precipitate irreversible agglomerates) and instead promote a loosely flocculated system that is easily dispersed when shaken. A loosely flocculated system is well believed to provide optimal stability for pMDI canisters. As a result of the formulation's properties, the formulation contained no ethanol and no surfactants / stabilizers.

[0144] The compounds can be formulated for topical or local application, such as topical application to the skin and mucous membranes, including the eyes, in the form of gels, creams, and lotions, as well as for application to the eyes or for intracisternal or intrathecal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucous membranes, or for inhalation therapy. Nasal solutions of the active compounds, alone or in combination with other excipients, can also be administered.

[0145] For nasal administration, the formulation may contain the esterified phosphonate compound dissolved or suspended in a liquid carrier, especially an aqueous carrier for aerosol application, which may contain a solubilizing or suspending agent such as propylene glycol, a surfactant, an absorption enhancer such as lecithin or cyclodextrin, or a preservative.

[0146] Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions, pH about 5 to 7.4, with appropriate salts.

[0147] Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein.

[0148] Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art.For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010,715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957.

[0149] For example, dosage forms for rectal administration include rectal suppositories, capsules, and tablets for systemic effects. Rectal suppositories are used herein to mean solid objects for insertion into the rectum that melt or soften at body temperature and release one or more pharmacologically or therapeutically active ingredients. Materials used in rectal suppositories are base materials or vehicles and agents for raising the melting point. Examples of base materials include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), and mono-, di-, and triglycerides of fatty acids. Combinations of various base materials can be used. Agents for raising the melting point of suppositories include spermaceti and wax. Rectal suppositories can be prepared either by compression or molding. In one embodiment, the weight of a rectal suppository is approximately 2 to 3 grams. Tablets and capsules for rectal administration are manufactured using the same materials and by the same methods as formulations for oral administration.

[0150] The compounds provided herein, or their derivatives, can also be formulated to target specific tissues, receptors, or other sites in the body of the subject being treated. Many such targeting methods are well known to those skilled in the art. All such targeting methods are contemplated for use in the present compositions. Non-limiting examples of targeting methods are described, for example, in U.S. Patent Nos. 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060, See US Pat. Nos. 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[0151] In some embodiments, liposome suspensions, including tissue-targeted liposomes such as tumor-targeted liposomes, may also be suitable as carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Pat. No. 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) can be formed by drying down phosphatidylcholine and phosphatidylserine (7:3 molar ratio) inside a flask. A solution of a compound provided herein in phosphate-buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[0152] The compound or derivative may be packaged as an article of manufacture containing packaging material, a compound or derivative provided herein that is effective for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder described above, within the packaging material, and a label indicating that the compound or composition or derivative thereof is used for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder described above.

[0153] The products provided herein contain packaging materials. Packaging materials for use in packaging products are well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the selected formulation and intended mode of administration and treatment. Various formulations of the compounds and compositions provided herein are contemplated as various treatments for any of the diseases or disorders described herein.

[0154] Dosage For use in treating or preventing infectious diseases, the compounds described herein, or pharmaceutical compositions thereof, are administered or applied in a therapeutically effective amount. In treating humans, a physician will determine the dosing regimen that is most appropriate for prophylactic or therapeutic treatment and in light of the age, weight, stage of the disease, and other factors specific to the subject being treated. The amount of active ingredient in the formulations provided herein that is effective in preventing or treating infectious diseases will vary depending on the nature and severity of the disease or disorder, as well as the route by which the active ingredient is administered. The frequency and dosage will also vary in light of factors specific to each subject, depending on the specific therapy (e.g., therapeutic or prophylactic agent) administered, the severity of the infection, the route of administration, and the subject's age, weight, response, and past medical history.

[0155] Exemplary dosages of the formulations include milligram or microgram amounts of active compound per kilogram of subject (e.g., from about 1 microgram per kilogram to 50 milligrams per kilogram, from about 10 micrograms per kilogram to 30 milligrams per kilogram, from about 100 micrograms per kilogram to 10 milligrams per kilogram, or from about 100 micrograms per kilogram to 5 milligrams per kilogram).

[0156] In some embodiments, a therapeutically effective dosage should produce a serum concentration of the active ingredient of about 0.001 ng / ml to about 50-200 μg / ml. The composition, in other embodiments, should provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg, in some embodiments, from about 10 mg to about 500 mg, of the active ingredient or combination of essential ingredients per dosage unit form.

[0157] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the exact dosage and duration of treatment are a function of the disease being treated and can be empirically determined using known testing protocols, or by extrapolation from in vivo or in vitro test data or subsequent clinical trials. It should be noted that concentrations and dosage values ​​may also vary with the severity of the disease to be alleviated. It should be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or monitoring the administration of the composition, and that the concentration ranges set forth herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions.

[0158] It may be necessary in some cases to use dosages of the active ingredients outside the ranges disclosed herein, as will be apparent to those skilled in the art. It is further noted that the clinical or treating physician will know how and when to interrupt, adjust, or terminate treatment in conjunction with the subject's response.

[0159] For systemic administration, the therapeutically effective dose can be estimated initially from in vitro assays, e.g., the IC as determined in cell culture. 50 (i.e., the concentration of test compound that causes death in 50% of the cell cultures), or IC as determined in cell culture. 100 A dose can be formulated in animal models to achieve a circulating concentration range that includes the compound (i.e., the concentration of the compound that is lethal in 100% of the cell cultures). Such information can be used to more accurately determine useful doses in humans.

[0160] Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques that are well known in the art. Those skilled in the art can readily optimize human administration based on animal data.

[0161] Instead, the initial dosage is determined based on the IC 50 , MIC and / or I 100 can be determined from the administered dosage of a known agent by comparing it with that of a known agent and adjusting the initial dosage accordingly. Optimal dosages can be obtained from these initial values ​​by routine optimization.

[0162] In cases of local administration or selective uptake, the effective local concentration of compound used may not be related to plasma concentration. One skilled in the art will be able to optimize therapeutically effective local dosages without undue experimentation.

[0163] Ideally, a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing substantial toxicity. Compound toxicity can be assessed using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., LD 50 (the dose that causes death in 50% of the population) or LD 100 The therapeutic index can be determined by measuring the lethal dose (the dose that is lethal in 100% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds that exhibit a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a non-toxic dosage range for use in subjects. The dosage of the compounds described herein preferably lies within a range of blood concentrations that includes the effective dose with little or no toxicity. Dosage can vary within this range depending on the dosage form employed and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al., 1975, In: The Pharmacological Basis of Therapeutics, Ch. 1, p. 1).

