Heterocyclic compounds for trapping aldehydes and uses thereof

Abstract

The present invention provides for the treatment, prevention and / or reduction of risk of diseases, disorders or conditions where aldehyde toxicity is implicated in the pathogenesis, including eye disorders, skin disorders, conditions associated with the damaging effects from blistering agents, and autoimmune, inflammatory, nervous system and cardiovascular diseases, by using the disclosed compounds or pharmacologic acceptable salts thereof.The present invention relates to compounds that are useful for scavenging disease-causing aldehydes.The present invention further relates to the method of using such compounds to treat diseases, disorders or conditions, such as those described herein, and pharmaceutical compositions of such compounds.

Description

[Technical field]

[0001] TECHNICAL FIELD OF THEINVENTION The present invention relates to compounds useful for scavenging disease-causing aldehydes. The present invention further relates to methods of using such compounds to treat diseases, disorders or conditions, such as those described herein, and to pharmaceutical compositions of such compounds.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 202,979, filed July 2, 2021, which is incorporated by reference herein in its entirety. [Background technology]

[0003] 2. Background of the Invention Metabolic and inflammatory processes in cells give rise to toxic aldehydes, such as malondialdehyde (MDA) and 4-hydroxyl-2-nonenal (4HNE). These aldehydes are highly reactive towards proteins, carbohydrates, lipids and DNA, leading to chemically modified biological molecules, activation of inflammatory mediators, such as NF-kappa B, and damage to a wide variety of organs. For example, retinaldehyde can react with phosphatidylethanolamine (PE) to form a highly toxic compound called A2E, a component of lipofuscin that is thought to be involved in the development and progression of age-related macular degeneration (AMD). Many body defense mechanisms function to remove or reduce the levels of toxic aldehydes. Novel small molecule therapeutics can be used to scavenge the "escaped" retinaldehyde in the retina, thus reducing the formation of A2E and lowering the risk of AMD.

[0004] Aldehydes are known to be involved in a wide variety of pathological conditions, such as dry eye, cataracts, keratoconus, Fuchs endothelial dystrophy in the cornea, uveitis, allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with photorefractive keratectomy (PRK) healing or other corneal healing, conditions associated with tear lipid breakdown or lacrimal gland dysfunction, inflammatory eye conditions, such as ocular rosacea (with or without meibomian gland dysfunction), and non-ocular disorders or conditions, such as skin cancer, psoriasis, contact skin ulcers, and the like. It has been implicated in conditions associated with inflammation, atopic dermatitis, acne vulgaris, Sjögren-Larsson syndrome, ischemia-reperfusion injury, inflammation, diabetes, neurodegeneration (e.g., Parkinson's disease), scleroderma, amyotrophic lateral sclerosis, autoimmune disorders (e.g., lupus), cardiovascular disorders (e.g., atherosclerosis), and the damaging effects of blister agents (Negre-Salvagre et al., 2008; Nakamura et al., 2007; Batista et al., 2012; Kenney et al., 2003; Int J Dermatol 43:494 (2004); Invest Ophthalmol Vis Sci 48:1552 (2007); Graefe's Clin Exp Ophthalmol 233:694 (1994); Molecular Vision 18:194 (2012). Thus, reducing or eliminating aldehydes should alleviate the symptoms and slow the progression of these pathological conditions.

[0005] MDA, HNE and other toxic aldehydes arise through a myriad of metabolic mechanisms, including fatty alcohol, sphingolipid, glycolipid, phytol, fatty acid, arachidonic acid metabolism (Rizzo, 2007), polyamine metabolism (Wood et al., 2006), lipid peroxidation, oxidative metabolism (Buddi et al., 2002; Zhou et al., 2005), and glucose metabolism (Pozzi et al., 2009). Aldehydes can crosslink with primary amino groups and other chemical moieties on proteins, phospholipids, carbohydrates, and DNA, often resulting in toxic outcomes, such as mutagenesis and carcinogenesis (Marnett, 2002). MDA is associated with diseased corneas, keratoconus, bullous keratopathy and other keratopathy, and Fuchs endothelial dystrophy corneas (Buddi et al., 2002). Also, skin disorders, such as Sjögren-Larsson syndrome, are likely associated with the accumulation of fatty aldehydes, such as octadecanal and hexadecanal (Rizzo et al., 2010). Furthermore, increased lipid peroxidation and the resulting production of aldehydes are associated with the toxic effects of blister agents (Sciuto et al., 2004 and Pal et al., 2009). Thus, there remains a need for methods of treating, preventing, and / or reducing the risk of diseases, disorders, or conditions in which aldehyde toxicity is implicated in the pathogenesis. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Int J Dermatol, 43:494 (2004) [Non-Patent Document 2] Invest Ophthalmol Vis Sci, 48:1552 (2007) [Non-Patent Document 3] Graefe's Clin Exp Ophthalmol, vol. 233: p. 694 (1994) [Non-Patent Document 4] Molecular Vision, 18:194 (2012) Summary of the Invention [Means for solving the problem]

[0007] Summary of the Invention It has now been found that compounds of the present invention and compositions thereof are useful for treating, preventing, and / or reducing the risk of diseases, disorders, or conditions in which aldehyde toxicity is implicated in the pathogenesis. In one aspect of the present invention, such compounds have the general formula I: [ka] or a pharma- ceutically acceptable salt thereof (wherein X, Y, W, R 1 , R 2 , R 3 and R 5 are as defined herein.

[0008] In another aspect, the present invention provides a compound of formula VI: [ka] or a pharma- ceutically acceptable salt thereof, c , R d , R 7 , R 8 , R 9 and R 10 each of which is as defined herein.

[0009] The compounds of the present invention and pharma- ceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders, or conditions associated with toxic aldehydes, including those described herein.

[0010] The compounds provided by the present invention are also useful in the study of certain aldehydes in biological and pathological phenomena. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a graph depicting the results of an eotaxin cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0012] [Diagram 2] FIG. 2 is a graph depicting the results of a G-CSF cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0013] [Diagram 3] FIG. 3 is a graph depicting the results of a GM-CSF cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0014] [Figure 4] FIG. 4 is a graph depicting the results of an IFNγ cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0015] [Diagram 5] FIG. 5 is a graph depicting the results of an IL-1α cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0016] [Figure 6] FIG. 6 is a graph depicting the results of an IL-1β cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0017] [Figure 7-1] FIG. 7 is a graph depicting the results of an IL-2 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 7-2] Same as above.

[0018] [Figure 8-1]FIG. 8 is a graph depicting the results of an IL-3 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 8-2] Same as above.

[0019] [Figure 9] FIG. 9 is a graph depicting the results of an IL-4 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0020] [Figure 10-1] FIG. 10 is a graph depicting the results of an IL-5 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 10-2] Same as above.

[0021] [Figure 11] FIG. 11 is a graph depicting the results of an IL-6 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0022] [Figure 12] FIG. 12 is a graph depicting the results of an IL-7 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0023] [Figure 13-1] FIG. 13 is a graph depicting the results of an IL-9 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 13-2] Same as above.

[0024] [Figure 14-1] FIG. 14 is a graph depicting the results of an IL-10 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 14-2] Same as above.

[0025] [Figure 15-1] FIG. 15 is a graph depicting the results of an IL-12(p40) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 15-2] Same as above.

[0026] [Figure 16-1] FIG. 16 is a graph depicting the results of an IL-12(p70) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 16-2] Same as above.

[0027] [Figure 17-1] FIG. 17 is a graph depicting the results of an IL-13 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 17-2] Same as above.

[0028] [Figure 18-1] FIG. 18 is a graph depicting the results of an IL-15 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 18-2] Same as above.

[0029] [Figure 19-1] FIG. 19 is a graph depicting the results of an IL-17 cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 19-2] Same as above.

[0030] [Figure 20-1] FIG. 20 is a graph depicting the results of a KC cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 20-2] Same as above.

[0031] [Figure 21-1] 21 is a graph showing the results of a leukemia inhibitory factor (LIF) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. LIF is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. [Figure 21-2] Same as above.

[0032] [Figure 22-1] FIG. 22 is a graph depicting the results of a LIX (CXCL5) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 22-2] Same as above.

[0033] [Figure 23-1] 23 is a graph showing the results of an MCP-1 (CCL2) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. MCP-1 recruits monocytes, memory T cells and dendritic cells to sites of inflammation. [Figure 23-2] Same as above.

[0034] [Figure 24-1] 24 is a graph showing the results of an M-CSF (CSF1) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. M-CSF differentiates hematopoietic stem cells into macrophages. [Figure 24-2] Same as above.

[0035] [Diagram 25] FIG. 25 is a graph depicting the results of a MIP-1a (CCL3) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the disclosure.

[0036] [Figure 26]FIG. 26 is a graph depicting the results of a MIP-1b (CCL4) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the disclosure.

[0037] [Figure 27-1] FIG. 27 is a graph depicting the results of a MIP2 (CXCL2) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the disclosure. [Figure 27-2] Same as above.

[0038] [Figure 28] FIG. 28 is a graph depicting the results of a RANTES (CCL) cytokine detection assay in samples taken from mouse subjects following administration of a compound of the disclosure.

[0039] [Figure 29-1] FIG. 29 is a graph depicting the results of a TNFα cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure. [Figure 29-2] Same as above.

[0040] [Diagram 30] FIG. 30 is a graph depicting the results of a VEGF cytokine detection assay in samples taken from mouse subjects following administration of a compound of the present disclosure.

[0041] [Diagram 31] FIG. 31 is a plot of HNE binding over time for various compounds of the disclosure.

[0042] [Diagram 32] FIG. 32 is a plot of percent completion of HNE binding over time for various compounds of the disclosure.

[0043] [Diagram 33] FIG. 33 is a plot of percent completion of HNE binding over time for various compounds of the disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0044] Detailed Description of the Invention 1. General Description of Certain Embodiments of the Invention In certain embodiments, the present invention provides compounds, compositions and methods for treating, preventing and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is implicated in the pathogenesis. In some embodiments, such compounds include compounds of the formulas described herein or pharma- ceutically acceptable salts thereof, where each variable is as defined herein and described in the embodiments. In some embodiments, the disclosed compounds contain amino and carbinol functional groups (such as propan-2-ol groups) that may be capable of scavenging or trapping aldehydes by forming an adduct.

[0045] In one aspect, the present invention provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, W is N or CR 4 and X is S, NH or O; Y is N or CR 6 and However, if X is S or O, then Y is CR 6 and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently represents hydrogen, deuterium, halogen, -NH, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic, or [ka] where R 1 , R2 , R 3 , R 4 , R 5 and R 6 One of the groups is -NH2, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Another one of [ka] and R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 Aliphatic; or R a and R b together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0046] In another aspect, the present invention provides a compound of formula VI: [ka] or a pharma- ceutically acceptable salt thereof, R 7 , R 8 , R 9 and R 10 each independently represents hydrogen, deuterium, halogen, -N(R)2, -CN, -OR, -SR or an optionally substituted C 1~6 It is aliphatic, R c is hydrogen or C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R d is hydrogen or C optionally substituted by 1, 2 or 3 deuterium or halogen atoms; 1~4 Aliphatic; or R c and R d together with the carbon atom to which they are attached form a 3-8 membered saturated cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2.Definition

[0047] The compounds of the present invention include those generally described above, and are further exemplified by the classes, subclasses and species disclosed herein.As used herein, the following definitions shall apply unless otherwise indicated.For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th Edition, CAS Edition.Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, (eds.): Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0048] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"), which has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0049] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., a saturated or partially unsaturated carbocyclic or heterocyclic ring system. As defined by IUPAC, a "bridge" is an unbranched chain of atoms, or an atom or valence bond, connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, each of which is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as described for the aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include the following: [ka] Includes.

[0050] The term "lower alkyl" refers to 1~4 It refers to a straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0051] The term "lower haloalkyl" refers to a C substituted with one or more halogen atoms. 1~4 It refers to a straight or branched chain alkyl group.

[0052] The term "heteroatom" refers to any atom of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or substitutable nitrogen of a heterocyclic ring, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR +(as in N-substituted pyrrolidinyl)).

[0053] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0054] As used herein, the term "divalent C 1~8 (or C 1~6 ) Saturated or unsaturated, straight or branched hydrocarbon chain" refers to straight or branched divalent alkylene chains, alkenylene chains, and alkynylene chains, as defined herein.

[0055] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n - and n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0056] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0057] The term "halogen" means F, Cl, Br or I.

[0058] The term "aryl" used alone or as part of a larger moiety, such as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in such systems is aromatic, and in which each ring in such systems contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Similarly, the scope of the term "aryl", as used herein, also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthoimidyl, phenanthridinyl, or tetrahydronaphthyl.

[0059] The terms "heteroaryl" and "heteroaralkoxy", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, and having 6, 10, or 14 pi-electrons shared in a cyclic arrangement, and having 1 to 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroara", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0060] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety, either saturated or partially unsaturated, having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or . + It may also be NR (as in N-substituted pyrrolidinyl).

[0061] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of these ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl moieties, independently, are optionally substituted.

[0062] As used herein, the term "partially unsaturated" refers to a ring moiety that contains at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0063] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced by suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. The combination of substituents envisioned by the present invention is preferably one that results in the formation of a stable or chemically feasible compound. The term "stable", as used herein, refers to a compound that is substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0064] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH) 0~4 R 〇 ;-(CH2) 0~4 OR 〇 ;-O(CH2) 0~4 R 〇 , -O-(CH2) 0~4 C(O)OR 〇 ;-(CH2) 0~4 CH(OR 〇 )2;-(CH2) 0~4 S.R. 〇 ;-(CH2) 0~4 Ph (this is R〇 substituted by -(CH2) 0~4 O(CH2) 0~1 Ph (this is R 〇 -CH=CHPh (which may be substituted by R 〇 substituted by -(CH2) 0~4 O(CH2) 0~1 -pyridyl (which is R 〇 -(CH2) 0~4 N(R 〇 )2;-(CH2) 0~4 N(R 〇 )C(O)R 〇 ;-N(R 〇 )C(S)R 〇 ;-(CH2) 0~4 N(R 〇 )C(O)NR 〇 2;-N(R 〇 )C(S)NR 〇 2;-(CH2) 0~4 N(R 〇 )C(O)OR 〇 ;-N(R 〇 )N(R 〇 )C(O)R 〇 ;-N(R 〇 )N(R 〇 )C(O)NR 〇 2;-N(R 〇 )N(R 〇 )C(O)OR 〇 ;-(CH2) 0~4 C(O)R 〇 ;-C(S)R 〇 ;-(CH2) 0~4 C(O)OR 〇 ;-(CH2) 0~4 C(O)SR 〇 ;-(CH2) 0~4 C(O)OSiR 〇 3;-(CH2) 0~4 O.C.(O)R 〇 ;-OC(O)(CH2) 0~4 SR-, SC(S)SR 〇 ;-(CH2) 0~4 SC(O)R 〇 ;-(CH2) 0~4C(O)NR 〇 2;-C(S)NR 〇 2;-C(S)SR 〇 ;-SC(S)SR 〇 , -(CH2) 0~4 OC(O)NR 〇 2;-C(O)N(OR 〇 )R 〇 ;-C(O)C(O)R 〇 ;-C(O)CH2C(O)R 〇 ;-C(NOR 〇 )R 〇 ;-(CH2) 0~4 SSR 〇 ;-(CH2) 0~4 S(O)2R 〇 ;-(CH2) 0~4 S(O)2OR 〇 ;-(CH2) 0~4 OS(O)2R 〇 ;-S(O)2NR 〇 2;-(CH2) 0~4 S(O)R 〇 ;-N(R 〇 )S(O)NR 〇 2;-N(R 〇 )S(O)2R 〇 ;-N(OR 〇 )R 〇 ;-C(NH)NR 〇 2;-P(O)2R 〇 ;-P(O)R 〇 2;-OP(O)R 〇 2;-OP(O)(OR 〇 )2;SiR 〇 3;-(C 1~4 Linear or branched alkylene)ON(R 〇 )2; or -(C 1~4 Linear or branched alkylene)C(O)ON(R 〇 )2, where R 〇 are each optionally substituted as defined below and independently represent hydrogen, C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, -CH2- (5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or any two independently occurring R 〇 together with the intervening atom(s) form a 3-12 membered saturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a partially unsaturated monocyclic or bicyclic ring, or an aryl monocyclic or bicyclic ring, which may be optionally substituted as defined below.

[0065] R 〇 (Or, two R's occurring independently 〇 Preferred monovalent substituents on the ring formed by combining with their intervening atoms are independently halogen, -(CH) 0~2 R ● , -(Halo R ● ), -(CH2) 0~2 OH, -(CH2) 0~2 OR ● , -(CH2) 0~2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● , -(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● , -(CH2) 0~2 S.R. ● , -(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● , -(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C 1~4 Linear or branched alkylene)C(O)OR ● Or -SSR ● and R● Each of is unsubstituted or, if preceded by "halo", substituted only with one or more halogens; 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 R is independently selected from Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 〇 Suitable divalent substituents on a saturated carbon atom of include ═O and ═S.