[0164] Treatment may be repeated intermittently. In certain embodiments, administration of the same formulation provided herein may be repeated, and administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0165] Methods of Use of the Compounds and Compositions Described herein are methods of using the disclosed compounds and pharmaceutical compositions to treat, prevent, or ameliorate symptoms of a medical disorder, such as amyotrophic lateral sclerosis or Alzheimer's disease, in a patient. Also described herein are methods of using the disclosed compounds and pharmaceutical compositions as antiviral and antibacterial agents. In some embodiments, the disclosed compounds and pharmaceutical compositions are used to treat a patient with HIV. In other embodiments, the disclosed compounds and pharmaceutical compositions are used to treat a patient with a Staphylococcus A infection. In practicing the method, a therapeutically effective amount of a compound or composition, as described herein, above, is administered to a patient with a disease or condition.

[0166] Combination therapy The compounds and compositions disclosed herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination with or sequentially with another therapeutic agent. Such other therapeutic agents include those known for treating, preventing, or ameliorating one or more symptoms associated with amyotrophic lateral sclerosis or Alzheimer's disease. Other therapeutic agents include those known for treating, preventing, or ameliorating one or more symptoms of viral or bacterial infections, particularly HIV or Staphylococcus A infections.

[0167] It should be understood that any suitable combination of the compounds and compositions provided herein with the therapeutic agents described above and, optionally, one or more additional pharmacologically active agents is contemplated within the scope of the present disclosure. In some embodiments, the compounds and compositions provided herein are administered before or after the one or more additional active ingredients.

[0168] Finally, it should be pointed out that there are alternative ways of implementing the invention. Thus, the present embodiments should be considered as illustrative and not restrictive, and the invention should not be limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents.

[0169] All publications and patents cited herein are incorporated by reference in their entirety.

[0170] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0171] General procedure for preparing α,β-unsaturated carboxylic acid: (E)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (200) [ka] 6-Methyl-1,3-benzodioxole-5-carbaldehyde (2 g, 12.2 mmol), malonic acid (5 g, 48.8 mmol), pyridine (15 mL), and piperidine (0.104 g, 0.120 mL, 1.22 mmol) were heated at 80-85 °C for 1 h and then at reflux (110-115 °C) for 3 h. The reaction mixture was poured into water and acidified with concentrated HCl. The solution was filtered, and the solid was washed with cold water (2x). The residue was dissolved in aqueous NaOH and then acidified using aqueous HCl. The solid was filtered and then washed with cold water. The product, (E)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (200), was used without further purification. MS (m / z): 193 [M+H].

[0172] Scheme 1 illustrates the preparation of compound 2. [ka] Scheme 1

[0173] 3-Benzyloxy-2-chloro-4-methoxy-benzaldehyde (203) [ka] A mixture of 2-chloro-3-hydroxy-4-methoxybenzaldehyde (201) (1 g, 5.4 mmol), benzyl bromide (202) (1 g, 6 mmol), and anhydrous KCO (1.5 g, 10.8 mmol) in acetonitrile (100 mL) was stirred at 40 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness and dissolved in 100 mL of CHCl. ​​The organic layer was washed with brine (2 × 50 mL) and HO (2 × 50 mL), dried over anhydrous NaSO, and evaporated to give 3-benzyloxy-2-chloro-4-methoxy-benzaldehyde (203) as an off-white solid (1.5 g, 99%). MS (m / z): 277 [M + H].

[0174] 2-Benzyloxy-3-chloro-1-methoxy-4-[(E)-2-nitrovinyl]benzene (204) [ka] A mixture of 3-benzyloxy-2-chloro-4-methoxy-benzaldehyde (203) (1.5 g, 5.4 mmol), nitromethane (3 g, 2.7 mL, 50 mmol), and NHOAc (1 g, 13 mmol) in AcOH (11 mL) was refluxed for 4 h. After cooling, the mixture was diluted with HO (100 mL) and extracted with CHCl (3 × 30 mL). The organic solution was washed with brine (2 × 50 mL) and HO (2 × 30 mL), dried over anhydrous NaSO, and evaporated to dryness to give the corresponding 2-benzyloxy-3-chloro-1-methoxy-4-[(E)-2-nitrovinyl]benzene (204) (1 g, 81%). MS (m / z): 320 [M + H].

[0175] 2-(3-benzyloxy-2-chloro-4-methoxy-4-phenyl)ethanamine (205) [ka] To a solution of 1M LiBH / THF (3.7 mL, 3.7 mmol) at room temperature under an argon atmosphere, MeSiCl (906 μl, 7.1 mmol) was added dropwise. After the addition was complete, a solution of 2-benzyloxy-3-chloro-1-methoxy-4-[(E)-2-nitrovinyl]benzene (204) (600 g, 1.8 mmol) in 3 mL of anhydrous THF was added dropwise. After the solution was stirred for 24 h, methanol (3 mL) was added, and the reaction mixture was evaporated to dryness. The residue was treated with 20% KOH (10 mL) and then extracted three times with dichloromethane (10 mL). The combined organic extracts were dried over anhydrous NaSO and evaporated to dryness to give the desired 2-(3-benzyloxy-2-chloro-4-methoxy-4-phenyl)ethanamine (205) (300 mg) as a crude oil, which was used without further purification. MS(m / z):292[M + H].

[0176] (E)-N-[2-(3-benzyloxy-2-chloro-4-methoxy-phenyl)ethyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (206) [ka] To a stirred solution of (E)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (200) (140 mg, 0.68 mmol) and 2-(3-benzyloxy-2-chloro-4-methoxy-4-phenyl)ethanamine (205) (200 mg, 0.68 mmol) in DMF (2 mL) was added HATU (310 g, 0.82 mmol) followed by diisopropylethylamine (351 mg, 0.473 mL, 15.0 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (50 mL), washed with 10% citric acid, saturated aqueous NaHCO3, dried (Na2SO4), filtered, and purified by flash chromatography (ethyl acetate / hexanes) to give compound 206. Yield 114 mg (35% overall yield from nitrostyrene). MS (m / z): 480 [M + H].

[0177] Example 1: 6-benzyloxy-5-chloro-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (2) [ka] A suspension of (E)-N-[2-(3-benzyloxy-2-chloro-4-methoxy-phenyl)ethyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (206) (114 mg, 0.24 mmol) in dry acetonitrile (10 mL) was stirred and heated to reflux. Phosphorus oxychloride (400 mg, 0.24 mL, 2.6 mmol) was then added dropwise. Heating at reflux was continued for another 1 h. The solution was completely evaporated to dryness under high vacuum to remove excess POCl. The residue was dissolved in chloroform (10 mL) and shaken with 2 M KOH (10 mL) and ether (20 mL). The separated upper layer was washed with water (2 × 10 mL) and evaporated in vacuo to give an oil, which was dissolved in ethanol (8 mL). Sodium borohydride (9.8 mg, 0.26 mmol) was then added, and the mixture was stirred at room temperature for 30 minutes. Excess reagent was destroyed by dropwise addition of 2 M HCl, and the reaction mixture was basified with 2 M NaOH. Most of the ethanol was removed in vacuo. The residue was partitioned between water (10 mL) and chloroform (10 mL). The organic layer was washed with water (2 × 10 mL). The solvent was removed in vacuo, and the residue was purified by column chromatography (dichloromethane / methanol) to give 6-benzyloxy-5-chloro-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (2) (10 mg, 10%). MS (m / z): 464 [M+H].

[0178] Scheme 2 illustrates the synthesis of compounds 6 and 10. [ka] Scheme 2

[0179] 3-Benzyloxy-4,5-dimethoxybenzaldehyde (208) [ka] A mixture of 3-hydroxy-4,5-dimethoxybenzaldehyde (207) (1 g, 5.5 mmol), benzyl bromide (202) (1 g, 6 mmol), and anhydrous KCO (1.5 g, 10.8 mmol) in acetonitrile (100 mL) was stirred at 40 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness and dissolved in 100 mL of CHCl. ​​The organic layer was washed with brine (2 × 50 mL) and HO (2 × 50 mL), dried over anhydrous NaSO, and evaporated to give 3-benzyloxy-4,5-dimethoxybenzaldehyde (208) as an off-white solid (1.2 g, 80%). MS (m / z): 273 [M + H].

[0180] 1-Benzyloxy-2,3-dimethoxy-5-[(E)-2-nitrovinyl]benzene (209) [ka] A mixture of 3-benzyloxy-4,5-dimethoxybenzaldehyde (208) (1.2 g, 4.4 mmol), nitromethane (3 g, 2.7 mL, 50 mmol), and NHOAc (800 mg, 10 mmol) in AcOH (11 mL) was refluxed for 4 h. After cooling, the mixture was diluted with HO (100 mL) and extracted with CHCl (3 × 30 mL). The organic solution was washed with brine (2 × 50 mL) and water (2 × 30 mL), dried over anhydrous NaSO, and evaporated to dryness to give the corresponding 1-benzyloxy-2,3-dimethoxy-5-[(E)-2-nitrovinyl]benzene (209) (1.1 g, 81%). MS (m / z): 316 [M + H].

[0181] 2-(3-benzyloxy-4,5-dimethoxy-phenyl)ethanamine (210) [ka] To a solution of 1M LiBH4 / THF (5.8 mL, 5.8 mmol) at room temperature and under an argon atmosphere, Me3SiCl (1.4 mL, 11 mmol) was added dropwise. After the addition was complete, a solution of 1-benzyloxy-2,3-dimethoxy-5-[(E)-2-nitrovinyl]benzene (209) (900 g, 2.8 mmol) in 4 mL of anhydrous THF was added dropwise. After the solution was stirred for 24 h, methanol (5 mL) was added and the reaction mixture was evaporated to dryness. The residue was treated with 20% KOH (10 mL) and then extracted three times with dichloromethane (10 mL). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated to dryness to give (3-benzyloxy-2-chloro-4-methoxy-phenyl)ethanamine (210) (200 mg) as a crude oil, which was used without further purification. MS (m / z): 288 [M + H].

[0182] (E)-N-[2-(3-benzoyloxy-4,5-dimethoxy-phenyl)ethyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (211) [ka] To a stirred solution of (E)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (143 mg, 0.68 mmol) (200) and 2-(3-benzyloxy-4,5-dimethoxy-phenyl)ethanamine (210) (200 mg, 0.68 mmol) in DMF (2 mL) was added HATU (310 g, 0.82 mmol) followed by diisopropylethylamine (351 mg, 0.473 mL, 15.0 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (50 mL), washed with 10% citric acid, saturated aqueous NaHCO3, dried (Na2SO4), filtered, and purified by flash chromatography (ethyl acetate / hexanes) to give compound 211. Yield (30% overall from nitrostyrene). MS (m / z): 476 [M + H].

[0183] Example 2: 6-benzyloxy-7,8-dimethoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (10) and 6-benzyloxy-5,7-dimethoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)]vinyl-1,2,3,4-tetrahydroisoquinoline (6) [ka] A suspension of (E)-N-[2-(3-benzyloxy-4,5-dimethoxy-phenyl)ethyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (211) (90 mg, 0.189 mmol) in dry acetonitrile (10 mL) was stirred and heated to reflux. Phosphorus oxychloride (400 mg, 0.24 mL, 2.6 mmol) was then added dropwise, and heating at reflux was continued for an additional 1 h. The solution was completely evaporated to dryness under high vacuum to remove excess POCl. The residue was dissolved in chloroform (10 mL) and shaken with 2 M KOH (10 mL) and ether (20 mL). The separated upper layer was washed with water (2 × 10 mL) and evaporated in vacuo to give an oil, which was dissolved in ethanol (8 mL). Sodium borohydride (4 mg, 0.11 mmol) was then added and the mixture was stirred at room temperature for 30 minutes. Excess reagent was destroyed by dropwise addition of 2 M HCl and the reaction mixture was basified with 2 M NaOH. Most of the ethanol was removed in vacuo and the residue was partitioned between water (10 mL) and chloroform (10 mL). The organic layer was washed with water (2 x 10 mL) and the solvent was removed in vacuo. The residue was purified by RP chromatography (acetonitrile 0.1% TFA / water 0.1% TFA) to give 10 mg (11%) of 6-benzyloxy-7,8-dimethoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (10) and 3 mg (3%) of 6-benzyloxy-5,7-dimethoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (6). MS (m / z): 460 [M + H]. The structure was confirmed by preparing an authentic sample of 6-benzyloxy-5,7-dimethoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (6) using the amine 2-(3-benzyloxy-2,4-dimethoxy-phenyl)ethanamine according to the same procedure outlined above.

[0184] Scheme 3 illustrates the preparation of compound 12. [ka] Scheme 4

[0185] 3-Benzyloxy-4-methoxy-acetophenone (214) [ka] A mixture of 3-hydroxy-4-methoxy-acetophenone (213) (16.6 g, 100 mmol), benzyl chloride (214) (13.8 mL, 120 mmol), and anhydrous K2CO3 (20.7 g, 150 mmol) in DMF (100 mL) was heated at reflux for 5 h. The reaction mixture was concentrated to dryness, and the residue was dissolved in EtOAc (100 mL) and then washed with 5% aqueous NaOH (3 × 30 mL). The organic layer was washed with brine (2 × 10 mL) and HO (2 × 30 mL), dried (Na2SO4), and evaporated to a residue that was purified by flash chromatography to provide (214) (22.9 g, 90%). MS (m / z): 257 [M + H].