[0066] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2~3 O- or -S(C(R * 2)) 2~3 R that contains S- and occurs independently * each represents hydrogen, C which may be substituted as defined below 1~6 A 5-6 membered unsubstituted saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from aliphatic, nitrogen, oxygen or sulfur. Preferred divalent substituents attached to a vicinal substitutable carbon of an "optionally substituted" group include -O(CR * 2) 2~3 R containing O- and occurring independently * each represents hydrogen, C which may be substituted as defined below 1~6 It is selected from an aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0067] R * Suitable substituents on the aliphatic groups include halogen, -R ● , -(Halo R● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, R ● each is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0068] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH2C(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2 or -N(R † )S(O)2R † Contains R † each independently represents hydrogen, optionally substituted C as defined below 1~6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, regardless of the above definition, two independently occurring R † together with the intervening atom(s) form an unsubstituted 3-12 membered saturated monocyclic or bicyclic ring, partially unsaturated monocyclic or bicyclic ring, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0069] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2 or -NO2, R ● each is unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and independently represents C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is within the scope of sound medical judgment and suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, vol. 66, pp. 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-1,2-propanediol, and 1,2-diol. These include benzenesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0071] Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N +(C 1~4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharma- ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0072] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations, Z and E double bond isomers, and Z and E conformational isomers about each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of a parent compound are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0073] The "retina" is a region of the central nervous system that contains approximately 150 million neurons. The retina is located at the back of the eye and resides in a specialized epithelial tissue called the retinal pigment epithelium (RPE). The retina initiates the first stage of visual processing by transducing visual stimuli in specialized neurons called "photoreceptors." The synaptic output of the photoreceptors is processed by an elaborate neural network in the retina and then transmitted to the brain. The retina has evolved two specialized classes of photoreceptors to operate under a wide range of light conditions: "rod" photoreceptors transmit visual images under low light conditions and mediate achromatic vision; and "cone" photoreceptors transmit visual images in dim to bright light conditions and mediate both color vision and high acuity vision.

[0074] All photoreceptors are compartmentalized into two regions, called the "outer" and "inner" segments. The inner segment is the cell body of the neuron that contains the cell nucleus. In the absence of retinal disease, the inner segment persists for life. The outer segment is the region where light-sensitive visual pigment molecules are concentrated in a densely arranged laminated membrane structure. Portions of the outer segment are periodically shed and regrow in a circadian process called outer segment renewal. The shed outer segments are taken up and metabolized by RPE cells.

[0075] The "macula" is the central region of the retina, containing the fovea, where visual images are processed by elongated cones in high spatial detail ("acuity"). "Macular degeneration" is a form of retinal neurodegeneration that attacks the macula and destroys high-performance vision in the central part of the visual field. Age-related macular degeneration (AMD) begins in the "atrophic form," characterized by residual lysosomal granules, called lipofuscin, in RPE cells, and by extracellular deposits, called "drusen." Drusen contain cellular waste products that are expelled by RPE cells. "Lipofuscin" and drusen can be detected clinically by ophthalmologists and quantified using fluorescent techniques. They may be the first clinical sign of macular degeneration.

[0076] Lipfuscin contains aggregates of A2E. Lipofuscin accumulates in RPE cells and harms them by several known mechanisms. As RPE cells are harmed, their biochemical activity decreases and photoreceptors begin to degenerate. Extracellular drusen can further damage RPE cells by impeding the supply of vascular nutrients to RPE cells. Drusen also trigger an inflammatory process that leads to choroidal neovascular infiltration of the macula in 1 in 10 patients who progress to wet AMD. Both dry and wet forms progress to blindness.

[0077] "ERG" is an acronym for electroretinogram, which is the measurement of the field potential generated by retinal neurons while responding to an experimentally defined light stimulus. ERG is a non-invasive measurement that can be performed either on a living subject (human or animal) or on a hemi-excised eye in solution that has been surgically removed from a living animal.

[0078] As used herein, the term "RAL" refers to retinaldehyde. The term "RAL-trap" refers to a therapeutic compound that binds to free RAL, thereby preventing RAL from Schiff base condensation with membrane phosphatidylethanolamine (PE). "Free RAL" is defined as RAL that is not bound to visual cycle proteins. The terms "trans-RAL" and "all-trans-RAL" are used interchangeably and refer to all trans-retinaldehyde.

[0079] A2E is a reaction by-product of a complex biochemical pathway called the "visual cycle," which works in concert in both RPE cells and photoreceptor outer segments. The visual cycle recycles a photoreactive aldehyde chromophore called "retinaldehyde," derived from vitamin A, and is essential for vision. In simplified terms, the visual cycle has four major steps: 1) conversion of vitamin A in the RPE to an aldehyde chromophore with a single photoreactive strained double bond (11-cis-RAL), 2) transport of 11-cis-RAL to the retina, where it binds to specialized photoreceptor proteins called opsins, 3) photoisomerization of the bound 11-cis-RAL by light to trans-RAL, which initiates the release of the bound RAL from the opsin binding site, and 4) conversion of trans-RAL (an aldehyde) to vitamin A (an alcohol) and transport of vitamin A back to the RPE, where the cycle begins again.

[0080] The aldehyde group on RAL helps bind the molecule to opsin by forming a reversible chemical bond to an amino acid side chain at the opsin binding site. While the aldehyde group on RAL is essential for tethering the molecule to the opsin binding site, it is otherwise detrimental due to its tendency to form Schiff bases with other biological amines. The first three reactions occur in the outer segments of photoreceptors and generate an intermediate product called A2PE. Once formed, A2PE partitions into the lipid phase and accumulates in the outer segment membrane of photoreceptors.

[0081] As mentioned above, macular degeneration and other forms of retinal disease whose pathogenesis involves accumulation of A2E and / or lipofuscin can be treated or prevented by reducing the amount of A2E formed.Compounds useful for doing so include RAL-traps, such as certain compounds disclosed herein.RAL-traps reduce the amount of A2E formed, for example, by forming covalent bonds with RAL that escapes sequestration.Therefore, the RAL that reacts with RAL-trap compounds is not available to react with phosphatidylethanolamine.

[0082] The phrases "parenteral administration" and "administered parenterally" are art-recognized terms and include modes of administration other than enteral and topical administration, such as injection, including, but not limited to, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0083] As used herein, "about" or "approximately" in reference to a numerical value means that the stated numerical value may vary by up to 10% of the stated value. For example, "about 10" refers to a value of 9.9 to 10.1 (10 + / - 0.1).

[0084] The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, stool, semen, tears or other bodily fluids, or extracts thereof. 3. Description of exemplary compounds

[0085] It has now been found that compounds of the present invention, and compositions thereof, are useful for treating, preventing, and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is implicated in the pathogenesis.

[0086] According to one aspect, the present invention provides a compound of formula I: [ka] or a pharma- ceutically acceptable salt thereof, W is N or CR 4 and X is S, NH or O; Y is N or CR 6 and However, if X is S or O, then Y is CR 6 and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each independently represents hydrogen, deuterium, halogen, -NH, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic, or [ka] where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 One of the groups is -NH2, and R 1 , R 2 , R 3 , R 4, R 5 and R 6 Another one of [ka] and R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 Aliphatic; or R a and R b together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0087] In some embodiments of Formula I, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 -NH2, one of the 1 , R 2 , R 3 , R 4, R 5 and R 6 Another one of [ka] The moieties are present on adjacent available carbon atoms. Non-limiting examples include R 1 When is -NH2, R 2 or R 6 One of them is the carbinol moiety ( [ka] ).

[0088] In some embodiments, R 1 and R 6 One of the is -NH2 and one is [ka] It is.

[0089] In some embodiments, R 1 and R 2 One of the is -NH2 and one is [ka] It is.

[0090] In some embodiments, R 2 and R 3 One of the is -NH2 and one is [ka] It is.

[0091] In some embodiments, R 3 and R 4 One of the is -NH2 and one is [ka] It is.

[0092] In some embodiments, R 4 and R 5 One of the is -NH2 and one is [ka] It is.

[0093] In some embodiments of Formula I, R 1 and R 6 One of the is -NH2 or [ka] It is.

[0094] In general, as defined above, W can be either N or CR. 4 In some embodiments, W is N. In some embodiments, W is CR 4 In some embodiments, W is selected from those depicted in Table 1 below.

[0095] Generally, as defined above, X is S, NH, or O. In some embodiments, X is S. In some embodiments, X is NH. In some embodiments, X is O. In some embodiments, X is selected from those depicted in Table 1 below.

[0096] Generally, Y is N or CR as defined above. 6 In some embodiments, Y is N. In some embodiments, Y is CR 6 In some embodiments, when X is NH, Y is N. In some embodiments, Y is selected from those depicted in Table 1 below.

[0097] In some embodiments, W is N, X is NH, and Y is N.

[0098] Generally, as defined above, R 1is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0099] In some embodiments, R 1 is H. In some embodiments, R 1 is D. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -NH2. In some embodiments, R 1 In some embodiments, R 1 is -OR. In some embodiments, R 1 In some embodiments, R 1 is replaced by C 1~6 In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0100] Generally, as defined above, R 2 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0101] In some embodiments, R 2 is H. In some embodiments, R 2 is D. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -NH2. In some embodiments, R 2 In some embodiments, R 2 is -OR. In some embodiments, R 2 In some embodiments, R 2 is replaced by C 1~6 In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 teeth, [ka] In some embodiments, R 2 is Br. In some embodiments, R 2 In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0102] Generally, as defined above, R 3 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0103] In some embodiments, R 3is H. In some embodiments, R 3 is D. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -NH2. In some embodiments, R 3 In some embodiments, R 3 is -OR. In some embodiments, R 3 In some embodiments, R 3 is replaced by C 1~6 In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0104] Generally, as defined above, R 4 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0105] In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is a halogen. In some embodiments, R 4is -NH2. In some embodiments, R 4 In some embodiments, R 4 is -OR. In some embodiments, R 1 In some embodiments, R 4 is replaced by C 1~6 In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0106] Generally, as defined above, R 5 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0107] In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -NH2. In some embodiments, R 5 In some embodiments, R 5 is -OR. In some embodiments, R 5In some embodiments, R 5 is replaced by C 1~6 In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 teeth, [ka] In some embodiments, R 5 In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0108] Generally, as defined above, R 6 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0109] In some embodiments, R 6 is H. In some embodiments, R 6 is D. In some embodiments, R 6 is a halogen. In some embodiments, R 6 is -NH2. In some embodiments, R 6 In some embodiments, R 6 is -OR. In some embodiments, R 6 In some embodiments, R 6 is replaced by C 1~6 In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 teeth, [ka] In some embodiments, R 6 is selected from those illustrated in Table 1 below.

[0110] Generally, as defined above, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic.

[0111] In some embodiments, R a is C 1~4 In some embodiments, R a is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R a is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0112] In some embodiments, R a is C 1~4 In some embodiments, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R a is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R a is C optionally substituted by 1, 2 or 3 halogen atoms1~4 In some embodiments, R a is methyl optionally substituted with 1, 2, or 3 halogen atoms. a is -CF3 or methyl.

[0113] Generally, as defined above, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic.

[0114] In some embodiments, R b is C 1~4 In some embodiments, R b is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R b is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0115] In some embodiments, R b is C 1~4 In some embodiments, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R b is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R b is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 In some embodiments, R b is methyl optionally substituted with 1, 2, or 3 halogen atoms. b is -CF3 or methyl.

[0116] Generally, as defined above, R a and Rb may be joined together with the carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1 to 2 heteroatoms each independently selected from nitrogen, oxygen and sulfur.

[0117] In some embodiments, R a and R b taken together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl. a and R b are taken together with the carbon atom to which they are attached to form a 3-8 membered heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur. a and R b together with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring. a and R b together with the carbon atom to which they are attached form an oxirane, oxetane, tetrahydrofuran, or aziridine.

[0118] In some embodiments, R a and R b are both methyl. In some embodiments, R a is methyl, R b is -CF3. In some embodiments, R a and R b is selected from those illustrated in Table 1 below.

[0119] In another embodiment, the compound of formula I is a compound of formula II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, or II-j: [ka] or a pharma- ceutically acceptable salt thereof, W, X, Y, R, R 1, R 2 , R 3 , R 4 , R 5 , R 6 , R a and R b each of which, both singly and in combination, is as defined above and described in the embodiments herein.

[0120] In another embodiment, the compound of formula I is a compound of formula III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, or III-j: [ka] or a pharma- ceutically acceptable salt thereof, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a and R b each of which, both singly and in combination, is as defined above and described in the embodiments herein.

[0121] In another embodiment, the compound of formula I is a compound of formula IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g or IV-h: [ka] [ka] or a pharma- ceutically acceptable salt thereof, W, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a and R bare each as defined above, both singly and in combination, and as described in the embodiments herein).

[0122] In another embodiment, the compound of formula I is a compound of formula Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi or Vj: [ka] or a pharma- ceutically acceptable salt thereof, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a and R b each of which, both singly and in combination, is as defined above and described in the embodiments herein.

[0123] In another aspect, the present invention provides a compound of formula VI: [ka] or a pharma- ceutically acceptable salt thereof, R 7 , R 8 , R 9 and R 10 each independently represents hydrogen, deuterium, halogen, -N(R)2, -CN, -OR, -SR or an optionally substituted C 1~6 It is aliphatic, R c is hydrogen or C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R d is hydrogen or C optionally substituted by 1, 2 or 3 deuterium or halogen atoms; 1~4 Aliphatic; or R c and R dtogether with the carbon atom to which they are attached form a 3-8 membered saturated cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0124] Generally, as defined above, R 7 is hydrogen, deuterium, halogen, -N(R)2, -CN, -OR, -SR or optionally substituted C 1~6 It is aliphatic.

[0125] In some embodiments, R 7 is H. In some embodiments, R 7 is D. In some embodiments, R 7 is a halogen. In some embodiments, R 7 is -N(R). In some embodiments, R 7 In some embodiments, R 7 is -OR. In some embodiments, R 7 In some embodiments, R 7 is replaced by C 1~6 In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R7 is selected from those illustrated in Table 1 below.

[0126] Generally, as defined above, R 8 is hydrogen, deuterium, halogen, -N(R)2, -CN, -OR, -SR or optionally substituted C 1~6 It is aliphatic.

[0127] In some embodiments, R 8 is H. In some embodiments, R 8 is D. In some embodiments, R 8 is a halogen. In some embodiments, R 8 is -N(R). In some embodiments, R 8 In some embodiments, R 8 is -OR. In some embodiments, R 8 In some embodiments, R 8 is replaced by C 1~6 In some embodiments, R 8 In some embodiments, R 8 In some embodiments, R 8 is selected from those illustrated in Table 1 below.

[0128] Generally, as defined above, R 9 is hydrogen, deuterium, halogen, -N(R)2, -CN, -OR, -SR or optionally substituted C 1~6 It is aliphatic.

[0129] In some embodiments, R 9 is H. In some embodiments, R 9 is D. In some embodiments, R 9 is a halogen. In some embodiments, R 9 is -N(R). In some embodiments, R 9 In some embodiments, R 9 is -OR. In some embodiments, R9 In some embodiments, R 9 is replaced by C 1~6 In some embodiments, R 9 In some embodiments, R 9 In some embodiments, R 9 is selected from those illustrated in Table 1 below.

[0130] Generally, as defined above, R 10 is hydrogen, deuterium, halogen, -N(R)2, -CN, -OR, -SR or optionally substituted C 1~6 It is aliphatic.

[0131] In some embodiments, R 10 is H. In some embodiments, R 10 is D. In some embodiments, R 10 is a halogen. In some embodiments, R 10 is -N(R). In some embodiments, R 10 In some embodiments, R 10 is -OR. In some embodiments, R 10 In some embodiments, R 10 is replaced by C 1~6 In some embodiments, R 10 In some embodiments, R 10 In some embodiments, R 10 is selected from those illustrated in Table 1 below.

[0132] Generally, as defined above, R c is hydrogen or C optionally substituted by 1, 2 or 3 deuterium or halogen atoms; 1~4 It is aliphatic.

[0133] In some embodiments, R c is hydrogen. In some embodiments, Rc is C 1~4 In some embodiments, R c is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R a is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0134] In some embodiments, R c is C 1~4 In some embodiments, R c is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R c is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R c is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 In some embodiments, R c is methyl optionally substituted with 1, 2, or 3 halogen atoms. c is methyl.

[0135] Generally, as defined above, R d is hydrogen or C optionally substituted by 1, 2 or 3 deuterium or halogen atoms; 1~4 It is aliphatic.

[0136] In some embodiments, R d is hydrogen. In some embodiments, R d is C 1~4 In some embodiments, R d is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R dis C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0137] In some embodiments, R d is C 1~4 In some embodiments, R d is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R d is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R d is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 In some embodiments, R d is methyl optionally substituted with 1, 2, or 3 halogen atoms. d is methyl.

[0138] Generally, as defined above, R c and R d together with the carbon atom to which they are attached form a 3-8 membered saturated cycloalkyl ring or a heterocyclyl ring containing 1 to 2 heteroatoms each independently selected from nitrogen, oxygen and sulfur.

[0139] In some embodiments, R c and R d taken together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl. c and R d are taken together with the carbon atom to which they are attached to form a 3-8 membered heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur. c and R dtogether with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring. c and R d together with the carbon atom to which they are attached form an oxirane, oxetane, tetrahydrofuran, or aziridine.

[0140] In some embodiments, R c and R d are both methyl. In some embodiments, R c and R d are hydrogen. In some embodiments, R c is methyl, R d In some embodiments, R c and R d is selected from those illustrated in Table 1 below.

[0141] In some embodiments, the compound of formula VI is [ka] In some embodiments, [ka] In some embodiments, the compound is [ka] isn't it.

[0142] According to one aspect, the present invention provides a compound of formula VII: [ka] or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 , R 5 and R 6each independently represents hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic, or [ka] where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 One of the groups is -NH2, and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Another one of [ka] and -NH2 [ka] are bonded to adjacent carbon atoms or have a peri-relationship, R 1’ is hydrogen, deuterium or C 1~6 is alkyl, R 6’ is hydrogen, deuterium or C 1~6 is alkyl, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 Aliphatic; or R a and R b together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0143] In another aspect, the present invention provides a compound of formula VIII: [ka] or a pharma- ceutically acceptable salt thereof, R 2 , R 3 , R 4 and R 5 each independently represents hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic, or [ka] where R 2 , R 3 , R 4 and R 5 One of the groups is -NH2, and R 2 , R 3 , R 4 and R 5 Another one of [ka] and -NH2 [ka] are attached to adjacent carbon atoms, R 1 and R 1’ are each independently hydrogen, deuterium or C 1~6 is alkyl, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 Aliphatic; or R a and R b together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6 independently selected from optionally substituted groups selected from aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; n is 1, 2 or 3.