[0186] Ethyl 3-(3-benzyloxy-4-methoxyphenyl)-2-butenoate (215) [ka] NaH (60 wt% in mineral oil, 1.95 g, 48.5 mmol) was suspended in THF (100 mL) and cooled to 0 °C. Triethylphosphonoacetate (9.6 mL, 48.5 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 30 min. 3-Benzyloxy-4-methoxy-acetophenone (214) (6.2 g, 24.2 mmol) was then dissolved in THF (0.1 mL / mmol) and added to the reaction mixture. The cooling bath was removed, and the mixture was stirred at 50 °C until complete conversion was detected (TLC). The reaction mixture was quenched by the slow addition of HO (2 mL / 1 mmol of ketone) and extracted with tert-butyl methyl ether (3 × 3 mL / mmol). The combined organic layers were dried (NaSO) and evaporated to give a residue that was purified by flash column chromatography to give compound 215 (6.4 g, 81%). MS(m / z): 327[M + H].

[0187] 3-(3-benzyloxy-4-methoxyphenyl)-2-butenoic acid (216) [ka] A mixture of ethyl ester 215 (6.4 g, 19.5 mmol) and alcoholic potassium hydroxide (4.0 g, 71 mmol KOH / 100 mL EtOH) was stirred at room temperature for 12 h. The solution was then concentrated to give a residue, which was purified by flash column chromatography on silica gel to give 216 (5.6 g, 96%). MS (m / z): 299 [M + H].

[0188] 3-(3-benzyloxy-4-methoxyphenyl)-1-nitro-2-butene (217) [ka] A suspension of 3-(3-benzyloxy-4-methoxyphenyl)-2-butenoic acid (216) (5.6 g, 18.8 mmol), CuBr (270 mg, 1.9 mmol), and tert-butyl nitrite (8.9 mL, 37.6 mmol) in acetonitrile (50 mL) was stirred at 80 °C for 18 h. The reaction was monitored for completion by TLC. Upon completion, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the crude product was purified by flash chromatography to give compound 217 (3.9 g, 70%). MS (m / z): 300 [M + H].

[0189] 2-Methyl-2-(3-benzyloxy-4-methoxyphenyl)-1-aminoethane (218) [ka] To a solution of 3-(3-benzyloxy-4-methoxyphenyl)-1-nitro-2-butene (217) (3.9 g, 13.2 mmol) in 40 mL of anhydrous THF under argon, a 2.0 M solution of LiAlH in THF (40 mL, 8 mmol) was slowly added, and the reaction mixture was heated at reflux for 2 h. The reaction mixture was cooled, and excess reagent was quenched by the dropwise addition of HO and 15% aqueous NaOH. The reaction mixture was extracted with CHCl (3 × 30 mL), and the combined organic layers were treated with 5% aqueous HCl. The aqueous acid layer was then basified (5% aqueous NHOH, pH 9) and extracted with CHCl. ​​The organic solution was washed with brine (2 × 30 mL) and HO (2 × 30 mL), dried (NaSO), and evaporated to give compound 218 (2.3 g, 63%). MS (m / z): 272 [M + H].

[0190] (E)-N-[2-(3-benzyloxy-4-methoxy-phenyl)propyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (219) [ka] To a stirred solution of (£)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (200) (140 mg, 0.68 mmol) and 2-(3-benzyloxy-4-methoxy-phenyl)propylamine (218) (185 mg, 0.68 mmol) in DMF (2 mL) was added HATU (310 g, 0.82 mmol) and diisopropylethylamine (351 mg, 0.473 mL, 15.0 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (50 mL), washed with 10% citric acid, saturated aqueous NaHCO3, dried (Na2SO4), filtered, and evaporated to give a residue that was purified by flash chromatography (ethyl acetate / hexanes) to provide compound 219. Yield 11.4 mg (35% overall yield from nitrostyrene). MS (m / z): 460 [M + H].

[0191] Example 3: 6-benzyloxy-7-methoxy-4-methyl-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (12) [ka] A suspension of (E)-N-[2-(3-benzyloxy-4-methoxyphenyl)propyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (219) (110 mg, 0.24 mmol) in dry acetonitrile (10 mL) was heated at reflux. Phosphorus oxychloride (400 mg, 0.24 mL, 2.6 mmol) was then added dropwise, and the reaction mixture was heated at reflux for an additional 1 h. The solvent and reagents were evaporated in vacuo, and the organic layer was washed with water (2 × 10 mL) and evaporated in vacuo to give an oil, which was then dissolved in ethanol (8 mL) and sodium borohydride (9.8 mg, 0.26 mmol) was added. The reaction mixture was stirred at room temperature for 30 min, and excess reagent was destroyed by the dropwise addition of 2 M HCl. The reaction mixture was basified with 2M NaOH, and the ethanol was removed in vacuo to give a residue that was partitioned between water (10 mL) and chloroform. The organic layer was washed with water (2 × 10 mL), dried, and evaporated to give a residue that was purified by column chromatography (dichloromethane / methanol) to give 6-benzoyloxy-7-methoxy-4-methyl-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (12) (10 mg, 10%). MS (m / z): 444 [M + H].

[0192] Scheme 4 illustrates the preparation of compound 24. [ka] Scheme 4

[0193] 3-Benzyloxy-4-methoxybenzaldehyde (221) [ka] A mixture of isovanillin (220) (10.0 g, 65.7 mmol), benzyl chloride (213) (11.3 mL, 98.6 mmol), and anhydrous K2CO3 (18.1 g, 131 mmol) in EtOH (100 mL) was refluxed for 5 h. After stirring, the reaction mixture was concentrated to dryness and redissolved in 60 mL of C2Cl2, followed by the addition of 5% aqueous NaOH (3 × 20 mL). The organic layer was washed with brine (2 × 30 mL) and H2O (2 × 30 mL), dried over anhydrous Na2SO4, and evaporated to dryness. Needle-like crystals corresponding to O-benzyloxyisovanillin (3-benzyloxy-4-methoxybenzaldehyde) (221) (13.5 g, 85%) were obtained after crystallization from MeOH / C2Cl2; mp 61–63 °C (lit. 61–64 °C). MS(m / z):243[M + H].