[0144] Generally, as defined above, R 1 and R 1’ are each independently hydrogen, deuterium or C 1~6 It is an alkyl.

[0145] In some embodiments, R 1 is H. In some embodiments, R 1 is D. In some embodiments, R 1 is C 1~6 It is an alkyl.

[0146] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0147] In some embodiments, R 1’ is H. In some embodiments, R 1’ is D. In some embodiments, R 1’ is C 1~6 It is an alkyl.

[0148] In some embodiments, R 1’ is selected from those illustrated in Table 1 below.

[0149] Generally, as defined above, R 2 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0150] In some embodiments, R 2 is H. In some embodiments, R 2 is D. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -NH2. In some embodiments, R 2 In some embodiments, R 2 is -OR. In some embodiments, R 2 In some embodiments, R 2 is -S(O)R. In some embodiments, R 2is -S(O)R. In some embodiments, R 2 is replaced by C 1~6 In some embodiments, R 2 teeth, [ka] It is.

[0151] In some embodiments, R 2 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 2 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0152] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0153] Generally, as defined above, R 3 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0154] In some embodiments, R 3 is H. In some embodiments, R 3 is D. In some embodiments, R 3 is a halogen. In some embodiments, R3 is -NH2. In some embodiments, R 3 In some embodiments, R 3 is -OR. In some embodiments, R 3 In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is replaced by C 1~6 In some embodiments, R 3 teeth, [ka] It is.

[0155] In some embodiments, R 3 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 3 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0156] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0157] Generally, as defined above, R 4 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0158] In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is -NH2. In some embodiments, R 4 In some embodiments, R 4 is -OR. In some embodiments, R 4 In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is replaced by C 1~6 In some embodiments, R 4 teeth, [ka] It is.

[0159] In some embodiments, R 4 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 4 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0160] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0161] Generally, as defined above, R 5 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0162] In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -NH2. In some embodiments, R 5 In some embodiments, R 5 is -OR. In some embodiments, R 5 In some embodiments, R 5 is -S(O)R. In some embodiments, R 5 is -S(O)R. In some embodiments, R 5 is replaced by C 1~6 In some embodiments, R 5 teeth, [ka] It is.

[0163] In some embodiments, R 5 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 5are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0164] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0165] Generally, as defined above, n is 1, 2 or 3.

[0166] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0167] In another aspect, the present invention provides a compound of formula IX: [ka] or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , R 3 and R 4 each independently represents hydrogen, deuterium, halogen, -NH, -CN, -OR, -SR, -S(O)R, -S(O)R, or an optionally substituted C 1~6 It is aliphatic, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 Aliphatic; or R a and R b together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0168] Generally, as defined above, R 1 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R or optionally substituted C 1~6 It is aliphatic.

[0169] In some embodiments, R 1 is H. In some embodiments, R 1 is D. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -NH2. In some embodiments, R 1 In some embodiments, R 1 is -OR. In some embodiments, R 1 In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is replaced by C 1~6 It is aliphatic.

[0170] In some embodiments, R 1 is hydrogen, deuterium, halogen, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C4~6 Cycloalkyl or C 1~6 In some embodiments, R 1 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0171] In some embodiments, R 1 is selected from those illustrated in Table 1 below.

[0172] Generally, as defined above, R 2 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R or optionally substituted C 1~6 It is aliphatic.

[0173] In some embodiments, R 2 is H. In some embodiments, R 2 is D. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -NH2. In some embodiments, R 2 In some embodiments, R 2 is -OR. In some embodiments, R 2 In some embodiments, R 2 is -S(O)R. In some embodiments, R 2 is -S(O)R. In some embodiments, R 2 is replaced by C 1~6 It is aliphatic.

[0174] In some embodiments, R 2 is hydrogen, deuterium, halogen, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl or C 1~6 In some embodiments, R 2are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0175] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0176] Generally, as defined above, R 3 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R or optionally substituted C 1~6 It is aliphatic.

[0177] In some embodiments, R 3 is H. In some embodiments, R 3 is D. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -NH2. In some embodiments, R 3 In some embodiments, R 3 is -OR. In some embodiments, R 3 In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is replaced by C 1~6 It is aliphatic.

[0178] In some embodiments, R 3 is hydrogen, deuterium, halogen, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl or C 1~6 In some embodiments, R 3 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C1~6 Alkyl) or C 1~6 It is an alkyl.

[0179] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0180] Generally, as defined above, R 4 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R or optionally substituted C 1~6 It is aliphatic.

[0181] In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is -NH2. In some embodiments, R 4 In some embodiments, R 4 is -OR. In some embodiments, R 4 In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is replaced by C 1~6 It is aliphatic.

[0182] In some embodiments, R 4 is hydrogen, deuterium, halogen, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl or C 1~6 In some embodiments, R 4 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0183] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0184] Generally, as defined above, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic.

[0185] In some embodiments, R a is C 1~4 In some embodiments, R a is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R a is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0186] In some embodiments, R a is C 1~4 In some embodiments, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R a is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R a is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 In some embodiments, R a is methyl optionally substituted with 1, 2, or 3 halogen atoms. a is -CF3 or methyl.

[0187] Generally, as defined above, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic.

[0188] In some embodiments, R b is C 1~4 In some embodiments, R b is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R b is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0189] In some embodiments, R b is C 1~4 In some embodiments, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R b is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R b is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 In some embodiments, R b is methyl optionally substituted with 1, 2, or 3 halogen atoms. b is -CF3 or methyl.

[0190] Generally, as defined above, R a and R b may be joined together with the carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1 to 2 heteroatoms each independently selected from nitrogen, oxygen and sulfur.

[0191] In some embodiments, R a and R b taken together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl. aand R b are taken together with the carbon atom to which they are attached to form a 3-8 membered heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur. a and R b together with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring. a and R b together with the carbon atom to which they are attached form an oxirane, oxetane, tetrahydrofuran, or aziridine.

[0192] In some embodiments, R a and R b are both methyl. In some embodiments, R a is methyl, R b is -CF3. In some embodiments, R a and R b is selected from those illustrated in Table 1 below.

[0193] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] It is.

[0194] In some embodiments, R 1 , R 2 , R 3 and R 4 In some embodiments, one, two, or three of R1 , R 2 , R 3 and R 4 One, two, or three of the are hydrogen.

[0195] In some embodiments, the compound of formula IX is [ka] but, [ka] nor any pharma- ceutically acceptable salt thereof.

[0196] In some embodiments, the compound of formula IX is [ka] or a pharma- ceutically acceptable salt thereof.

[0197] In another aspect, the present invention provides a compound of formula X: [ka] or a pharma- ceutically acceptable salt thereof, R 1 , R 2 , R 3 , R 4 and R 5 each independently represents hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] where R 1 , R 2 , R 3 , R 4 and R 5 One of the groups is -NH2, and R 1 , R 2 , R 3 , R 4 and R5 Another one of [ka] and -NH2 [ka] are attached to adjacent carbon atoms, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 Aliphatic; or R a and R b together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; R is hydrogen, deuterium, and C 1~6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0198] Generally, as defined above, R 1 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0199] In some embodiments, R 1 is H. In some embodiments, R 1 is D. In some embodiments, R 1 is a halogen. In some embodiments, R 1 is -NH2. In some embodiments, R 1 In some embodiments, R 1 is -OR. In some embodiments, R 1 In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is -S(O)R. In some embodiments, R 1 is replaced by C 1~6 In some embodiments, R 1 teeth, [ka] It is.

[0200] In some embodiments, R 1 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 1 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0201] In some embodiments, R 1is selected from those illustrated in Table 1 below.

[0202] Generally, as defined above, R 2 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0203] In some embodiments, R 2 is H. In some embodiments, R 2 is D. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is -NH2. In some embodiments, R 2 In some embodiments, R 2 is -OR. In some embodiments, R 2 In some embodiments, R 2 is -S(O)R. In some embodiments, R 2 is -S(O)R. In some embodiments, R 2 is replaced by C 1~6 In some embodiments, R 2 teeth, [ka] It is.

[0204] In some embodiments, R 2 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R2 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0205] In some embodiments, R 2 is selected from those illustrated in Table 1 below.

[0206] Generally, as defined above, R 3 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0207] In some embodiments, R 3 is H. In some embodiments, R 3 is D. In some embodiments, R 3 is a halogen. In some embodiments, R 3 is -NH2. In some embodiments, R 3 In some embodiments, R 3 is -OR. In some embodiments, R 3 In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is replaced by C 1~6 In some embodiments, R 3 teeth, [ka] It is.

[0208] In some embodiments, R 3 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 3 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0209] In some embodiments, R 3 is selected from those illustrated in Table 1 below.

[0210] Generally, as defined above, R 4 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0211] In some embodiments, R 4 is H. In some embodiments, R 4 is D. In some embodiments, R 4 is a halogen. In some embodiments, R 4 is -NH2. In some embodiments, R 4 In some embodiments, R 4 is -OR. In some embodiments, R 4 In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is -S(O)R. In some embodiments, R 4 is replaced by C 1~6 In some embodiments, R4 teeth, [ka] It is.

[0212] In some embodiments, R 4 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 4 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0213] In some embodiments, R 4 is selected from those illustrated in Table 1 below.

[0214] Generally, as defined above, R 5 is hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C 1~6 Aliphatic or [ka] It is.

[0215] In some embodiments, R 5 is H. In some embodiments, R 5 is D. In some embodiments, R 5 is a halogen. In some embodiments, R 5 is -NH2. In some embodiments, R 5 In some embodiments, R 5is -OR. In some embodiments, R 5 In some embodiments, R 5 is -S(O)R. In some embodiments, R 5 is -S(O)R. In some embodiments, R 5 is replaced by C 1~6 In some embodiments, R 5 teeth, [ka] It is.

[0216] In some embodiments, R 5 are hydrogen, deuterium, halogens, -NH2, -CN, -O(C 1~6 alkyl), -S(C 1~6 alkyl), -S(O)R, C 4~6 Cycloalkyl, C 1~6 Alkyl or [ka] In some embodiments, R 5 are hydrogen, deuterium, halogens, -CN, -OMe, -S(C 1~6 alkyl), -S(O)(C 1~6 Alkyl) or C 1~6 It is an alkyl.

[0217] In some embodiments, R 5 is selected from those illustrated in Table 1 below.

[0218] Generally, as defined above, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic.

[0219] In some embodiments, R a is C 1~4 In some embodiments, R ais C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R a is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0220] In some embodiments, R a is C 1~4 In some embodiments, R a is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R a is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R a is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 In some embodiments, R a is methyl optionally substituted with 1, 2, or 3 halogen atoms. a is -CF3 or methyl.

[0221] Generally, as defined above, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 It is aliphatic.

[0222] In some embodiments, R b is C 1~4 In some embodiments, R b is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R b is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 It is aliphatic.

[0223] In some embodiments, R b is C1~4 In some embodiments, R b is C optionally substituted by one, two or three deuterium or halogen atoms; 1~4 In some embodiments, R b is C optionally substituted with one, two or three deuterium atoms 1~4 In some embodiments, R b is C optionally substituted by 1, 2 or 3 halogen atoms 1~4 In some embodiments, R b is methyl optionally substituted with 1, 2, or 3 halogen atoms. b is -CF3 or methyl.

[0224] Generally, as defined above, R a and R b may be joined together with the carbon atom to which they are attached to form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1 to 2 heteroatoms each independently selected from nitrogen, oxygen and sulfur.

[0225] In some embodiments, R a and R b taken together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl. a and R b are taken together with the carbon atom to which they are attached to form a 3-8 membered heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen, and sulfur. a and R b together with the carbon atom to which they are attached form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring. a and R b together with the carbon atom to which they are attached form an oxirane, oxetane, tetrahydrofuran, or aziridine.

[0226] In some embodiments, R a and R b are both methyl. In some embodiments, R a is methyl, R b is -CF3. In some embodiments, R a and R b is selected from those illustrated in Table 1 below.

[0227] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] It is.

[0228] In some embodiments, the compound of formula X has formula Xa or Xb: [ka] or a pharma- ceutically acceptable salt thereof, R, R 3 , R 4 , R 5 , R a and R b each of which, both singly and in combination, is as defined above and as described in embodiments herein.

[0229] In another aspect, the present invention provides a compound selected from one of those depicted in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0230] In some embodiments, the present invention provides a compound depicted in Table 1 above, or a pharma- ceutically acceptable salt thereof.

[0231] In certain embodiments, the present invention provides any of the compounds described above and herein, or a pharma- ceutically acceptable salt thereof. 4. Uses of the Compounds and Pharmaceutically Acceptable Compositions Thereof

[0232] Certain compounds described herein have been found to be useful for scavenging toxic aldehydes, such as MDA and HNE.Without wishing to be bound by theory, it is believed that compounds described herein undergo Schiff base condensation with MDA, HNE, or other toxic aldehydes, forming complexes with aldehydes in energetically favorable reactions, thus reducing or eliminating the aldehydes available for reaction with proteins, lipids, carbohydrates, or DNA.Importantly, compounds described herein can react with aldehydes to form compounds with cyclic structures containing aldehydes, thus capturing aldehydes and preventing them from being released back into the cellular environment.

[0233] In one aspect, the present invention provides a method of reducing the level of one or more toxic aldehydes in a subject, comprising administering to a subject in need thereof a disclosed compound as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0234] In another aspect, the present invention provides a method for reducing the level of one or more toxic aldehydes in a biological sample, comprising contacting the biological sample with a disclosed compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein. In some embodiments, the method is carried out in vitro.

[0235] In some embodiments, the toxic aldehyde is selected from formaldehyde, acetaldehyde, acrolein, glyoxal, methylglyoxal, hexadecanal, octadecanal, hexadecenal, succinic semialdehyde, malondialdehyde, 4-hydroxynonenal, 4-hydroxy-2E-hexenal, 4-hydroxy-2E,6Z-dodecadienal, retinaldehyde, leukotriene B4 aldehyde, and octadecenal.

[0236] In some embodiments, the toxic aldehyde is formaldehyde. In some embodiments, the toxic aldehyde is acetaldehyde. In some embodiments, the toxic aldehyde is acrolein. In some embodiments, the toxic aldehyde is glyoxal. In some embodiments, the toxic aldehyde is methylglyoxal. In some embodiments, the toxic aldehyde is hexadecanal. In some embodiments, the toxic aldehyde is octadecanal. In some embodiments, the toxic aldehyde is hexadecenal. In some embodiments, the toxic aldehyde is succinic semialdehyde (SSA). In some embodiments, the toxic aldehyde is malondialdehyde (MDA). In some embodiments, the toxic aldehyde is 4-hydroxynonenal. In some embodiments, the toxic aldehyde is retinaldehyde. In some embodiments, the toxic aldehyde is 4-hydroxy-2E-hexenal. In some embodiments, the toxic aldehyde is 4-hydroxy-2E,6Z-dodecadienal. In some embodiments, the aldehyde is leukotriene B4 aldehyde. In some embodiments, the aldehyde is octadecenal.

[0237] In some embodiments, the compounds reduce systemic inflammation in a patient.

[0238] In some embodiments, the compound reduces the plasma level of a biomarker selected from IL-1β, IL-6, IL-10 and tumor necrosis factor alpha. In some embodiments, the compound reduces the plasma level of a biomarker selected from RASP. In some embodiments, RASP is malondialdehyde (MDA) and / or 4-hydroxynonenal (4-HNE).

[0239] In some embodiments, the method further comprises reducing the level of reactive aldehyde species (RASP) in the patient's blood, such as malondialdehyde (MDA) or 4-hydroxynonenal (HNE).

[0240] In some embodiments, the level of RASP is reduced by at least 30%, at least 40%, or at least 50%. In some embodiments, the level of RASP is reduced by about 30% to 75%. In some embodiments, the level of RASP is reduced by about 20% to about 60%, or about 20% to about 50%, or about 20% to about 30%.

[0241] In another aspect, the present invention provides a method of treating a disease, disorder, or condition described herein, comprising administering to a subject in need thereof a disclosed compound or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described herein.

[0242] As used herein, the terms "treatment", "treat" and "treating" refer to reversing the progression, alleviating, delaying the onset or inhibiting a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to susceptible individuals prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). In some embodiments, treatment is also continued after symptoms have resolved, for example, to prevent, delay, or reduce the severity of their recurrence.

[0243] The present invention relates to compounds as described herein for treating, preventing, and / or reducing the risk of a disease, disorder, or condition in which aldehyde toxicity is implicated in the pathogenesis.

[0244] Examples of diseases, disorders, or conditions in which aldehyde toxicity is implicated include, but are not limited to, ocular diseases, disorders, or conditions, including corneal diseases (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuchs' endothelial dystrophy), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid breakdown or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens-Johnson syndrome, ocular rosacea (with or without meibomian gland dysfunction)). In one example, the ocular disease, disorder, or condition is not macular degeneration, such as age-related macular degeneration ("AMD"), or Stargardt's disease. In further examples, the ocular disease, disorder, or condition is dry eye syndrome, ocular rosacea, or uveitis.

[0245] Examples of diseases, disorders, conditions, or indications in which aldehyde toxicity is implicated also include non-ocular disorders including psoriasis, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, Sjogren-Larsson syndrome and other ichthyoses, actinic elastosis / wrinkles, skin firmness and elasticity, swelling, eczema, smoking or irritant induced skin changes, skin incisions, burns and / or wounds associated with skin conditions, lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease, sepsis, atherosclerosis, ischemia-reperfusion injury, Parkinson's disease, Alzheimer's disease, succinic semialdehyde dehydrogenase deficiency (SSADHD), multiple sclerosis, amyotrophic lateral sclerosis, diabetes, metabolic syndrome, age-related disorders, and fibrotic diseases. In a further example, the non-ocular disorder is a skin disease, disorder or condition selected from contact dermatitis, atopic dermatitis, allergic dermatitis, and radiation dermatitis. In another example, the non-ocular disorder is a skin disease, disorder or condition selected from Sjogren-Larsson syndrome and cosmetic indications associated with burns and / or wounds.