[0194] 3-Benzyloxy-4-methoxy-β-ethyl-β-nitrostyrene (222) [ka] 3-Benzyloxy-4-methoxybenzaldehyde (2.42 g, 10 mmol) (221) and ammonium acetate (770 mg, 10 mmol) were mixed with 1-nitropropane (9.0 mL, 100 mmol) and heated at 160 °C for 22 h. The reaction mixture was then cooled to room temperature, and excess 1-nitropropane was removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with water (10 mL), brine (10 mL), dried (MgSO), filtered, concentrated in vacuo, and recrystallized from ethanol (20 mL). The solid was dried in vacuo to give compound 222 as a yellow powder (2.0 g, 65%). MS (m / z): 314 [M + H].

[0195] 2-Amino-1-(3-benzyloxy-4-methoxyphenyl)butane (223) [ka] To a solution of 3-benzyloxy-4-methoxy-β-ethyl-β-nitrostyrene (222) (3.1 g, 10.0 mmol) in 20 mL of anhydrous THF was added a 2.0 M solution of LiAlH in THF (20 mL, 40 mmol) under argon and refluxed for 2 h. After cooling the solution, excess reagent was destroyed by the addition of HO and 15% aqueous NaOH. After partial evaporation of the filtered fraction, the aqueous solution was extracted with CHCl (3 × 30 mL), and the organic layer was treated with 5% aqueous HCl. The resulting aqueous acid layer was made basic (5% aqueous NHOH, pH 9) and extracted with CHCl. The organic solution was washed with brine (2 × 30 mL) and HO (2 × 30 mL), dried over anhydrous NaSO, and evaporated to dryness to provide 2-amino-1-(3-benzyloxy-4-methoxyphenyl)butane (223) (1.7 g, 60%). MS (m / z): 286 [M + H].

[0196] (E)-N-[2-(3-benzyloxy-4-methoxyphenyl)butyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (224) [ka] To a stirred solution of (£)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (200) (159 mg, 0.77 mmol) and 2-amino-1-(3-benzyloxy-4-methoxy-phenyl)butane (223) (220 mg, 0.77 mmol) in DMF (2 mL) was added HATU (351 mg, 0.92 mmol) followed by diisopropylethylamine (397 mg, 0.5 mL, 3.1 mmol). The reaction mixture was stirred at room temperature for 1 h. The solution was diluted with EtOAc (50 mL), washed with 10% citric acid, saturated aqueous NaHCO₃, dried (Na₂SO₄), filtered, and purified by flash chromatography (ethyl acetate / hexane) to give compound 224. Yield 90 mg (30% overall yield from nitrostyrene). MS (m / z): 474 [M + H].

[0197] Example 4: 6-benzyloxy-7-methoxy-3-ethyl-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (24) [ka] A suspension of (E)-N-[2-(3-benzyloxy-4-methoxyphenyl)butyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (224) (100 mg, 0.21 mmol) in dry acetonitrile (10 mL) was stirred and heated to reflux. Phosphorus oxychloride (223 mg, 0.14 mL, 1.5 mmol) was then added dropwise, and heating at reflux was continued for 1 h. The solution was evaporated to dryness under high vacuum to remove excess POCl. The residue was dissolved in chloroform (10 mL) and shaken with 2 M KOH (10 mL) and ether (20 mL). The separated upper layer was washed with water (2 × 10 mL) and evaporated in vacuo to give an oil that was dissolved in ethanol (8 mL). Sodium borohydride (5.6 mg, 0.15 mmol) was then added, and the mixture was stirred at room temperature for 30 min. Excess reagent was destroyed by dropwise addition of 2M HCl. The reaction mixture was then basified with 2M NaOH, and most of the ethanol was removed in vacuo. The residue was partitioned between water (10 mL) and chloroform (10 mL). The organic layer was washed with water (2 × 10 mL), and the solvent was removed in vacuo. The residue was purified by RP chromatography (acetonitrile 0.1% TFA / water 0.1% TFA) to give 10 mg (11%) of 6-benzyloxy-7-methoxy-3-ethyl-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (24). MS (m / z): 458 [M + H].

[0198] Scheme 5 illustrates the preparation of compound 59. [ka] Scheme 5

[0199] Preparation of the benzyl ether of 2,3-dihydroxy-4-methoxyacetophenone (226) [ka] A mixture of 2,3-dihydroxy-4-methoxy-acetophenone (225) (9.1 g, 50 mmol), benzyl chloride (213) (7.6 g, 60 mmol), and anhydrous KCO (10.35 g, 75 mmol) in DMF (50 mL) was refluxed for 5 h. The reaction mixture was concentrated to dryness and redissolved in 100 mL of EtOAc, followed by the addition of 5% aqueous NaOH (3 × 30 mL). The organic layer was washed with brine (2 × 30 mL) and HO (2 × 30 mL), dried over anhydrous NaSO, evaporated to dryness, and purified by flash chromatography to provide compound 226. MS (m / z): 273 + H].

[0200] Preparation of the methyl ether of the benzyl ether of 2,3-dihydroxy-4-methoxyacetophenone (227) [ka] A mixture of hydroxylacetophenone (226) (6.8 g, 25 mmol), methyl iodide (7.05 g, 50 mmol), and anhydrous K2CO3 (1.43 g, 37.5 mmol) in DMF (50 mL) was stirred at room temperature for 12 h. The reaction mixture was concentrated to dryness, redissolved in 100 mL of EtOAc, and 5% aqueous NaOH (3 × 30 mL) was added. The organic layer was washed with brine (2 × 30 mL) and HO (2 × 30 mL), dried over anhydrous Na2SO4, evaporated to dryness, and purified by flash chromatography to provide compound 227. MS (m / z): 287 (M + H].

[0201] Preparation of unsaturated ester (228) [ka] NaH (60 wt% in mineral oil, 1.95 g, 48.5 mmol) was suspended in THF (100 mL) and cooled to 0 °C. Triethylphosphonoacetate (9.6 mL, 48.5 mmol) was added dropwise, and the reaction mixture was stirred at 0 °C for 30 min. A solution of acetophenone (6.92 g, 24.2 mmol) in THF was slowly added to the reaction mixture. The cooling bath was removed, and the mixture was stirred at 50 °C until complete conversion was detected (TLC). After quenching the reaction by the addition of HO (2 mL / 1 mmol of ketone), the aqueous phase was extracted with t-butyl methyl ether (3 × 3 mL / mmol), and the combined organic layers were dried over NaSO and filtered. All volatiles were removed under reduced pressure, and the crude product was purified by flash column chromatography to give compound 228. MS (m / z): 357 (M + H].