[0246] In a further example, the disease, disorder, or condition in which aldehyde toxicity is implicated is an age-related disorder. Examples of age-related diseases, disorders, or conditions include skin wrinkling, dryness, and pigmentation.

[0247] Examples of diseases, disorders, or conditions in which aldehyde toxicity is implicated further include conditions associated with the toxic effects of blister agents or burns from alkaline agents. The compounds described herein reduce or eliminate toxic aldehydes, thus treating, preventing, and / or reducing the risk of these diseases or disorders.

[0248] In some embodiments, the present invention relates to the treatment, prevention and / or reduction of the risk of ocular diseases, disorders or conditions in which aldehyde toxicity is implicated in the pathogenesis, comprising administering a compound described herein to a subject in need of such treatment, prevention and / or reduction of the risk of ocular diseases, disorders or conditions in which aldehyde toxicity is implicated in the pathogenesis.Ocular diseases, disorders or conditions include, but are not limited to, corneal diseases (e.g., dry eye syndrome, cataracts, keratoconus, bullous keratopathy and other keratopathies, and Fuchs' endothelial dystrophy in the cornea), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, conditions associated with PRK healing and other corneal healing, and conditions associated with tear lipid breakdown or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens-Johnson syndrome, ocular rosacea (with or without meibomian gland dysfunction)). In some embodiments, the eye disease, disorder or condition is macular degeneration. In some embodiments, the eye disease, disorder or condition is AMD or Stargardt's disease. In one embodiment, in the eye disease, disorder or condition, the amount or concentration of MDA or HNE is increased in eye tissue or cell. For example, the amount or concentration of aldehyde (e.g., MDA or HNE) is increased at least 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2-fold, 2.5-fold, 5-fold, 10-fold when compared with that in normal eye tissue or cell. The compounds described herein reduce aldehyde (e.g., MDA and / or HNE) concentration in a concentration-dependent manner. The amount or concentration of aldehyde (e.g., MDA or HNE) can be measured by methods or techniques known in the art, such as those described in Tukozkan et al., Furat Tip Dergisi 11: 88-92 (2006).

[0249] In some embodiments, the ocular disease, disorder, or condition is dry eye syndrome. In a second class, the ocular disease, disorder, or condition is a condition associated with PRK healing and other corneal healing. For example, the present invention is directed to ongoing PRK healing or other corneal healing, comprising administering a compound described herein to a subject in need thereof. In a third class, the ocular disease, disorder, or condition is an ocular condition associated with high aldehyde levels as a result of inflammation, such as uveitis, scleritis, ocular Stevens-Johnson syndrome, and ocular rosacea (with or without meibomian gland dysfunction). In a fourth class, the ocular disease, disorder, or condition is keratoconus, cataract, bullous keratopathy and other keratopathy, Fuchs endothelial dystrophy, ocular cicatricial pemphigoid, or allergic conjunctivitis. The compounds described herein may be administered topically or systemically as described herein below.

[0250] In some embodiments, the present invention relates to the treatment, prevention, and / or reduction of risk of skin disorders or conditions, or cosmetic signs, in which aldehyde toxicity is implicated in the pathogenesis, comprising administering a compound described herein to a subject in need thereof. Skin disorders or conditions include, but are not limited to, psoriasis, scleroderma, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, and Sjogren-Larsson syndrome and other ichthyoses, and cosmetic signs are actinic elastosis / wrinkles, skin firmness and elasticity, swelling, eczema, smoking or irritant-induced skin changes, skin incisions, or burns and / or wounds associated with skin conditions. In some embodiments, the present invention relates to the treatment of age-related diseases, disorders, or conditions of the skin, as described herein.

[0251] Various skin disorders or conditions, such as atopic dermatitis, localized (disciform) lupus, psoriasis, and scleroderma, are characterized by high MDA and HNE levels (Br J Dermatol 149: 248 (2003); JEADV 26: 833 (2012); Clin Rheumatol 25: 320 (2006)). In addition, ichthyosis, a characteristic of Sjögren-Larsson syndrome (SLS), is caused by the accumulation of fatty aldehydes, which disrupts the normal function and secretion of lamellar bodies (LBs), leading to intercellular lipid deposition in the stratum corneum (SC) and defective water barrier in skin layers (WB Rizzo et al. (2010)). In SLS patients, mutations in the gene encoding fatty aldehyde dehydrogenase, which metabolizes fatty aldehydes, have significantly reduced or eliminated activity. Therefore, aldehyde-reducing or -eliminating compounds, such as those described herein, can be used to treat, prevent, and / or reduce the risk of skin disorders or conditions in which aldehyde toxicity is implicated in the pathogenesis, such as those described herein.Furthermore, with the improvement of water barrier and prevention of aldehyde-mediated inflammation, including fibrosis and elastosis (Chairpotto et al., 2005), many cosmetic indications, such as solar elastosis / wrinkles, skin firmness, elasticity (swelling), eczema, smoking or irritant-induced skin changes and skin incision cosmetic procedures, and skin conditions associated with burns and / or wounds, can be treated using the methods of the present invention.

[0252] In some embodiments, the skin disease, disorder or condition is psoriasis, scleroderma, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, or Sjogren-Larsson syndrome and other ichthyosis.In one case, the skin disease, disorder or condition is contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, or Sjogren-Larsson syndrome and other ichthyosis.In the second class, the cosmetic indication is actinic elastosis / wrinkles, skin firmness and elasticity, swelling, eczema, smoking or irritant-induced skin changes, skin conditions associated with skin incision or burns and / or wounds.

[0253] In some embodiments, the present invention relates to the treatment, prevention, and / or reduction of the risk of conditions associated with the toxic effects of blister agents or burns from alkaline agents, where aldehyde toxicity is implicated in the pathogenesis, comprising administering to a subject in need thereof a compound as described herein.

[0254] Blistering agents include, but are not limited to, sulfur mustard, nitrogen mustard, and phosgene oxime. The toxic or damaging effects of blistering agents include pain, irritation, and / or tears in the skin, eyes, and / or mucous membranes, as well as conjunctivitis and / or corneal damage to the eye. Sulfur mustard is the compound bis(2-chloroethyl) sulfide. Nitrogen mustards include the compounds bis(2-chloroethyl)ethylamine, bis(2-chloroethyl)methylamine, and tris(2-chloroethyl)amine. Sulfur mustard or its analogs can cause oxidative stress, particularly an increase in HNE levels, and can induce an oxidative stress response by depleting the antioxidant defense system, thereby increasing lipid peroxidation, thus increasing aldehyde levels (Jafari et al. (2010); Pal et al. (2009)). Antioxidants, such as silibinin, when applied topically, attenuate skin damage induced by exposure to sulfur mustard or its analogs, and increased activity of antioxidant enzymes may be a compensatory response to reactive oxygen species generated by sulfur mustard (Jafari et al., 2010; Tewari-Singh et al., 2012). Furthermore, interventions that reduce free radical species have been effective post-exposure treatments for phosgene-induced lung injury (Sciuto et al., 2004). Thus, compounds that reduce or eliminate aldehydes, such as those described herein, can be used to treat, prevent, and / or reduce the risk of conditions associated with the toxic effects of blister agents, such as sulfur mustard, nitrogen mustard, and phosgene oxime.

[0255] Alkaline agents include, but are not limited to, lime, lye, ammonia, and drain cleaners. Compounds that reduce or eliminate aldehydes, such as those described herein, can be used to treat, prevent, and / or reduce the risk of conditions associated with burns from alkaline agents.

[0256] In some embodiments, the present invention relates to the treatment, prevention, and / or reduction of risk of autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological disease, disorder, or condition, or metabolic syndrome, or diabetes, in which aldehyde toxicity is implicated in the pathogenesis, comprising administering a compound described herein to a subject in need of such treatment, prevention, and / or reduction of risk of autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological disease, disorder, or condition, or metabolic syndrome, or diabetes, in which aldehyde toxicity is implicated in the pathogenesis, including, but not limited to, lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis. Inflammatory diseases, disorders or conditions include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), sepsis, and fibrosis (e.g., renal, hepatic, pulmonary, and cardiac fibrosis). Cardiovascular diseases, disorders or conditions include, but are not limited to, atherosclerosis and ischemia-reperfusion injury. Nervous system diseases, disorders or conditions include, but are not limited to, Parkinson's disease, Alzheimer's disease, succinic semialdehyde dehydrogenase deficiency, multiple sclerosis, amyotrophic lateral sclerosis, and the neurological aspects of Sjogren-Larsson syndrome (cognitive delay and spasticity).

[0257] The present invention is also directed to the use of the compounds described herein in the manufacture of a medicament for the treatment, prevention and / or reduction of the risk of a disease, disorder or condition in which aldehyde toxicity is implicated in the pathogenesis. More specifically, this aspect of the invention is directed to the use of the compounds described herein in the manufacture of a medicament for the treatment, prevention, and / or reduction of the risk of (1) ophthalmic diseases, disorders, or conditions, including, but not limited to, corneal diseases (e.g., dry eye syndrome, cataracts, keratoconus, bullous and other keratopathy, and Fuchs' endothelial dystrophy), other ocular disorders or conditions (e.g., allergic conjunctivitis, ocular cicatricial pemphigoid, PRK healing and other conditions associated with corneal healing, and conditions associated with tear lipid breakdown or lacrimal gland dysfunction), and other ocular conditions associated with high aldehyde levels as a result of inflammation (e.g., uveitis, scleritis, ocular Stevens-Johnson syndrome, and ocular rosacea (with or without meibomian gland dysfunction)). For example, diseases, disorders, or conditions include, but are not limited to, psoriasis, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, Sjogren-Larsson syndrome and other ichthyoses, actinic elastosis / wrinkles, skin firmness and elasticity, swelling, eczema, smoking or irritant-induced skin changes, skin incisions, and skin conditions associated with burns and wounds, (3) toxic effects of blister agents or acetaminophen. conditions associated with burns from alkaline agents, or (4) autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological diseases (including, for example, lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease, sepsis, atherosclerosis, ischemia-reperfusion injury, Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetes, metabolic syndrome, and fibrotic diseases).

[0258] The present invention also relates to the use of the compounds described herein in treating, preventing and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is involved in the pathogenesis.More specifically, this aspect of the present invention relates to the use of the compounds described herein in treating, preventing and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is involved in the pathogenesis.More specifically, this aspect of the present invention relates to the use of the compounds described herein in treating, preventing and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is involved in the pathogenesis.More specifically, this aspect of the present invention relates to the use of the compounds described herein in treating, preventing and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is involved in the pathogenesis.More specifically, this aspect of the present invention relates to the use of the compounds described herein in treating, preventing and / or reducing the risk of diseases, disorders or conditions in which aldehyde toxicity is involved in the pathogenesis. For example, the disease, disorder or condition includes, but is not limited to, psoriasis, localized (disciform) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, Sjogren-Larsson syndrome and other ichthyoses, actinic elastosis / wrinkles, skin firmness and elasticity, swelling, eczema, smoking or irritant induced skin changes, skin incisions, and skin conditions associated with burns and wounds, (3) conditions associated with the toxic effects of erosive agents or burns from alkaline agents, or (4) autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological diseases (e.g., lupus, scleroderma, asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, inflammatory bowel disease, sepsis, atherosclerosis, ischemia-reperfusion injury, Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetes, metabolic syndrome, and fibrotic diseases.

[0259] In some embodiments, the disease, disorder, or condition is a viral infection.

[0260] In some embodiments, the viral infection is caused by a coronavirus, hepatitis A virus, hepatitis B virus, dengue virus, yellow fever virus, Zika virus, influenza virus, respiratory syncytial virus (RSV), norovirus, herpes virus, human immunodeficiency virus (HIV), Ebola virus, human T-lymphotropic virus (HTLV)-1 and -2, Epstein-Barr virus, Lassa virus, or Crimean-Congo hemorrhagic fever virus.

[0261] In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the coronavirus is an alpha, beta, gamma, or delta coronavirus. In some embodiments, the coronavirus is associated with severe respiratory conditions such as SARS.

[0262] In some embodiments, the viral infection is caused by a coronavirus, which is 229E (alphacoronavirus), NL63 (alphacoronavirus), OC43 (betacoronavirus), HKU1 (betacoronavirus), MERS-CoV (betacoronavirus that causes Middle East Respiratory Syndrome, i.e., MERS), SARS-CoV (betacoronavirus that causes Severe Acute Respiratory Syndrome, i.e., SARS), or SARS-CoV-2 (coronavirus disease 2019, i.e., COVID-19).

[0263] In some embodiments, the viral infection is caused by SARS-CoV-2.

[0264] In some embodiments, the viral infection is caused by an influenza virus.

[0265] In some embodiments, the viral infection is caused by an influenza virus, and the viral infection is selected from influenza A and influenza B. In some embodiments, the influenza virus is B / Yamagata or B / Victoria.

[0266] In some embodiments, the viral infection is caused by an influenza virus selected from H5N1, H1N1, and H3N2.

[0267] In some embodiments, the viral infection is caused by the Zika virus.

[0268] In some embodiments, a second therapeutic agent is administered to the patient, where the second therapeutic agent is selected from an antiviral agent, an antibiotic, and an NSAID.

[0269] In some embodiments, the second therapeutic agent is an antiviral agent, where the antiviral agent is suitable for treating a viral infection.

[0270] In some embodiments, the second therapeutic agent is selected from chloroquine, remdesivir, hydroxychloroquine, interferon, ribavirin, umifenovir, teicoplanin, lopinavir, ritonavir, nitazoxanide, camostat, favipiravir, tocilizumab, and passive antibody therapy.

[0271] In some embodiments, the invention provides a method of treating, preventing, and / or reducing the risk of a skin disease, disorder or condition selected from atopic dermatitis, atopic eczema, and psoriasis, or an ocular disease, disorder or condition selected from diabetic macular edema and Stargardt's disease, comprising administering to a patient in need thereof a disclosed pharmaceutical composition comprising a disclosed compound.

[0272] In some embodiments, the disclosure provides for the use of a pharmaceutical composition as described herein in the manufacture of a medicament for treating, preventing, and / or reducing the risk of a skin disease, disorder or condition selected from atopic dermatitis, atopic eczema, and psoriasis, or an ocular disease, disorder or condition selected from diabetic macular edema and Stargardt's disease.

[0273] In some embodiments, the method of the present disclosure is directed to the treatment of atopic dermatitis.In some embodiments, the method of treating or reducing the risk of atopic dermatitis comprises administering to the patient in need thereof an effective amount of the compound disclosed herein.Generally, atopic dermatitis is characterized as an inflammatory condition of the skin that presents with erythema, pruritus, scaling, lichenification and vesicular papules.The pathogenesis of atopic dermatitis is multifactorial and involves a complex immunological cascade, including the destruction of epidermal barrier, IgE dysregulation, defective cell-mediated immune response of the skin and genetic factors.

[0274] In some embodiments, the patient being treated has a history of atopy (atopic disease). In general, atopy refers to a personal or family history of atopic eczema, asthma, and allergies.

[0275] In some embodiments, the atopic dermatitis being treated is recurrent atopic dermatitis, which is a flare, exacerbation, or recurrence of atopic dermatitis following remission of a disease, disorder, or condition.

[0276] In some embodiments, the patient to be treated is identified as having loss of function of profilaggrin (FLG) mutation. Inactive precursor profilaggrin protein is a large, complex, highly phosphorylated polypeptide that is the main component of keratohyalin F granules visible in the granular cell layer of the epidermis. Various mutations in FLG gene have been identified in individuals with atopic dermatitis and are risk factors for atopic skin (see, for example, O'Regan et al., J Allergy Clinical Immunol., 2009; 124(3) Supplement 2:R2-R6).

[0277] In some embodiments, the patient has a loss of function profilaggrin (FLG) mutation that results in reduced FLG protein expression.

[0278] In some embodiments, the atopic dermatitis being treated is mild to moderate atopic dermatitis.

[0279] In some embodiments, the atopic dermatitis being treated is moderate to severe atopic dermatitis.

[0280] In some embodiments, the atopic dermatitis being treated is in the acute phase, hi some embodiments, acute atopic dermatitis presents as a vesicular, weeping, crusting rash.

[0281] In some embodiments, the atopic dermatitis being treated is in a subacute phase. In some embodiments, the subacute atopic dermatitis presents with dry, scaly, erythematous papules and plaques.

[0282] In some embodiments, the atopic dermatitis being treated is in a chronic stage. In some embodiments, the chronic atopic dermatitis exhibits lichenification due to repeated scratching.

[0283] In some embodiments, the disclosed method is directed to the treatment of psoriasis. In some embodiments, the method of treating or reducing the risk of psoriasis comprises administering to a patient in need thereof an effective amount of the compound disclosed herein. Generally, psoriasis is a chronic immune-mediated disease characterized by raised, red, scaly patches on the surface of the skin. These conditions result in part from the accelerated growth cycle of skin cells.

[0284] In some embodiments, the psoriasis being treated is plaque psoriasis, which usually appears as red, blistered, inflamed lesions covered with silvery-white scales, most often on the elbows, knees, scalp and lower back.

[0285] In some embodiments, the psoriasis to be treated is guttate psoriasis.Guttate psoriasis often begins in childhood or adulthood.Guttate psoriasis appears as small, red, individual spots on the surface of the skin, where the spots are usually not as thick or crusty as the lesions in plaque psoriasis.