[0202] 3-(3-benzyloxy-2,4-dimethoxyphenyl)-2-butenoic acid (229) [ka] A mixture of ethyl ester 228 (6.94 g, 19.5 mmol) and alcoholic potassium hydroxide (4.0 g, 71 mmol KOH / 100 mL EtOH) was stirred at room temperature for 12 h. The solvent was removed and the residue was purified by flash column chromatography to give acid 229. MS (m / z): 329 [M+H].

[0203] 3-(3-benzyloxy-2,4-dimethoxyphenyl)-1-nitro-2-butene (230) [ka] A mixture of 3-(3-benzyloxy-2,4-dimethoxyphenyl)-2-butenoic acid (229) (6.16 g, 18.8 mmol), CuBr (270 mg, 1.9 mmol), tert-butyl nitrite (8.9 mL, 37.6 mmol), and acetonitrile (50 mL) was stirred at 80 °C for 12–18 h until judged complete by TLC. The reaction mixture was cooled to room temperature, the solvent was evaporated, and the residue was purified by flash chromatography to provide compound 230. MS (m / z): 330 [M + H].

[0204] 2-Methyl-2-(3-benzyloxy-4-methoxyphenyl)-1-aminoethane (231) [ka] To a solution of 3-(3-benzyloxy-2,4-dimethoxyphenyl)-1-nitro-2-butene (230) (4.34 g, 13.2 mmol) in 40 mL of anhydrous THF was added a 2.0 M solution of LiAlH in THF (40 mL, 8 mmol) under argon, and the reaction mixture was heated at reflux for 2 h. The solution was then cooled, and excess reagent was destroyed by the dropwise addition of HO and 15% aqueous NaOH. After partial evaporation of the filtered fraction, the aqueous solution was extracted with CHCl (3 × 30 mL), and the organic layer was treated with 5% aqueous HCl. The resulting aqueous acid layer was made basic (5% aqueous NHOH, pH 9) and extracted with CHCl. The organic solution was washed with brine (2 × 30 mL) and HO (2 × 30 mL), dried over anhydrous NaSO, and evaporated to give 2-methyl-2-(3-benzyloxy-2,4-dimethoxyphenyl)-1-aminoethane (231). MS (m / z): 302 [M + H].

[0205] (E)-N-[2-(3-benzyloxy-2,4-dimethoxy-phenyl)propyl]-3-(6-methyl-1,3-benzodioxol-5-yl)-prop-2-enamide (232) [ka] To a stirred solution of (E)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (140 mg, 0.68 mmol) (200) and 2-(3-benzyloxy-2,4-dimethoxy-phenyl)propylamine (231) (205 mg, 0.68 mmol) in DMF (5 mL) was added HATU (310 g, 0.82 mmol) and diisopropylethylamine (351 mg, 0.473 mL, 15.0 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (50 mL), washed with 10% citric acid, saturated aqueous NaHCO3, dried (Na2SO4), and evaporated to give a residue that was purified by flash chromatography (ethyl acetate / hexanes) to give compound 232. MS (m / z): 490 [M + H].

[0206] Example 5: 6-Benzyloxy-5,7-dimethoxy-4-methyl-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (59) [ka] A suspension of (£)-N-[2-(3-benzyloxy-2,4-dimethoxy-phenyl)propyl]-3-(6-methyl-1,3-benzodioxol-5-yl)-prop-2-enamide (232) (118 mg, 0.24 mmol) in dry acetonitrile (10 mL) was stirred and heated to reflux. Phosphorus oxychloride (400 mg, 0.24 mL, 2.6 mmol) was then added dropwise, and heating at reflux was continued for an additional 1 h. The reaction mixture was then evaporated in vacuo to give a residue that was dissolved in chloroform (20 mL) and washed with 2 M KOH (10 mL) and water (2 × 10 mL). The organic layer was dried and evaporated to give an oil that was dissolved in ethanol (8 mL) and to which sodium borohydride (9.8 mg, 0.26 mmol) was slowly added. The reaction mixture was stirred at room temperature for 30 minutes, and excess reagent was destroyed by dropwise addition of 2M HCl. The reaction mixture was basified with 2M NaOH and extracted with chloroform (3 x 20 mL). The combined organic extracts were dried and evaporated to provide 6-benzyloxy-5,7-dimethoxy-4-methyl-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (59). MS (m / z): 474 [M + H].

[0207] Scheme 6 illustrates the synthesis of compound 1. [ka] Scheme 6

[0208] 3-Benzyloxy-2-fluoro-4-methoxy-benzaldehyde (234) [ka] A mixture of 2-fluoro-3-hydroxy-4-methoxybenzaldehyde (233) (1 g, 5.4 mmol, 1 equiv.), benzyl bromide (202) (1.36 g, 7.93 mmol, 1.5 equiv.), and anhydrous K2CO3 (0.9 g, 5.29 mmol) in DMF (15 mL) was stirred at 60 °C for 12 h. The reaction mixture was diluted with ethyl acetate (50 mL), then washed with water (2 × 25 mL) and brine (1 × 25 mL), dried over anhydrous Na2SO4, and evaporated to give a residue that was purified by column chromatography to 3-benzyloxy-2-fluoro-4-methoxy-benzaldehyde (234). MS (m / z): 261 [M + H].

[0209] 2-Benzyloxy-3-fluoro-1-methoxy-4-[(E)-2-nitrovinyl]benzene (235) [ka] A mixture of 3-benzyloxy-2-fluoro-4-methoxy-benzaldehyde (234) (1.4 g, 5.4 mmol), nitromethane (3 g, 2.7 mL, 50 mmol), and NHOAc (1 g, 13 mmol) in AcOH (11 mL) was refluxed for 4 h. After cooling, the mixture was diluted with HO (100 mL) and extracted with CHCl (3 × 30 mL). The combined organic extracts were washed with brine (2 × 50 mL) and HO (2 × 30 mL), dried over anhydrous NaSO, and evaporated to dryness to give the corresponding 2-benzyloxy-3-fluoro-1-methoxy-4-[(E)-2-nitrovinyl]benzene (235). MS (m / z): 304 [M + H].