[0286] In some embodiments, the psoriasis to be treated is inverse psoriasis. Inverse psoriasis usually appears as non-scaly, red lesions that occur in plaque psoriasis. The lesions may be smooth and shiny and may occur in the armpits, groin, chest, and in skin folds.

[0287] In some embodiments, the psoriasis to be treated is pustular psoriasis. Pustular psoriasis appears as white pustules or non-infected pus blisters with red surrounding skin. Pustular psoriasis can affect certain areas of the body, such as the hands and feet, or most of the body.

[0288] In some embodiments, the psoriasis to be treated is erythrodermic psoriasis. Erythrodermic psoriasis is inflammatory and manifests as peeling or flaking skin, accompanied by severe itching and pain. Edema may also be present.

[0289] In some embodiments, the psoriasis being treated is mild psoriasis. Mild forms affect about 10% or less of the total skin surface.

[0290] In some embodiments, the psoriasis being treated is moderate to severe psoriasis. Moderate to severe forms affect >10% or more of the total skin surface and may require oral or systemic administration of therapeutic agents.

[0291] In some embodiments, the psoriasis being treated is early-onset psoriasis (type I psoriasis).

[0292] In some embodiments, the psoriasis being treated is late-onset psoriasis (type II psoriasis).

[0293] In some embodiments, the disclosed method is directed to the treatment of diabetic macular edema (DME). In some embodiments, the method of treating or reducing the risk of diabetic macular edema (DME) comprises administering to a patient in need thereof an effective amount of the compound disclosed herein. In general, DME is a complication of diabetes, and is sometimes referred to as diabetic retinopathy. Damage to the microvessels of the retina that occurs from diabetes can cause fluid to leak into the retina, which leads to swelling of the surrounding tissues, including the macula, which can lead to blindness.

[0294] In some embodiments, the patient being treated is diagnosed with type 1 diabetes.

[0295] In some embodiments, the patient being treated is diagnosed with type 2 diabetes.

[0296] In some embodiments, the DME treated is clinically significant macular edema (CSME).Clinically, CSME is defined as DME that meets at least one of the following criteria: (a) retinal thickening in the center of the macula or within 500 μm from the center; (b) hard white spot in the center of the macula or within 500 μm from the center when adjacent retinal thickening is present (not counting residual hard white spot that remains after retinal thickening disappears); and (c) retinal thickening of any area (s) of 1 nipple area or larger, any part of which is within 1 nipple diameter of the center of the macula.

[0297] In some embodiments, the DME being treated is centrally-involved DME, in which the central macula is generally the thickest part of the retina and is an inversion of normal geometry.

[0298] In some embodiments, the DME being treated is non-centrally involved DME. Non-centrally involved DME is one in which there is no central involvement of the macula.

[0299] In some embodiments, the DME treated is focal DME.Focal edema often occurs with clusters of microaneurysms, sometimes surrounded by an incomplete ring of hard exudate.Focal edema is accompanied by less macular thickening, good visual acuity, and less severe retinopathy.

[0300] In some embodiments, the DME being treated is diffuse DME. Diffuse macular edema results from dilation of retinal capillaries in the retina and involves thickening of larger areas of the retina.

[0301] In some embodiments, the DME being treated is accompanied by retinal detachment or severe non-cleared vitreous hemorrhage.

[0302] In some embodiments, the patient being treated has undergone focal laser photocoagulation therapy.

[0303] In some embodiments, the patient being treated has undergone grid laser photocoagulation therapy.

[0304] In some embodiments, the method of the present disclosure is directed to the treatment of Stargardt's disease. In some embodiments, the method of treating or reducing the risk of Stargardt's disease comprises administering to a patient in need thereof an effective amount of a compound disclosed herein. In general, Stargardt's disease is an inherited form of macular dystrophy characterized by bilateral blindness, including color vision impairment and central scotoma, with characteristic macular atrophy and yellow-white spots at the level of the retinal pigment epithelium (RPE) of the posterior pole. Stargardt's disease may also be called Stargardt's macular dystrophy, juvenile macular degeneration or fundus flaviformis. The occurrence of Stargardt's disease is most common in childhood, with a second peak in early adulthood and least frequent in late adulthood. A good prognosis is generally associated with late onset.

[0305] In some embodiments, the Stargardt's disease being treated is childhood-onset Stargardt's disease.

[0306] In some embodiments, the Stargardt's disease being treated is adult-onset or late-onset Stargardt's disease.

[0307] In some embodiments, the severity of Stargardt's disease can be classified based on electrophysiological assessment (see, e.g., Tanna et al., British Journal of Ophthalmology 2017; 101:25-30).

[0308] In some embodiments, the Stargardt's disease to be treated is classified as Group 1. Group 1 Stargardt's disease exhibits a severe pattern of electroretinogram (ERG) abnormalities (macular dysfunction) with a normal full-field ERG.

[0309] In some embodiments, the Stargardt's disease being treated is classified as Group 2. Group 2 Stargardt's disease exhibits features of Group 1 with the additional generalized loss of cone function. Group 2 patients have an intermediate variable prognosis.

[0310] In some embodiments, the Stargardt's disease being treated is classified as Group 3. Group 3 Stargardt's disease shows a more generalized loss of both cone and rod function. Group 3 patients show the worst prognosis.

[0311] In some embodiments, the patient to be treated has been identified as having a mutation in the retina-specific ATP-binding cassette transporter (ABCA4) gene resulting in reduced or defective ABCA4 function. Mutations in ABCA4 are the most common form of inherited Stargardt disease.

[0312] In some embodiments, the patient to be treated has been identified as having a mutation in the ABCA4 gene associated with childhood-onset Stargardt disease. Exemplary mutations associated with childhood-onset Stargardt disease include, among others, 634C>T, 768G>T, 1317G>A, 1531C>T, 1557C>A, 5308T>G, 6088C>T, or 6449G>A.

[0313] In some embodiments, the patient to be treated is identified as having a mutation in the ABCA4 gene associated with adult-onset or late-onset Stargardt disease. Exemplary mutations associated with adult-onset or late-onset Stargardt disease include, among others, 769-784C>T, 2486C>T, 5603A>T, or 5882G>A.

[0314] As further discussed below, the compounds described herein or pharma- ceutically acceptable salts thereof can be administered systemically to treat the indications described herein. In some embodiments, the compounds or pharma- ceutically acceptable salts thereof are administered orally as part of a solid pharmaceutical composition. In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the pharmaceutical composition is administered as a liquid by nasogastric tube.

[0315] In some embodiments, in the case of ocular manifestations of diabetic macular edema or Stargardt's disease, the compound or a pharma- ceutically acceptable salt thereof is administered intravitreally.

[0316] In some embodiments, the disease, disorder or condition is acute respiratory distress syndrome (ARDS). In some embodiments, the ARDS is associated with a viral infection. In some embodiments, the viral infection is associated with viral sepsis.

[0317] In some embodiments, the viral infection is associated with viral pneumonia.

[0318] In some embodiments, the method of treating ARDS comprises administering to a patient having ARDS caused by or associated with a viral infection an effective amount of a pharmaceutical composition disclosed herein.

[0319] In some embodiments, the viral infection is caused by a coronavirus, hepatitis A virus, hepatitis B virus, dengue virus, yellow fever virus, Zika virus, influenza virus, norovirus, herpes virus, respiratory syncytial virus (RSV), human immunodeficiency virus (HIV), Ebola virus, human T-lymphotropic virus (HTLV)-1 and -2, Epstein-Barr virus, Lassa virus, or Crimean-Congo hemorrhagic fever virus.

[0320] In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the viral infection is caused by a coronavirus selected from 229E, NL63, OC43, HKU1, MERS-CoV, SARS-CoV, and SARS-CoV-2.

[0321] In some embodiments, the viral infection is caused by a coronavirus. In some embodiments, the coronavirus is an alpha, beta, gamma, or delta coronavirus. In some embodiments, the coronavirus is associated with severe respiratory conditions such as SARS.

[0322] In some embodiments, the viral infection is caused by a coronavirus, which is 229E (alphacoronavirus), NL63 (alphacoronavirus), OC43 (betacoronavirus), HKU1 (betacoronavirus), MERS-CoV (betacoronavirus that causes Middle East Respiratory Syndrome, i.e., MERS), SARS-CoV (betacoronavirus that causes Severe Acute Respiratory Syndrome, i.e., SARS), or SARS-CoV-2 (coronavirus disease 2019, i.e., COVID-19).

[0323] In some embodiments, the viral infection is due to respiratory syncytial virus (RSV), influenza virus, coronavirus, or herpes virus.

[0324] In some embodiments, the viral infection is due to a coronavirus.

[0325] In some embodiments, the coronavirus is selected from 229E, NL63, OC43, HKU1, MERS-CoV, SARS-CoV and SARS-CoV-2.

[0326] In some embodiments, the viral infection is due to SARS-CoV-2.

[0327] In some embodiments, the viral infection is due to an influenza virus.

[0328] In some embodiments, the influenza virus is influenza A or influenza B.

[0329] In some embodiments, the influenza virus is B / Yamagata or B / Victoria.

[0330] In some embodiments, the influenza virus is H5N1, H1N1, or H3N2.

[0331] In some embodiments, the ARDS is associated with a bacterial infection.

[0332] In some embodiments, the bacterial infection is associated with bacterial sepsis.

[0333] In some embodiments, the bacterial infection is associated with bacterial pneumonia.

[0334] In some embodiments, the bacterial infection is due to Streptococcus pneumoniae, Staphylococcus aureus, Legionella pneumophila, Pneumocystis jirovecii, or Haemophilus influenza.

[0335] In some embodiments, ARDS is associated with acute injury to the lungs caused by chemical toxins or physical trauma.

[0336] In some embodiments, the acute injury to the lung is due to a chemical toxin.

[0337] In some embodiments, the chemical toxin that causes acute lung injury is a choking agent, a vesicant, or a nerve agent.

[0338] In some embodiments, the chemical toxin is an asphyxiant, where the asphyxiant is chlorine gas, phosgene, carbonyl chloride, hydrogen sulfide, or ammonia.

[0339] In some embodiments, the chemical toxin is a vesicant, in which case the vesicant is a sulfur mustard or a nitrogen mustard.

[0340] In some embodiments, the chemical toxin is a nerve agent, and the nerve agent is tabun, sarin, soman, or VX.

[0341] In some embodiments, ARDS is associated with acute injury to the lungs caused by a biological toxin.

[0342] In some embodiments, the biological toxin is ricin, botulinum toxin, or Staphylococcal enterotoxin B.

[0343] In some embodiments, the patient is being treated with mechanical ventilation.

[0344] In some embodiments, the disease, disorder, or condition is an inflammatory condition. In some embodiments, the inflammatory disorder is systemic. In some embodiments, the inflammatory disorder is localized to a specific tissue or organ. In some embodiments, the disease, disorder, or condition treated by the compounds of the present disclosure is non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), inflammatory bowel disease (inflammatory bowel disease), or other conditions. disease), Crohn's disease, ulcerative colitis (UC), psoriasis, IBS (irritable bowel syndrome or spastic colon) (including spastic colon), ankylosing spondylitis, osteoporosis, rheumatoid arthritis (RA), psoriatic arthritis, chronic obstructive pulmonary disease (COPD), atherosclerosis, pulmonary arterial hypertension, pyridoxine-dependent epilepsy, atopic dermatitis, atopic eczema, rosacea, multiple sclerosis (MS), systemic lupus erythematosus (SLE), lupus nephritis, sepsis, eosinophilic esophagitis, chronic kidney disease (CKD), renal fibrosis, chronic eosinophilic pneumonia, extrinsic allergic alveolitis, pre-eclampsia, endometriosis, polycystic ovary syndrome (PCOS), reduced fertility in women, reduced sperm viability and motility or cyclophosphamide-induced hemorrhagic cystitis.

[0345] In some embodiments, the disease, disorder or condition treated by the compounds of the present disclosure is chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), emphysema due to alpha-1 antitrypsin deficiency, or pulmonary arterial hypertension (PAH).

[0346] In some embodiments, the disease, disorder or condition treated by the compounds of the present disclosure is light chain deposition disease, IgA nephropathy, end stage renal disease, gout, pseudogout, diabetic nephropathy, diabetic neuropathy, traumatic brain injury, noise-induced hearing loss, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, primary biliary cirrhosis, primary sclerosing cholangitis, uterine leiomyoma, sarcoidosis or chronic kidney disease.

[0347] In some embodiments, the disease, disorder or condition treated by the compounds of the present disclosure is an ocular inflammatory disorder. In some embodiments, the ocular inflammatory disorder is diabetic macular edema (DME), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), age-related macular degeneration (AMD), dry eye disease (DED), allergic conjunctivitis (AC), dry eye disease with allergic conjunctivitis, non-infectious anterior uveitis, posterior uveitis, panuveitis, postoperative ocular pain and inflammation.

[0348] In some embodiments, the disease, disorder or condition is one of those described in WO2019 / 075136, which is incorporated herein by reference.

[0349] In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered once, twice, three or four times daily.In some embodiments, the compound or a pharma- ceutically acceptable salt thereof is administered twice daily.

[0350] In some embodiments, the dose of the compound or a pharma- ceutically acceptable salt thereof is administered systemically.

[0351] In some embodiments, the dose of the compound or a pharma- ceutically acceptable salt thereof is administered orally.

[0352] In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the pharmaceutical composition is administered as a liquid by nasogastric tube.

[0353] In some embodiments, the method further comprises administering to the patient an effective amount of a second therapeutic agent suitable for treating ARDS.

[0354] In some embodiments, the second therapeutic agent is an anti-inflammatory agent selected from a steroid, an anti-GM-CSF antibody, and a pulmonary surfactant.

[0355] Chronic cough, pneumonia and pulmonary sepsis are clinically distinct respiratory diseases, disorders or conditions. Chronic cough is generally defined as a cough that lasts longer than 8 weeks, excluding cough accompanied by underlying fever, such as from bacterial or viral infection; chronic obstructive pulmonary disease (COPD) and other non-asthmatic lung diseases; lung or esophageal cancer; pneumonia; interstitial lung disease; and obstructive sleep apnea. Pneumonia is an infection of the lungs by pathogens such as bacteria, viruses or fungi. Pneumonia is distinct from acute respiratory distress syndrome, which may be caused by acute injury to the lungs unrelated to infection by pathogens. Pneumonia is usually diagnosed by a combination of clinical diagnosis from clinical history, physical and / or laboratory tests, and chest X-ray (CXR), which can distinguish pneumonia from other airway infections. Pulmonary sepsis also affects the lungs, but can be attributed to sepsis because of the susceptibility of the lungs and because sepsis can develop from infection of the lungs by pathogens.

[0356] Alcohol-induced hepatitis, minimal change disease, and focal segmental glomerulosclerosis affect the liver or kidneys rather than the lungs. Alcohol-induced hepatitis results from chronic alcohol abuse and is characterized by injury to the liver. Distinct features include hyperbilirubinemia and levels of the liver function markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Minimal change disease and focal segmental glomerulosclerosis are diseases, disorders, or conditions that affect the kidneys. Both minimal change disease and focal segmental glomerulosclerosis fall within the broader spectrum of disorders of nephrotic syndrome and are characterized by urinary protein. Minimal change disease can progress to focal segmental glomerulosclerosis, the latter of which is associated with injury and scarring to the kidney in a focal segmental pattern.

[0357] In some embodiments, the pharmaceutical compositions described herein are used to treat, prevent and / or reduce the risk of a respiratory disease, disorder or condition selected from chronic cough, atopic asthma, allergic rhinitis, sinusitis, hay fever, pneumonia and pulmonary sepsis, or an organ disease, disorder or condition selected from alcohol-induced hepatitis, minimal change disease and focal segmental glomerulosclerosis.

[0358] As set forth above, in one aspect, the disclosure provides a method of treating, preventing and / or reducing the risk of a respiratory disease, disorder or condition selected from chronic cough, atopic asthma, allergic rhinitis, sinusitis, hay fever, pneumonia and pulmonary sepsis, or an organ disease, disorder or condition selected from alcohol-induced hepatitis, minimal change disease and focal segmental glomerulosclerosis, comprising administering an effective amount of a pharmaceutical composition described herein.

[0359] In some embodiments, atopic (or allergic) asthma is triggered by indoor, outdoor or occupational allergens, including pollen, dust, animals (e.g., cat dander or dog hair), or allergens such as dust mites. In some embodiments, a patient with atopic asthma also has another condition selected from seasonal allergies, eczema and food allergies.

[0360] In some embodiments, the disease, disorder or condition is pulmonary sepsis. In some embodiments, the disease, disorder or condition is sepsis or septic shock. In some embodiments, the disease, disorder or condition is keratitis. In some embodiments, the disease, disorder or condition is graft-versus-host disease, such as graft-versus-host disease after corneal or organ transplantation. In some embodiments, the disease, disorder or condition is arthritis, osteoarthritis, or rheumatoid arthritis. In some embodiments, the disease, disorder or condition is multiple sclerosis. In some embodiments, the disease, disorder or condition is amyotrophic lateral sclerosis. In some embodiments, the disease, disorder or condition is Alzheimer's disease. In some embodiments, the disease, disorder or condition is Huntington's disease. In some embodiments, the disease, disorder or condition is Parkinson's disease. In some embodiments, the disease, disorder or condition is fibrosis.

[0361] In some embodiments, the disease, disorder, or condition is keratitis. In some embodiments, the disease, disorder, or condition is neurotrophic keratitis. In some embodiments, the disease, disorder, or condition is scleritis.

[0362] In some embodiments, the disclosure provides for the use of a pharmaceutical composition as described herein in the manufacture of a medicament for treating, preventing and / or reducing the risk of a respiratory disease, disorder or condition selected from chronic cough, atopic asthma, allergic rhinitis, sinusitis, hay fever, pneumonia and pulmonary sepsis, or an organ disease, disorder or condition selected from alcohol-induced hepatitis, minimal change disease and focal segmental glomerulosclerosis.