[0210] 2-(3-benzyloxy-2-fluoro-4-methoxy-phenyl)ethanamine (236) [ka] To a solution of 2-benzyloxy-3-fluoro-1-methoxy-4-[(E)-2-nitrovinyl]benzene (235) (1.6 g, 5.29 mmol) in THF (20 mL) in an ice bath was added LiAlH (15.85 mL, 31.7 mmol) in THF dropwise. After the addition was complete, the reaction mixture was heated at reflux for 12 h, cooled to 0 °C, and water (1.2 mL) and 15% NaOH (1.2 mL) were added, followed by water (3 × 1.2 mL). The reaction mixture was stirred at room temperature for 30 min. Ethyl acetate (100 mL) was added, and the reaction mixture was stirred for an additional 30 min. It was filtered through a pad of Celite, dried (NaSO), and evaporated to give 2-(3-benzyloxy-2-fluoro-4-methoxy-phenyl)ethanamine (236) as a viscous solid, which was used in the next step without further purification. MS (m / z): 276 [M + H].

[0211] (E)-N-[2-(3-benzyloxy-2-fluoro-4-methoxy-phenyl)ethyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (237) [ka] To a stirred solution of (£)-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enoic acid (200) (140 mg, 0.68 mmol) and 2-(3-benzyloxy-2-fluoro-4-methoxy-phenyl)ethanamine (236) (187 mg, 0.68 mmol) in DMF (10 mL) was added HATU (312 g, 0.82 mmol) followed by diisopropylethylamine (439 mg, 3.4 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with EtOAc (50 mL), washed with 10% citric acid, saturated aqueous NaHCO3, dried (Na2SO4), filtered, and purified by flash chromatography (ethyl acetate / hexanes) to give compound 237. MS (m / z): 464 [M + H].

[0212] Example 6: 6-Benzyloxy-5-fluoro-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (1) [ka] A suspension of (E)-N-[2-(3-benzyloxy-2-fluoro-4-methoxy-phenyl)ethyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (237) (111 mg, 0.24 mmol) in dry acetonitrile (10 mL) was stirred and heated to reflux. Phosphorus oxychloride (400 mg, 0.24 mL, 2.6 mmol) was then added dropwise and heated at reflux for another 1 h. The solution was evaporated to dryness under high vacuum to remove excess POCl. The residue was dissolved in chloroform (10 mL) and shaken with 2 M KOH (10 mL) and ether (20 mL). The separated upper layer was washed with water (2 × 10 mL) and evaporated in vacuo to give an oil, which was dissolved in methanol (8 mL). Sodium borohydride (9.8 mg, 0.26 mmol) was then added. The mixture was stirred at room temperature for 2 h. The solvent was evaporated, the residue was taken up in ethyl acetate, and then saturated NaHCO3 solution was added, and the reaction mixture was stirred at room temperature for 30 min. The organic layer was dried (MgSO4) and evaporated to give a residue that was purified by column chromatography to give the desired 6-benzyloxy-5-fluoro-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (1). MS (m / z): 448 [M + H].

[0213] Scheme 7 illustrates the preparation of compound 60. [ka] Scheme 7

[0214] (E)-N-[2-(3-benzyloxy-2-fluoro-4-methoxy-phenyl)ethyl]-3-(6-methyl-1,3-benzodioxol-5-yl)prop-2-enamide (238) [ka] To a stirred solution of 4,5-dimethoxy-2-methyl-benzoic acid (237) (133 mg, 0.68 mmol) and 2-(3-benzyloxy-2-fluoro-4-methoxy-phenyl)ethanamine (236) (187 mg, 0.68 mmol) in DMF (5 mL) was added HATU (312 g, 0.82 mmol) and diisopropylethylamine (439 mg, 3.4 mmol). The reaction mixture was stirred at room temperature for 1 h. The solution was diluted with EtOAc (50 mL), washed with 10% aqueous HCl acid, saturated aqueous NaHCO, dried (NaSO), filtered, and purified by flash chromatography (ethyl acetate / hexanes) to give compound 238. MS (m / z): 454 [M + H].

[0215] Example 7: Preparation of Compound 60 [ka] A suspension of the amide (109 mg, 0.24 mmol) in dry acetonitrile (10 mL) was stirred and heated to reflux. Phosphorus oxychloride (400 mg, 0.24 mL, 2.6 mmol) was then added dropwise, and heating at reflux was continued for another 1 h. The solution was evaporated to dryness under high vacuum to remove excess POCl. The residue was dissolved in chloroform (10 mL) and shaken with 2 M KOH (10 mL) and ether (20 mL). The separated upper layer was washed with water (2 × 10 mL) and evaporated in vacuo to give an oil that was dissolved in methanol (8 mL). Sodium borohydride (9.8 mg, 0.26 mmol) was then added, and the mixture was stirred at room temperature for 2 h. The solvent was evaporated, the residue was taken up in ethyl acetate, and saturated NaHCO solution was then added, and the reaction mixture was stirred at room temperature for 30 min. The organic layer was dried (MgSO4) and evaporated to give a residue which was purified by column chromatography (dichloromethane / methanol) to give 1,2,3,4-tetrahydroisoquinoline (60). MS (m / z): 438 [M + H].

[0216] Scheme 8 illustrates the preparation of compound 36. [ka] Scheme 8

[0217] Preparation of amine 241 [ka] To a solution of the amine (1.29 g, 5.0 mmol, 1.0 equiv) in dry DMF (5 mL) was added triethylamine (606 mg, 6.0 mmol, 1.2 equiv) and 3-chloropropionitrile (68 mg, 5.5 mmol, 1.1 equiv) and the reaction mixture was stirred at room temperature. The reaction mixture was quenched by the addition of water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic layers were washed with saturated NaCl solution (1 × 30 mL), dried (MgSO4), and evaporated in vacuo to give a residue which was purified by column chromatography (DCM, MeOH) to give amine 241. MS (m / z): 311 [M+ H].

[0218] 3-[6-benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanenitrile (243) [ka] A solution of amine 241 (100 mg, 0.323 mmol, 1.0 equiv.) and aldehyde 242 (68 mg, 0.387 mmol, 1.2 equiv.) in formic acid (mL) was heated at 80 °C for 24 h. Excess formic acid was removed in vacuo to give a residue. The residue was taken up in ethyl acetate, and saturated NaHCO was then carefully added, and the mixture was stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were dried (MgSO) and evaporated in vacuo to give a residue that was purified by column chromatography (DCM, MeOH) to give 3-[6-benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanenitrile (243). MS(m / z): 483 [M+H].

[0219] Example 8: 6-Benzyloxy-2-hydroxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinoline (36) [ka] To a stirred solution of (3-[6-benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanenitrile (243) (48 mg, 0.1 mmol) under argon at −78 °C was added m-chloroperoxybenzoic acid (19 mg, 0.11 mmol) in dichloromethane (0.2 ml). After 1 h at −78 °C, the reaction was allowed to warm to room temperature and stirred there overnight. The mixture was evaporated to dryness and the residue was purified by RP chromatography (acetonitrile 0.1% TFA / water 0.1% TFA) to give 6-benzyloxy-2-hydroxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinoline. MS (m / z): 446 [M + H].

[0220] Scheme 9 illustrates the preparation of compound 62. [ka] Scheme 9

[0221] Preparation of Compound 245 [ka] A solution of amine 241 (100 mg, 0.323 mmol, 1.0 equiv.) and aldehyde 244 (58 mg, 0.387 mmol, 1.2 equiv.) in formic acid (mL) was heated at 80 °C for 24 h. Excess formic acid was removed in vacuo to give a residue. The residue was taken up in ethyl acetate, and then saturated NaHCO was carefully added, and the mixture was stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The combined organic extracts were dried (MgSO) and evaporated in vacuo to give a residue that was purified by column chromatography (DCM, MeOH) to give compound 245. MS (m / z): 457 [M + H].

[0222] Example 9: Preparation of Compound 62 [ka] To a solution of nitrile 245 (46 mg, 0.1 mmol) under argon at −78° C., m-chloroperoxybenzoic acid (19 mg, 0.11 mmol) in dichloromethane (0.2 ml) was added with stirring. After stirring at −78° C. for 1 h, the reaction was allowed to warm to room temperature and stirred overnight. The mixture was evaporated to dryness, and the residue was purified by RP chromatography (acetonitrile 0.1% TFA / water 0.1% TFA) to give compound 62. MS (m / z): 420 [M + H].

[0223] Scheme 10 illustrates the preparation of compound 63. [ka] Scheme 10

[0224] Example 10: 6-Benzyloxy-5-chloro-2-hydroxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinoline (63) [ka] Using the procedure of Grassl et al., Organic Letters (2019), 21(2), 494-497, 6-benzyloxy-5-chloro-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-1,2,3,4-tetrahydroisoquinoline (2) (46 mg, 0.1 mmol) in MeOH (0.2 mL) was treated with acrylonitrile (33 μl, 0.5 mmol) at room temperature and stirred overnight at 55° C. The mixture was evaporated to dryness to give 3-[4-chloro-6-benzyloxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanenitrile, which was then taken up in dichloromethane (0.2 mL). The solution was cooled to -78 °C, and m-chloroperoxybenzoic acid (19 mg, 0.11 mmol) in dichloromethane (0.2 mL) was slowly added under argon and with rapid stirring. After stirring at -78 °C for 1 h, the reaction was allowed to warm to room temperature and stirred overnight. The mixture was evaporated to dryness, and the residue was purified by RP chromatography (acetonitrile 0.1% TFA / water 0.1% TFA) to give 6-benzyloxy-5-chloro-2-hydroxy-7-methoxy-1-[(E)-2-(6-methyl-1,3-benzodioxol-5-yl)vinyl]-3,4-dihydro-1H-isoquinoline (63). MS (m / z): 480 [M+H].

[0225] Nematode assay C. elegans were grown on standard NGM (nematode growth medium) plates until the first day of adulthood, at which point they were collected, placed in 96-well plates, and treated with appropriate doses of compound or control. Recording of nematode locomotion began immediately using the NicroTracker ONE instrument, which provided a "Well Activity" output over time. All drug treatments were performed in biological triplicates (Patten et al., JCI Insight. 2017 Nov 16;2(22):e97152. doi:10.1172 / jci.insight.97152. PMID:29202456; PMCID:PMC572378).

[0226] Inhibition of HIV-1 replication. MT-2 diffuse infection assay Inhibition of HIV-1 viral replication was assayed in a diffuse infection using MT-2 cells and the NL4-3 RLuc reporter virus. For dose-response curves, compounds were first diluted in DMSO to 100x the starting concentration in a 96-well plate and then subjected to a series of 3-fold dilutions in DMSO for a total of 8 or 9 dilutions. When testing a single compound concentration, the compound was diluted in DMSO to 100x the desired concentration. Compounds were then diluted 50x in infection medium prepared by diluting the NL4-3 RLuc virus stock to 400 IU / 100 μl with complete RPMI. 100 μl of the 50x diluted compound was then transferred to 20,000 MT-2 cells pre-seeded in a 96-well plate in 100 μl of complete RPMI for a final volume of 200 μl, followed by a 96-hour incubation at 37°C. The final MOI in the infection plate was 0.02, and the final DMSO concentration in all wells was 1%. All assays were performed in triplicate. For each replicate, one well received DMSO only and one well received medium only for normalization and background correction. To assay inhibition of HIV-1 replication, 100 μl of medium was removed and discarded, and 10 μl of 15 μM EnduRen luminescent enzyme substrate was added to each well, followed by incubation at 37°C for 1.5 h. Plates were read on a luminescence plate reader (Synergy H1; BioTek Instruments, Inc.).

[0227] Table 2, below, reports the biological activity of selected compounds as measured by the nematode assay and the MT-2 diffuse infection assay.

[0228] [Table 2]

Claims

1. The following structural formula: 【Chemistry 1】 wherein R 5 is hydrogen, fluoro, alkyl, or alkenyl; R 6 is fluoro, alkyl, alkenyl, —OR 27 , or —NR 28 R 29 ; R 8 is hydrogen, —SO 2 R 47 , —OR 48 , —SO 2 NR 69 R 70 , —CONR 71 R 72 , —COR 73 , —CO 2 R 74 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R 27 is alkyl, alkenyl, halo-substituted alkyl, or halo-substituted alkenyl; R 28 , R 29 , and R 69 -R 73 are independently hydrogen, alkyl, or alkenyl; R 74 is alkyl or alkenyl; R 47 is alkyl, alkenyl, aryl, or heteroaryl; A compound wherein R 48 is hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, or aryl.

2. The following structure: 【Chemistry 2】 or a solvate, hydrate or pharmaceutically acceptable salt thereof.

3. 10. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable vehicle.

4. A therapeutic agent for treating amyotrophic lateral sclerosis, comprising the compound of claim 2.

5. A therapeutic agent for treating amyotrophic lateral sclerosis, comprising the pharmaceutical composition according to claim 3.

6. The following structure: 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 or 【Chemistry 11】 or a solvate, hydrate, or salt thereof.

7. 10. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable vehicle.

8. A therapeutic agent for treating amyotrophic lateral sclerosis, comprising the compound of claim 6.

9. A therapeutic agent for amyotrophic lateral sclerosis, comprising the pharmaceutical composition according to claim 7.

10. 10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable vehicle.

11. A therapeutic agent for amyotrophic lateral sclerosis, comprising the compound of claim 1.

12. A therapeutic agent for amyotrophic lateral sclerosis, comprising the pharmaceutical composition according to claim 10.

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