[0363] In some embodiments, the disclosure provides a method of treating ethanol toxicity, comprising administering to a subject in need thereof an effective amount of a disclosed compound. In some embodiments, the disclosure provides a use of a disclosed compound or a pharmaceutical composition described herein in the manufacture of a medicament for treating, preventing and / or reducing the risk of ethanol toxicity. In some embodiments, the disclosure provides a method of treating a hangover, comprising administering to a subject in need thereof an effective amount of a disclosed compound. In some embodiments, the disclosure provides a use of a disclosed compound or a pharmaceutical composition described herein in the manufacture of a medicament for treating, preventing and / or reducing the risk of hangover.

[0364] In some embodiments, the method of the present disclosure is directed to the treatment of chronic cough. In some embodiments, the method of treating or reducing the risk of chronic cough comprises administering to a patient in need thereof an effective amount of the pharmaceutical composition disclosed herein. In general, chronic cough is characterized as a cough that continues for a period of more than 8 weeks (see, for example, Irwin et al., Chest, 2018; 153(1):196-209; Morice, AH, European Respiratory J., 2004; 24:481-492). Chronic cough can be triggered and / or caused by various underlying causes, such as asthma, gastroesophageal reflux disease (GERD), nonasthmatic eosinophilic bronchitis (NAEB) and upper airway cough syndrome (otherwise known as postnasal drip syndrome). Differential diagnosis of chronic cough excludes causes of cough accompanied by fever, such as bacterial or viral infections; chronic obstructive pulmonary disease (COPD) and other nonasthmatic lung diseases; lung or esophageal cancer; pneumonia; interstitial lung disease; and obstructive sleep apnea (see, e.g., Perotin et al., Ther Clin Risk Manag, 2018: 14:1041-1051).

[0365] In some embodiments, the chronic cough being treated is associated with upper respiratory tract cough syndrome.

[0366] In some embodiments, the chronic cough to be treated is associated with gastroesophageal reflux disease or laryngopharyngeal reflux disease.

[0367] In some embodiments, the chronic cough being treated is associated with asthma.

[0368] In some embodiments, the chronic cough being treated is associated with non-asthmatic eosinophilic bronchitis.

[0369] In some embodiments, the patient being treated has a history of one or more of the following: treatment with angiotensin-converting enzyme (ACE) inhibitors, smoking, asthma, exposure to environmental respiratory irritants, and bronchitis.

[0370] In some embodiments, the methods of the present disclosure are directed to the treatment of pneumonia, hi some embodiments, the pneumonia is unrelated to or does not occur simultaneously with acute respiratory distress syndrome (ARDS).

[0371] In some embodiments, the patient being treated has pneumonia, and the pneumonia has a diagnosis different from eosinophilic pneumonia (i.e., the pneumonia is unrelated to eosinophilic pneumonia).

[0372] In some embodiments, the pneumonia being treated is community-acquired pneumonia.

[0373] In some embodiments, the pneumonia being treated is hospital-acquired pneumonia.

[0374] In some embodiments, the pneumonia being treated is bacterial pneumonia or viral pneumonia.

[0375] In some embodiments, the patient being treated has been diagnosed with a bacterial infection with, inter alia, Streptococcus pneumoniae, Haemophilus influenzae, S. aureus, Group A streptococci, Moraxella catarrhalis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Legionella spp, Mycoplasma pneumoniae, Chlamydia pneumoniae, or C. psittaci.

[0376] In some embodiments, the patient being treated is diagnosed with a viral infection with influenza virus (e.g., influenza A or influenza B), respiratory syncytial virus (RSV), parainfluenza, metapneumovirus, coronavirus, rhinovirus, hantavirus, or adenovirus.

[0377] In some embodiments, the pneumonia being treated is lobar pneumonia.

[0378] In some embodiments, the pneumonia being treated is upper lobar, middle lobar, or lower lobar pneumonia.

[0379] In some embodiments, the pneumonia being treated is focal pneumonia, alveolar pneumonia, or interstitial pneumonia.

[0380] In some embodiments, the pneumonia being treated is bronchopneumonia.

[0381] In some embodiments, the methods of the present disclosure are directed to the treatment of atopic asthma.In some embodiments, the methods of the present disclosure are directed to the treatment of allergic rhinitis.

[0382] In some embodiments, the disclosed method is directed to treating sepsis or reducing the risk thereof.In some embodiments, the disclosed method is directed to treating pulmonary sepsis or sepsis-induced lung injury.Generally, pulmonary sepsis or sepsis-induced lung injury is characterized by lung injury resulting from sepsis.Mainly, pneumonia is often the starting point of septic process, and disseminated infectious process is associated with systemic inflammatory response (SIRS), in which case the first organ affected is usually the lung, so the lung is the organ most frequently affected by sepsis.

[0383] In some embodiments, the pulmonary sepsis or sepsis-induced lung injury that is treated is not accompanied by (ie, is not associated with) acute respiratory distress syndrome (ARDS).

[0384] In some embodiments, the disclosed method is directed to the treatment of alcoholism. In some embodiments, the disclosed method is directed to the treatment of alcoholic hepatitis. In general, alcohol-induced hepatitis includes liver injury and associated inflammatory conditions resulting from chronic alcohol abuse. The hallmark or marker of this disease is hyperbilirubinemia. In some embodiments, alcohol-induced hepatitis is differentiated from cirrhosis in that alcohol-induced hepatitis appears to be reversible, whereas cirrhosis is a permanent injury to the liver.

[0385] In some embodiments, the alcohol-induced hepatitis is free of (ie, does not involve) cirrhosis of the liver.

[0386] In some embodiments, patients being treated for alcohol-induced hepatitis are determined to have elevated levels of aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) compared to levels in a control group not afflicted with alcohol-induced hepatitis.

[0387] In some embodiments, the level of AST in the control group (ie, no alcohol-induced hepatitis) is about 8-48 IU / L and the level of ALT in the control group is about 7-55 IU / L.

[0388] In some embodiments, the patient to be treated has an AST:ALT ratio of more than 2:1. This ratio is characteristic of patients with alcoholic liver disease. Patients with a history of alcohol abuse but without severe alcoholic hepatitis or liver cirrhosis usually have an AST / ALT ratio of less than 1.0.

[0389] In some embodiments, the method of the present disclosure is directed to the treatment of minimal change disease, sometimes referred to as lipoid nephrosis or nephropathy. In some embodiments, the method of treating or reducing the risk of minimal change disease comprises administering to a patient in need thereof an effective amount of a compound disclosed herein. In general, minimal change disease is a renal disease resulting from histopathological lesions in the glomerulus and is characterized by urinary protein, leading to edema and intravascular volume reduction. Minimal change disease is a common form of nephrotic syndrome.

[0390] In some embodiments, the minimal change disease being treated is associated with nephrotic syndrome.

[0391] In some embodiments, the minimal change disease being treated is coincident with urinary protein, particularly excessive urinary protein.

[0392] Minimal change disease may also progress to focal segmental glomerulosclerosis. Thus, in some embodiments, the disclosed method is directed to the treatment of focal segmental glomerulosclerosis (FGS). In some embodiments, the method of treating or reducing the risk of FGS comprises administering to a patient in need thereof an effective amount of a compound disclosed herein. In general, FGS describes a common lesion in both progressive kidney disease and excessive urinary protein and podocyte damage. Kidney injury and scarring are characterized by focal involvement in a segmental pattern. FGS is also a common cause of nephrotic syndrome.

[0393] In some embodiments, the FSGS being treated is primary FSGS.

[0394] In some embodiments, the FSGS being treated is secondary FSGS.

[0395] In some embodiments, the FSGS treated is familial FSGS.Autosomal dominant FSGS is associated with mutations in the gene encoding reverse formin 2 (INF2), the alpha-actinin-4 gene ACTN4; the gene encoding TRPC6 cation channel protein; and the gene encoding FilGAP protein ARHGAP24 (see, for example, Pollak, MR, Adv Chronic Kidney Dis., 2014, 21(5): 422-425).Latent forms of FSGS are associated with mutations in the gene encoding nephrin NPHS1; and the gene encoding phospholipase C epsilon 1 PLCE1 (see, for example, Pollak, supra).

[0396] In some embodiments, the FSGS being treated is associated with nephrotic syndrome.

[0397] In some embodiments, the FSGS being treated is concurrent with renal failure and / or urinary protein, particularly excessive urinary protein.

[0398] In some embodiments, the patient being treated for FSGS has a prior history of minimal change disease.

[0399] In some embodiments, the pharmaceutical compositions of the present disclosure comprising a compound described herein or a pharma- ceutical acceptable salt thereof are administered systemically to treat the indications described herein, hi some embodiments, the pharmaceutical compositions are administered orally.

[0400] In some embodiments, the pharmaceutical composition is a liquid. In some embodiments, the pharmaceutical composition is administered as a liquid by nasogastric tube.

[0401] Those skilled in the art will understand that the diseases, disorders or conditions listed herein may involve more than one pathological mechanism.For example, the diseases, disorders or conditions listed herein may involve dysregulation in immune and inflammatory response.Therefore, the above classification of diseases, disorders or conditions is not absolute, and the diseases, disorders or conditions may be considered to be immune, inflammatory, cardiovascular, nervous system and / or metabolic diseases, disorders or conditions.

[0402] Individuals with aldehyde dehydrogenase deficiency have been found to have high aldehyde levels and increased risk of Parkinson's disease (PNAS, 110:636 (2013)) and Alzheimer's disease (BioChem Biophys Res Commun., 273:192 (2000)). In Parkinson's disease, aldehydes specifically interfere with the physiological function of dopamine (Free Radic Biol Med, 51:1302 (2011); Mol Aspects Med, 24:293 (2003); Brain Res, 1145:150 (2007)). Furthermore, aldehyde levels are elevated in multiple sclerosis, amyotrophic lateral sclerosis, autoimmune diseases such as lupus, rheumatoid arthritis, psoriasis, scleroderma, and fibrotic diseases, and increased levels of HNE and MDA are associated with the progression of atherosclerosis and diabetes (J. Cell. Mol. Med. 15:1339 (2011); Arthritis Rheum 62:2064 (2010); Clin Exp Immunol 101:233 (1995); Int J Rheum Dis 14:325 (2011); JEADV 26:833 (2012); Clin Rheumatol 25:320 (2006); Gut 54:987 (2005); J Am Soc Nephrol, 20:2119 (2009)). MDA has further been implicated in the increased formation of foam cells leading to atherosclerosis (Leibundgut et al., Current Opinion in Pharmacology, 13:168 (2013)). Aldehyde-related toxicity also plays an important role in the pathogenesis of many inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD) (Bartoli et al., Mediators of Inflammation, 2011, article 891752).Therefore, compounds that reduce or eliminate aldehydes, such as those described herein, can be used to treat, prevent, and / or reduce the risk of autoimmune, immune-mediated, inflammatory, cardiovascular, or neurological diseases, disorders, or conditions, or metabolic syndrome, or diabetes.For example, compounds described herein prevent aldehyde-mediated cell death in neurons.In addition, compounds described herein downregulate a wide range of pro-inflammatory cytokines and / or upregulate anti-inflammatory cytokines, indicating that compounds described herein are useful for treating inflammatory diseases, such as multiple sclerosis and amyotrophic lateral sclerosis.

[0403] As discussed above, the disclosed compounds can be administered to a subject to treat or prevent macular degeneration and other forms of retinal disease whose pathogenesis involves the accumulation of A2E and / or lipofuscin. Other diseases, disorders, or conditions characterized by the accumulation of A2E can be treated similarly.

[0404] In one embodiment, a compound that reduces the formation of A2E is administered to a subject.For example, the compound can compete with PE for reaction with trans-RAL, thereby reducing the amount of A2E that is formed.In another embodiment, a compound that prevents the accumulation of A2E is administered to a subject.For example, the compound can compete with PE for reaction with trans-RAL quite well, and does not form A2E.

[0405] The treated individuals are classified into three groups: (1) those who are clinically diagnosed with macular degeneration or other forms of retinal disease whose etiology involves A2E and / or lipofuscin accumulation, based on visual defects (including but not limited to dark adaptation, contrast sensitivity and acuity) as determined by visual inspection and / or electroretinography, and / or retinal health as shown by fundoscopic examination of retinal and RPE tissues for drusen accumulation, tissue atrophy and / or lipofuscin fluorescence, (2) those who are presymptomatic to macular degenerative disease but are considered to be at risk based on abnormal results in any or all of the same measures, and (3) those who are presymptomatic but are considered to be genetically at risk based on a family history of macular degenerative disease and / or genotyping results showing one or more alleles or polymorphisms associated with the disease. The composition is administered topically or systemically, one or more times per month, week or day. The dosage may be selected to avoid side effects in dark-adapted visual performance, if any. Treatment is continued for at least 1 month, 3 months, 6 months, or 12 months, or longer. Patients can be examined at 1 month, 3 months, 6 months, or 12 months, or longer intervals to evaluate safety and efficacy. Efficacy is measured by examining the visual performance and retinal health as described above.

[0406] In one embodiment, the subject is diagnosed with symptoms of macular degeneration and then administered the disclosed compound. In another embodiment, the subject can be identified as at risk for developing macular degeneration (risk factors include smoking history, age, female gender, and family history) and then administered the disclosed compound. In another embodiment, the subject can have dry AMD in both eyes and then administered the disclosed compound. In another embodiment, the subject can have wet AMD in one eye but dry AMD in the other eye and then administered the disclosed compound. In yet another embodiment, the subject can be diagnosed with Stargardt's disease and then administered the disclosed compound. In another embodiment, the subject is diagnosed with symptoms of other forms of retinal disease whose etiology involves accumulation of A2E and / or lipofuscin and then administered the compound. In another embodiment, a subject may be identified as at risk of developing other forms of retinal disease whose etiology involves accumulation of A2E and / or lipofuscin, and then the disclosed compound is administered. In some embodiments, the compound is administered prophylactically. In some embodiments, a subject is diagnosed with a disease before retinal damage is evident. For example, a subject is found to carry a genetic mutation for ABCA4 and is diagnosed as at risk for Stargardt's disease before any ophthalmic signs are evident, or a subject is found to have early macular changes indicative of macular degeneration before the subject is aware of any impact on vision. In some embodiments, a human subject may know that they are in need of treatment or prevention of macular generation.

[0407] In some embodiments, the subject may be monitored for the extent of macular degeneration. The subject may be monitored in various ways, for example, by eye examination, dilated eye examination, fundus examination, visual acuity test and / or biopsy. The monitoring may be performed at various times. For example, the subject may be monitored after the compound is administered. The monitoring may be performed, for example, one day, one week, two weeks, one month, two months, six months, one year, two years, five years, or any other period after the first administration of the compound. The subject may be monitored repeatedly. In some embodiments, the dose of the compound may be changed in response to the monitoring.

[0408] In some embodiments, the disclosed method may be combined with other methods, such as photodynamic therapy, for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin.For example, a patient may be treated with more than one therapy for one or more diseases or disorders.For example, a patient may have one eye suffering from dry AMD, which is treated with the compound of the present invention, and the other eye suffering from wet AMD, which is treated with, for example, photodynamic therapy.

[0409] In some embodiments, compounds for treating or preventing macular degeneration or other forms of retinal disease whose etiology involves the accumulation of A2E and / or lipofuscin may be administered chronically. Compounds may be administered daily, more than once a day, twice a week, three times a week, weekly, biweekly, monthly, bimonthly, semi-annually, annually, and / or biennially.

[0410] Sphingosine 1-phosphate, a bioactive signaling molecule with diverse cellular functions, is irreversibly degraded by the endoplasmic reticulum enzyme sphingosine 1-phosphate lyase to yield trans-2-hexadecenal and phosphoethanolamine. trans-2-hexadecenal has been demonstrated to cause cytoskeletal reorganization, abscission, and apoptosis in multiple cell types via a JNK-dependent pathway. See Biochem Biophys Res Commun. 2012 Jul 20;424(1):18-21. These findings and the known chemical properties of related α,β-unsaturated aldehydes raise the possibility that trans-2-hexadecenal may interact with additional cellular constituents. trans-2-Hexadecenal was shown to react readily with deoxyguanosine and DNA to produce the diastereoisomers of the cyclic 1,N(2)-deoxyguanosine adducts 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8R-hydroxy-6R-tridecylpyrimido[1,2-a]purin-10(3H)one and 3-(2-deoxy-β-d-erythro-pentofuranosyl)-5,6,7,8-tetrahydro-8S-hydroxy-6S-tridecylpyrimido[1,2-a]purin-10(3H)one. These findings demonstrate that trans-2-hexadecenal produced endogenously by sphingosine 1-phosphate lyase reacts directly with DNA adducts derived from DNA-forming aldehydes that potentially have mutagenic consequences.

[0411] Succinic semialdehyde dehydrogenase deficiency (SSADHD), also known as 4-hydroxybutyric aciduria or gamma-hydroxybutyric aciduria, is the most common autosomal recessive genetic disorder of GABA metabolism (Vogel et al., 2013). It presents with developmental delay and hypotonia in early childhood, and severe expressive language disorder and obsessive-compulsive disorder phenotypes in adolescence and adulthood. Epilepsy occurs in half of patients, usually as generalized tonic-clonic seizures, although occasional absence and myoclonic seizures occur (Pearl et al., 2014). In adolescence and adulthood, more than two-thirds of patients present with potentially disabling neuropsychiatric problems (i.e., ADHD, OCD, and aggression). Metabolically, there is an accumulation of the major inhibitory neurotransmitters GABA and gamma-hydroxybutyrate (GHB), which are neuromodulatory monocarboxylic acids (Snead and Gibson, 2005). In addition, several other intermediates specific to the disorder have been detected in both patients and the corresponding murine models. Vigabatrin (VGB; γ-vinyl-GABA), an irreversible inhibitor of GABA-transaminase, is a logical choice for the treatment of SSADH deficiency, as it blocks the conversion of GABA to GHB. Outcomes are variable, and in selected patients, treatment has led to deterioration (Good, 2011; Pellock, 2011; Escalera et al., 2010; Casarano et al., 2011; Matern et al., 1996; Al-Essa et al., 2000). Targeted therapy for SSADHD remains elusive, and to date, interventions are only palliative. Thus, in some embodiments, the present invention provides a method for treating SSADHD, comprising administering to a subject in need thereof an effective amount of the disclosed compound or a pharma- ceutically acceptable salt thereof.In some embodiments, the method improves the symptoms of SSADHD selected from developmental delay, hypotonia, severe expressive speech disorder, obsessive-compulsive disorder, epilepsy (e.g., generalized tonic-clonic seizures, myoclonic seizures) or neuropsychiatric disorders (e.g., ADHD, OCD and aggression).In some embodiments, the method reduces the bioaccumulation of GHB and / or GABA. 5. Pharmaceutically acceptable compositions

[0412] The compounds and compositions are administered according to the method of the present invention using any amount and any route of administration effective for treating or reducing the severity of the disease, disorder or condition presented above. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. However, it will be understood that the total amount of the compounds and compositions of the present invention to be used per day will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder to be treated, the activity of the specific compound used, the specific composition used, the age, weight, general health, sex and diet of the patient, the time of administration, the route of administration, and the excretion rate of the specific compound used, the duration of treatment, drugs used in combination or simultaneously with the specific compound used, and similar factors well known in the medical field.

[0413] The pharma- ceutically acceptable compositions of the invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment or drops), orally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention are administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, one or more times per day, to obtain the desired therapeutic effect.

[0414] Liquid dosage forms for oral administration include, but are not limited to, pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromatics.

[0415] Injectable preparations, for example, sterile aqueous or oily suspensions for injection, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Injectable sterile preparations can also be injectable sterile solutions, suspensions or emulsions, for example, in 1,3-butanediol, in parenterally acceptable non-toxic diluents or solvents. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any non-irritating non-volatile oils can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0416] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium prior to use.

[0417] In order to prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0418] Compositions for rectal or vaginal administration can be prepared by mixing the compounds of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound, preferably a suppository.

[0419] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharma- ceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) bulking agents or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, etc. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[0420] Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and can also be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0421] As mentioned above, the active compound can also be in microencapsulated form with one or more excipients. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms can also contain additional substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is normal practice. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents. They can optionally contain opacifying agents and can also be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0422] Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is admixed under sterile conditions with a pharma- ceutical acceptable carrier, and any necessary preservatives, or buffers, as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0423] The compounds of the present invention can also be administered topically, for example, directly to the eye, for example, as eye drops or eye ointments. Eye drops typically contain an effective amount of at least one compound of the present invention and a carrier that can be safely applied to the eye. For example, eye drops are in the form of an isotonic solution, and the pH of the solution is adjusted so as not to cause eye irritation. In many cases, the epithelial barrier prevents the penetration of molecules into the eye. Therefore, most currently used ophthalmic drugs are supplemented with some form of penetration enhancer. These penetration enhancers work by loosening the tight junctions of the uppermost epithelial cells (Burstein, 1985, Trans Ophthalmol Soc UK 104(Pt4):402-9; Ashton et al., 1991, J Pharmacol Exp Ther 259(2):719-24; Green et al., 1971, Am J Ophthalmol 72(5):897-905). The most commonly used penetration enhancer is benzalkonium chloride, which also acts as a preservative against microbial contamination (Tang et al., 1994, J Pharm Sci 83(1):85-90; Burstein et al., 1980, Invest Ophthalmol Vis Sci 19(3):308-13). Benzalkonium chloride is typically added to a final concentration of 0.01-0.05%.

[0424] Topical administration can be in the form of creams, suspensions, emulsions, ointments, drops, oils, lotions, patches, tapes, inhalants, sprays, or controlled release topical formulations, including gels, films, patches, and adhesives. Intraocular administration can take the form of subconjunctival, subtenon, retrobulbar, or intravitreal injections, depots, or implants. Compounds administered by these routes can be in solution or suspension form. Compounds administered by depot injections can contain pharma- ceutically acceptable carriers or excipients, which can be natural or synthetic, biodegradable or non-biodegradable, and can facilitate drug release in a controlled manner. Implants used for controlled release of compounds can be made of natural or synthetic, biodegradable or non-biodegradable materials. Carriers are acceptable in that they are compatible with other components of the composition and are not toxic to patients. Some examples of carriers include: (1) sugars, such as lactose, glucose, and sucrose, (2) starches, such as corn starch and potato starch, (3) cellulose, and (4) cyclodextrin. Useful topical formulations are described in PCT Publication No. WO2011 / 072141, the contents of which are incorporated herein by reference.

[0425] Preparations for topical administration to the skin can include, for example, ointments, creams, gels and pastes that contain the primary amine compound in a medicament acceptable carrier. Preparations of the primary amine compound for topical use can include preparations of oily or water-soluble ointment bases, as known to those skilled in the art. For example, these preparations can include vegetable oils, animal fats, and semi-solid hydrocarbons, such as those obtained from petroleum. Specific components used can include white ointment, yellow ointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum, white petrolatum, spermaceti, glycerin starch, white wax, yellow wax, lanolin, anhydrous lanolin and glyceryl monostearate. Various water-soluble ointment bases can also be used, including glycol ethers and derivatives, polyethylene glycol, polyoxyl 40 stearate and polysorbates.

[0426] Formulations for topical administration may be administered in the range of 0.001-10%, 0.05-10%, 0.1-10%, 0.2-10%, 0.5-10%, 1-10%, 2-10%, 3-10%, 4-10%, 5-10% or 7-10% (weight / volume), or in the range of 0.001-2.0%, 0.001-1.5% or 0.001-1.0% (weight / volume), or in the range of 0.05-2.0%, 0.05-1.5% or 0.05-1. The compound used in the present application may be contained in a concentration in the range of 0% (weight / volume), or in the range of 0.1-5.0%, 0.1-2.0%, 0.1-1.5%, or 0.1-1.0% (weight / volume), or in the range of 0.5-5.0%, 0.5-2.0%, 0.5-1.5%, or 0.5-1.0% (weight / volume), or in the range of 1-5.0%, 1-2.0%, or 1-1.5% (weight / volume). Formulations for topical administration may also contain the compounds used in the present application in concentrations ranging from 0.001 to 2.5%, 0.01 to 2.5%, 0.05 to 2.0%, 0.1 to 2.0%, 0.2 to 2.0%, 0.5 to 2.0% or 1 to 2.0% (weight / weight), or in the ranges of 0.001 to 2.0%, 0.001 to 1.5%, 0.001 to 1.0% or 0.001 to 5% (weight / weight).

[0427] In eye drop formulations, the compositions may contain the active compound in a concentration of 0.01-20%, 0.02-15%, 0.04-10%, 0.06-5%, 0.08-1% or 0.09-0.5% (weight / volume), with or without adjustment of the pH and / or osmolality of the solution. More specifically, eye drop formulations may contain a compound described herein in a concentration of 0.09-0.5% (weight / volume), e.g., 0.1%, 0.25% or 0.5%.

[0428] In one example, the pharmaceutical composition includes a composition made by combining a therapeutically effective amount of a compound described herein with an oligomeric or polymeric carrier, such as a cyclodextrin or chemically modified cyclodextrin, including trimethyl-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 3-hydroxypropyl-β-cyclodextrin, and β-cyclodextrin sulfobutylether sodium salt (or potassium salt). An exemplary oligomeric or polymeric carrier is β-cyclodextrin sulfobutylether sodium salt. The amount of β-cyclodextrin sulfobutylether sodium salt in the composition can range from about 0.01% to 30% weight / volume. In one example, the concentration of β-cyclodextrin sulfobutylether sodium salt is 5 to 25% weight / volume. Further exemplary concentrations of β-cyclodextrin sulfobutylether sodium salt are 6 to 20% weight / volume. In one example, the concentration of β-cyclodextrin sulfobutyl ether is 6-12% weight / volume. Further examples of the concentration of β-cyclodextrin sulfobutyl ether are 9-10% weight / volume, including 9.5% weight / volume. The amount of the compound described herein in the composition can range from 0.01-20%, 0.02-15%, 0.04-10%, 0.06-5%, 0.08-1%, or 0.09-0.5% (weight / volume). More specifically, the composition can contain the compound described herein at a concentration of 0.09-0.5% (weight / volume), for example 0.1%.

[0429] The compounds described herein may be administered orally, and thus the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, such as, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders, or granules, emulsions, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use may be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, in order to provide pharma- ceutically elegant and palatable preparations.

[0430] For oral administration in the form of tablet or capsule (e.g., gelatin capsule), the active drug component can be combined with an oral non-toxic pharma- ceutically acceptable inert carrier, such as ethanol, glycerol, water, etc. Furthermore, if desired or necessary, suitable binders, lubricants, disintegrants, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, polyethylene glycol, wax, etc. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, silica, talcum, stearic acid, its magnesium or calcium salt, and / or polyethylene glycol, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum starch, agar, alginic acid or its sodium salt, or effervescent mixture, croscarmellose or its sodium salt, etc. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine.

[0431] Tablets contain active ingredient mixed with non-toxic pharma- ceutically acceptable excipients suitable for tablet manufacture.These excipients can be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc.Tablets can be uncoated or they can be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time.

[0432] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a dispenser or pressurized container which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0433] For transmucosal or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and include, for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives.Transmucosal administration can be achieved by using nasal spray or suppository.For transdermal administration, active compound is formulated into ointment, salve, gel or cream as generally known in the art.

[0434] Parenteral formulations containing the compounds described herein can be prepared in aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The preparations can be sterilized and / or contain adjuvants, such as preservatives, stabilizing agents, wetting agents, or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutic agents. The compositions are prepared according to conventional methods and can contain about 0.1-75%, preferably about 1-50%, of the compounds described herein.

[0435] In certain embodiments, the invention is directed to compositions described herein that include a prodrug of a compound of formula I or VI, or a pharma- ceutically acceptable salt thereof. The term "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (e.g., by hydrolysis) to a compound of formula I or VI, or a pharma- ceutically acceptable salt thereof. Various forms of prodrugs are known in the art, such as those discussed in, for example, Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (eds.), Methods in Enzymology, Vol. 4, Academic Press (1985); Krogsgaard-Larsen et al., (eds.), Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, pp. 113-191 (1991); Bundgaard et al., Journal of Drug Delivery Reviews, Vol. 8:1-38 (1992); Bundgaard, J. of Pharmaceutical Sciences, Vol. 77:285 and infra (1988); and Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is incorporated herein by reference in its entirety.

[0436] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any way. EXAMPLES

[0437] Example As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods are directed to the synthesis of specific compounds of the invention, it is understood that the following general methods, as well as other methods known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds described herein. Abbreviation equiv or eq: molar equivalent o / n: overnight rt: room temperature UV: Ultraviolet HPLC: High-performance liquid chromatography Rt: retention time LCMS or LC-MS: Liquid Chromatography Mass Spectrometry NMR: nuclear magnetic resonance CC: Column chromatography TLC: Thin Layer Chromatography sat: saturation aq: water-based Ac: Acetyl ACN or MeCN: Acetonitrile DCM: dichloromethane DCE: Dichloroethane DEA: Diethylamine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide DIPEA: Diisopropylethylamine EA or EtOAc: Ethyl acetate BINAP: (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene TEA: Triethylamine THF: tetrahydrofuran TBS: tert-butyldimethylsilyl KHMDS: Potassium hexamethyldisilylazide Tf: Trifluoromethanesulfonate Ms: methanesulfonyl NBS: N-bromosuccinimide NMP: N-methylpyrrolidinone PE: Petroleum ether TFA: Trifluoroacetic acid FA: Formic acid MMPP: Magnesium monoperoxyphthalate HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Cy: Cyclohexyl Tol: Toluene PTSA: p-Toluenesulfonic acid NMP: N-methyl-2-pyrrolidone TFA: 1,1,1,-trifluoroacetone Example 1 Synthesis of thiophene core compounds Synthesis of 2-(3-aminobenzo[b]thiophen-2-yl)-1,1,1-trifluoropropan-2-ol (I-1) [ka] Synthesis of methyl 3-aminobenzo[b]thiophene-2-carboxylate 3:

[0438] To a solution of 2-fluorobenzonitrile 1 (30.0 g, 1.0 equiv.) in DMF (165 mL) was added methyl thioglycolate 2 (2.5 equiv.) followed by t-BuOK (2.5 equiv.) at 0-5° C. After 15 min, the reaction mixture was slowly warmed to room temperature and stirred for 4 h. After consumption of the starting material (determined by TLC), the reaction mixture was poured into crushed ice and the precipitated solid was filtered. The collected solid was dried to give 3 (37.0 g, 72%) as an off-white solid. 1 H NMR (CD3OD, 500 MHz): δ 7.91 (d, 1H), 7.71 (d, 1H), 7.46 (t, 1H), 7.35 (t, 1H), 3.84 (s, 3H). Synthesis of benzo[b]thiophene-3-amine 4:

[0439] To a solution of 3 (20.0 g, 1.0 equiv.) in NMP (100 mL) was added piperazine (5.0 equiv.) and the reaction mixture was stirred at 180° C. for 6 h. After consumption of the starting material (determined by TLC), the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 4 (13.0 g, 90%) as a light brown solid. 1 H NMR (DMSO-d6, 500 MHz): δ 7.83-7.79 (m, 2H), 7.34-7.28 (m, 2H), 6.16 (s, 1H), 5.27 (s, 2H). Synthesis of I-1:

[0440] To a solution of 4 (5.0 g, 1 equiv.) in THF (40 mL) under nitrogen was added methylmagnesium bromide (3.0 equiv., 2 M solution) at 0-5° C. After stirring for 30 min, trifluoroacetone (1.2 equiv.) was added at 0-5° C. and the reaction temperature was allowed to slowly warm to room temperature. After consumption of the starting material (determined by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give I-1 (1.59 g, 18%) as a yellow solid. 1 H NMR (DMSO-d6; 500 MHz): δ 7.85-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.36-7.31 (m, 2H), 7.13 (s, 1H), 5.41 (s, 2H), 1.74 (s, 3H); Mass: m / z 262.23(+ve); HPLC purity: 98.85%. Synthesis of 2-(3-amino-4-bromobenzo[b]thiophen-2-yl)-1,1,1-trifluoropropan-2-ol (I-2) [ka] Synthesis of I-2:

[0441] Compound I-2 was prepared from 2-fluoro-6-bromobenzonitrile using the procedure described for the synthesis of I-1. I-2 was obtained as a pale yellow solid (3.0 g, 41%). 1H NMR (DMSO-d6, 500 MHz): δ 7.86 (d, 1H), 7.57 (d, 1H), 7.36 (s, 1H), 7.23 (t, 1H), 5.51 (s, 2H), 1.75 (s, 3H); Mass: m / z 340.07 (-ve); HPLC purity: 99.58%. Synthesis of 2-(3-amino-6-(trifluoromethyl)benzo[b]thiophen-2-yl)-1,1,1-trifluoropropan-2-ol (I-3) [ka] Synthesis of I-3:

[0442] Compound I-3 was prepared from 2-fluoro-4-(trifluoromethyl)benzonitrile using the procedure described for the synthesis of I-1. I-3 was obtained as a pale yellow solid (1.9 g, 42%). 1 H NMR (DMSO-d6, 400 MHz): δ 8.28 (s, 1H), 8.07 (d, 1H), 7.65 (dd, 1H), 7.26 (s, 1H), 5.57 (s, 2H), 1.77 (s, 3H); Mass: m / z 330.27(+ve); HPLC purity: 98.06%. Synthesis of 2-(3-aminobenzo[b]thiophen-4-yl)-1,1,1-trifluoropropan-2-ol (I-4) [ka] Synthesis of I-4:

[0443] To a solution of 3-amino-4-bromo[b]benzothiophene (1 g, 1 eq., obtained using the procedure described for the synthesis of benzo[b]thiophene-3-amine in the synthesis for I-1, using 2-fluoro-6-bromobenzonitrile instead of 2-fluorobenzonitrile) in THF under nitrogen was added n-butyllithium (3.0 eq., 1.6 M solution in hexane) at −70° C. After stirring for 30 min, trifluoroacetone (1.2 eq.) was added at −70° C. and the reaction temperature was allowed to slowly warm to room temperature. After consumption of the starting material (determined by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give crude I-4 as a pale yellow solid. The crude material was purified by F / C chromatography to give a pure sample of I-4 as an off-white solid (127 mg, 11%). 1 H NMR (DMSO-d6, 400 MHz): δ 7.84 (d, 1H), 7.54 (dd~t, 1H), 7.32 (d, 1H), 6.34 (s, 1H), 5.58 (s, 2H), 4.90 (S, 1H), 1.51 (s, 3H); Mass: m / z 262(+ve); HPLC purity: 98.06%. Synthesis of 2-(3-aminobenzo[b]thiophen-4-yl)propan-2-ol (I-5) [ka] Synthesis of I-5:

[0444] Compound I-5 was prepared using the procedure described for the synthesis of I-4, but using acetone instead of TFA. I-5 was purified by silica gel column (1:5 ethyl acetate:hexane) and obtained as a pale yellow solid (5.0 mg, 2.7). 1 H NMR (DMSO-d6; 500 MHz): δ 7.87 (d, 1H), 7.52 (d, 1H), 7.18 (t, 1H), 6.45 (s, 1H), 5.24 (bs, 2H); mass: m / z 206.06(-ve). Synthesis of 2-(3-amino-4-(trifluoromethyl)benzo[b]thiophen-2-yl)-1,1,1-trifluoropropan-2-ol (I-14) [ka] Synthesis of methyl 3-amino-4-(trifluoromethyl)benzo[b]thiophene-2-carboxylate 2:

[0445] To a stirred solution of 2-fluoro-6-(trifluoromethyl)benzonitrile 1 (2.0 g, 1.0 equiv.) in DMF (10 mL) at 0-5° C. was added methyl thioglycolate (2.5 equiv.) followed by t-BuOK (1.5 equiv.). After 15 min, the reaction mixture was allowed to warm slowly to room temperature and stirred for 6 h. After consumption of the starting material (by TLC), the reaction mass was poured onto crushed ice and stirred at room temperature for 1 h, and the resulting solid was filtered and dried to give 2 (0.75 g, 25%) as red-brown flakes. 1 H NMR (DMSO-d6, 400 MHz): δ 7.90-7.85 (m, 2H), 7.82-7.79 (m, 1H), 4.26 (s, 2H), 3.66 (s, 3H). Synthesis of 4-(trifluoromethyl)benzo[b]thiophene-3-amine 3:

[0446] To a stirred solution of 2 (0.7 g, 1.0 equiv.) in NMP (3.5 mL) was added piperazine (0.66 g, 3 equiv.) and the reaction was stirred at 180° C. for 6 h. After consumption of the starting material (by TLC), the reaction was cooled to room temperature, diluted with ice-cold water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 3 (0.3 g, 54%) as a light brown solid. 1 H NMR (DMSO-d6, 500 MHz): δ 8.20 (d, 1H), 7.76 (d, 1H), 7.45 (t, 1H), 6.78 (s, 1H), 4.75 (bs, 2H). Synthesis of I-14:

[0447] To a stirred solution of 3 (0.3 g, 1.0 equiv.) in THF (10 mL) under nitrogen was added methylmagnesium bromide (3.5 equiv., 2 M solution) at 0° C. After stirring for 1 h, trifluoroacetone (1.5 equiv.) was added and the reaction mixture was stirred at room temperature for 4 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with saturated NH4Cl solution at 0° C. and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography using 60-120 silica gel eluted with ethyl acetate:hexane (15:85). Evaporation of pure fractions afforded I-14 (155 mg, 34%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 8.20-8.19 (d, 1H), 7.81-7.80 (d, 1H), 7.53-7.49 (m, 2H) 5.04 (bs, 2H),1.79 (s, 3H). Synthesis of 2-(3-amino-7-(trifluoromethyl)benzo[b]thiophen-2-yl)-1,1,1-trifluoropropan-2-ol (I-15) [ka] Synthesis of methyl 3-amino-7-(trifluoromethyl)benzo[b]thiophene-2-carboxylate 2:

[0448] To a stirred solution of 2-fluoro-3-(trifluoromethyl)benzonitrile 1 (2.0 g, 1.0 equiv.) in DMF (10 mL) at 0-5° C. was added methyl thioglycolate (2.5 equiv.) followed by t-BuOK (1.5 equiv.). After 15 min, the reaction mixture was slowly warmed to room temperature and stirred for 6 h. After consumption of the starting material (by TLC), the reaction mass was poured onto crushed ice and stirred at room temperature for 1 h, and the precipitated solid was filtered and dried to give 2 (2.6 g, 89%) as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.66 (s, 1H), 8.10 (d, 1H), 7.80 (dd, 1H), 3.81 (s, 3H). Synthesis of 7-(trifluoromethyl)benzo[b]thiophene-3-amine 3:

[0449] To a stirred solution of 2 (2.6 g, 1.0 equiv.) in NMP (13 mL) was added piperazine (2.5 g, 3 equiv.) and the reaction was stirred at 180° C. for 6 h. After consumption of the starting material (by TLC), the reaction was cooled to room temperature, diluted with ice-cold water, and then extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 3 (1.7 g, 82%) as a light brown solid. 1 H NMR (DMSO-d6, 400 MHz): δ 8.46 (d, 1H), 7.94 (d, 1H), 7.63 (t, 1H), 7.31 (s, 1H), 5.54 (bs, 2H). Synthesis of I-15:

[0450] To a stirred solution of 3 (1.7 g, 1.0 equiv.) in THF (20 mL) under nitrogen was added methylmagnesium bromide (3.0 equiv., 2 M solution) at 0° C. After stirring for 1 h, trifluoroacetone (1.25 equiv.) was added and the reaction mixture was stirred at room temperature for 4 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution at 0° C. and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography silica gel eluted with ethyl acetate:hexane (15:85) and the pure fractions were evaporated to give I-15 (250 mg, 10%) as an off-white solid. 1 H NMR (DMSO-d6, 400MHz): δ 8.17 (d, 1H), 7.76 (d, 1H), 7.56 (t, 1H),7.26 (bs,1H), 5.58 (bs, 2H), 1.78 (s, 3H). Synthesis of 2-(3-amino-5-(trifluoromethyl)benzo[b]thiophen-2-yl)-1,1,1-trifluoropropan-2-ol (I-16): [ka] Synthesis of methyl 3-amino-5-(trifluoromethyl)benzo[b]thiophene-2-carboxylate 2:

[0451] To a stirred solution of 2-fluoro-5-(trifluoromethyl)benzonitrile 1 (2.0 g, 1.0 equiv.) in DMF (10 mL) at 0-5° C. was added methyl thioglycolate (2.5 equiv.) followed by t-BuOK (1.5 equiv.). After 15 min, the reaction mixture was slowly warmed to room temperature and stirred for 5 h. After consumption of the starting material (by TLC), the reaction mass was poured onto crushed ice and stirred at room temperature for 1 h, and the precipitated solid was filtered and dried to give 2 (2.3 g, 79%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 8.66 (s, 1H), 8.19 (d, 1H), 7.80 (dd, 1H) 3.81 (s, 3H). Synthesis of 5-(trifluoromethyl)benzo[b]thiophene-3-amine 3:

[0452] To a stirred solution of 2 (2.3 g, 1.0 equiv.) in NMP (11.5 mL) was added piperazine (2.15 g, 3 equiv.) and the reaction was stirred at 200° C. for 5 h. After consumption of the starting material (by TLC), the reaction was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with ice-cold water, separated, dried over Na2SO4, and evaporated under reduced pressure to give 3 (1.2 g, 66%) as an off-white solid (low melting point solid). 1 H NMR (DMSO-d6, 500 MHz): δ 8.30 (t, 1H), 8.05 (d, 1H), 7.60-7.57 (m, 1H), 6.35 (s, 1H), 5.54 (bs, 2H). Synthesis I-16:

[0453] To a stirred solution of 3 (0.5 g, 1.0 equiv.) in THF (10 mL) under nitrogen was added methylmagnesium bromide (3.0 equiv., 2 M solution) at 0° C. After stirring for 1 h, trifluoroacetone (1.5 equiv.) was added and the reaction mixture was stirred at room temperature for 3 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution at 0° C. and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by washing with n-hexane to give I-16 (400 mg, 52.7%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 8.33 (s, 1H), 8.03 (d, 1H), 7.63 -7.61 (m, 1H), 5.63 (bs, 2H), 1.77 (s, 3H). Example 2 Synthesis of indazole core compounds Synthesis of 2-(3-amino-1H-indazol-4-yl)propan-2-ol (I-6) [ka] Synthesis of 4-iodo-1H-indazol-3-amine 2:

[0454] To a solution of 2-fluoro-6-iodobenzonitrile 1 (3.0 g, 1.0 equiv.) in t-butanol (60 mL) was added hydrazine hydrate (2.0 vol.) at room temperature. The reaction mixture was stirred at 105-110 °C for 5 h. After consumption of the starting material (determined by TLC), the reaction mixture was allowed to cool to room temperature, poured into ice-cold water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 2 (3.0 g, 96%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 11.77 (s, 1H), 7.34 (d, 1H), 7.28 (d, 1H), 6.95-6.91 (m, 1H), 5.03 (s, 2H). Synthesis of I-6:

[0455] Under nitrogen atmosphere, n-butyllithium (5.0 equiv., 1.6 M solution) was added to a solution of 2 (1.0 g, 1.0 equiv.) in THF at -70°C. After stirring for 30 min, acetone (5.0 equiv.) was added at -70°C and the reaction temperature was slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 2 h. After consumption of the starting material (determined by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography to give I-6 (15.0 mg, 1.5%) as a tan solid. 1 H NMR (DMSO-d6, 400 MHz): δ 11.48 (s, 1H), 7.15-7.07 (m, 2H), 6.78 (d, 1H), 5.83 (s, 1H), 5.68 (s, 2H), 1.59 (s, 6H); Mass: m / z 192.01(+ve); HPLC purity: 95.69%. Synthesis of 2-(3-amino-1H-indazol-4-yl)-1,1,1-trifluoropropan-2-ol (I-9) [ka] Synthesis of I-9:

[0456] Using the procedure described for the synthesis of I-6, compound I-9 was prepared starting from 2-fluoro-6-bromobenzonitrile instead of 2-fluoro-6-iodobenzonitrile and using TFA instead of acetone in step 2. I-9 was obtained as a light brown solid (120 mg, 8%). 1 H NMR (DMSO-d6, 400 MHz): δ 11.81 (s, 1H), 7.79 (s, 1H), 7.31-7.29 (m, 1H), 7.19 (t, 1H), 6.94 (d, 1H), 5.49 (s, 2H), 1.79 (s, 3H); Mass: m / z 246.30(+ve); HPLC purity: 95.15%. Example 3 Synthesis of dihydroquinoxalinone core compounds Synthesis of (R)-3-(hydroxymethyl)-7-methoxy-3,4-dihydroquinoxalin-2(1H)-one (I-7) [ka] Synthesis of methyl (R)-3-hydroxy-2-((4-methoxy-2-nitrophenyl)amino)propanoate 4:

[0457] To a solution of 1-fluoro-4-methoxy-2-nitrobenzene 1 (5.0 g, 1.0 equiv.) in DMSO (25.0 mL) was added NaHCO3 (6.0 equiv.) at room temperature, followed by D-serine 2 (2.0 equiv.). The reaction mixture was stirred at 100-105 °C for 4 h. After consumption of the starting material (determined by TLC), the reaction mixture was cooled to room temperature, then methyl iodide (2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 4 h. After consumption of the starting material (determined by TLC), the reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography [ethyl acetate:hexane (2:8)] to give 4 (7.5 g, 95%) as a pale yellow solid. 1 H NMR (CDCl3, 500 MHz): δ 8.41 (bs, 1H), 7.67 (d, 1H), 7.16-7.13 (m, 1H), 6.87 (d, 1H), 4.38-4.36 (m, 1H), 4.07-4.04 (m, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.13 (bs, 1H). Synthesis of I-7:

[0458] To a solution of 4 (7.5 g, 1.0 equiv.) in methanol (80 mL) was added PTSA (0.1 equiv.) and palladium on carbon (10%) under nitrogen atmosphere. The reaction mixture was stirred at room temperature under balloon pressure of hydrogen for 16 h. After consumption of the starting material (determined by TLC), the reaction mixture was filtered through a Celite pad and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography [ethyl acetate:hexane (3:7)] to give I-7 (0.9 g, 16%) as a pale yellow solid. 1 H NMR (CD3OD, 400 MHz): δ 6.70 (d, 1H), 6.47-6.39 (m, 2H), 3.83-3.72 (m, 3H), 3.69 (s, 3H): Mass: m / z 207.01(-ve); HPLC purity: 95.81%. Synthesis of 3-(2-hydroxypropan-2-yl)-3,4-dihydroquinoxalin-2(1H)-one (I-8) [ka] Synthesis of ethyl-3,3-dimethyloxirane-2-carboxylate 3:

[0459] To a solution of ethyl chloroacetate 1 (10.0 g, 1.0 equiv.) in diethyl ether (50.0 mL) was added acetone 2 (1.1 equiv.) under nitrogen atmosphere, and the reaction mixture was stirred at −10° C. for 10 min under nitrogen atmosphere. After 5 min, NaOEt (0.8 equiv.) was added in two portions while maintaining the reaction temperature below 5° C. The reaction mixture was stirred at −10° C. for 2 h, and then the reaction mixture was allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature for 3 h. After consumption of the starting material (determined by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with diethyl ether. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography [ethyl acetate:hexane (2:8)] to give 3 (8.0 g, 68%) as a colorless liquid. 1H NMR (CDCl3, 400 MHz): δ 4.25 (t, 2H), 4.06 (s, 1H), 1.42 (s, 3H), 1.38 (s, 3H), 1.29 (t, 3H). Synthesis of (I-8):

[0460] To a solution of 3 (26.0 g, 1.0 equiv.) in ethanol (100 mL) was added LiOH (0.3 equiv.) followed by o-phenylenediamine (0.7 equiv.) at room temperature. The reaction mixture was heated to 80° C. and stirred for 72 h. After consumption of the starting material (determined by TLC), ethanol was evaporated under reduced pressure and diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure. The crude material obtained was triturated in ethyl acetate:hexane (1:3) and filtered. The collected solid was dried to give I-8 (1.6 g, 4.3%) as a pale yellow solid. 1 H NMR (CD3OD, 400 MHz): δ 7.05-7.01 (m, 1H), 6.97-6.92 (m, 3H), 3.86 (s, 1H), 1.30 (s, 3H), 1.24 (s, 3H): Mass: m / z 207.01(-ve); HPLC purity: 99.52%. Synthesis of (R)-3-(hydroxymethyl)-3,4-dihydroquinoxalin-2(1H)-one (I-10) [ka] Synthesis of I-10:

[0461] Compound I-10 was prepared using the procedure described for the synthesis of I-7, starting with 1-fluoro-2-nitrobenzene instead of 1-fluoro-4-methoxy-2-nitrobenzene. I-10 was purified by silica gel column chromatography [ethyl acetate:hexane (3:7)] and obtained as a pale yellow solid (1.6 g, 57%). 1H NMR (CDCl3, 400 MHz): δ 8.26 (bs, 1H), 6.93-6.89 (m, 1H), 6.78-6.70 (m, 3H), 4.13-4.04 (m, 3H), 3.92-3.87 (m, 1H), 2.67 (bs, 1H): Mass: m / z 176.99(-ve); HPLC purity: 98.55%. Synthesis of (R)-3-(hydroxymethyl)-7-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one (I-11) [ka] Synthesis of I-11:

[0462] Compound I-11 was prepared using the procedure described for the synthesis of I-7, starting with 1-fluoro-2-nitro-4-(trifluoromethyl)benzene instead of 1-fluoro-4-methoxy-2-nitrobenzene. I-11 was purified by silica gel column chromatography [ethyl acetate:hexane (3:7)] and obtained as a pale yellow solid (1.5 g, 47%). 1 H NMR (CD3OD, 500 MHz): δ 7.07 (m, 1H), 6.96 (d, 1H), 6.77 (d, 1H), 4.04-4.02 (m, 1H), 3.83-3.75 (m, 2H): Mass: m / z 245.08(-ve); HPLC purity: 96.79%. Synthesis of (S)-3-(hydroxymethyl)-3,4-dihydroquinoxalin-2(1H)-one (I-12) [ka] Synthesis of I-12:

[0463] Compound I-12 was prepared using the procedure described for the synthesis of I-7, starting with L-serine instead of D-serine and 1-fluoro-2-nitrobenzene instead of 1-fluoro-4-methoxy-2-nitrobenzene. I-12 was purified by silica gel column chromatography [ethyl acetate:hexane (3:7)] and obtained as a pale yellow solid (5.6 g, 50%). 1 H NMR (CDCl3, 400 MHz): δ 7.95 (bs, 1H), 6.93-6.89 (m, 1H), 6.78-6.70 (m, 3H), 4.13-4.04 (m, 3H), 3.92-3.87 (m, 1H), 2.60-2.57 (m, 1H): Mass: m / z 177.02(-ve); HPLC purity: 98.10%. Synthesis of (S)-3-(hydroxymethyl)-7-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one (I-13) [ka] Synthesis of I-13:

[0464] Compound I-13 was prepared using the procedure described for the synthesis of I-7, starting with L-serine instead of D-serine and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene instead of 1-fluoro-4-methoxy-2-nitrobenzene. I-13 was purified by silica gel column chromatography [ethyl acetate:hexane (3:7)] and obtained as a pale yellow solid (5.5 g, 52%). 1 H NMR (CD3OD, 500 MHz): δ 7.07 (m, 1H), 6.96 (d, 1H), 6.77 (d, 1H), 4.04-4.02 (m, 1H), 3.83-3.75 (m, 2H): Mass: m / z 245.06(-ve); HPLC purity: 95.48%. Example 4 Synthesis of other core compounds Synthesis of 2-(3-aminobenzofuran-2-yl)-1,1,1-trifluoropropan-2-ol (I-20) [ka] Synthesis of 1-(3-aminobenzofuran-2-yl)ethanone 2:

[0465] To a stirred solution of 2-hydroxybenzonitrile 1 (1.0 g, 1.0 equiv.) in acetonitrile (16 mL) in a sealed tube at room temperature was added potassium carbonate (1.5 equiv.) followed by chloroacetone (1.0 equiv.). The reaction mixture was stirred at 70° C. for 8 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature and diluted with water. The formed precipitate was filtered and dried under vacuum at 40° C. to give a brown solid (0.8 g, 54%). 1 H NMR (DMSO-d6, 400 MHz): δ 7.97 (d, 1H), 7.54-7.48 (m, 2 H), 7.27-7.24 (m, 1H), 6.92 (s, 2H), 2.37 (s, 3H); Mass: 176[+ve] Synthesis of N-(2-acetylbenzofuran-3-yl)-2,2,2-trifluoroacetamide 3:

[0466] To a stirred solution of 2 (0.3 g, 1.0 equiv.) in THF (3 mL) at room temperature was added TEA (2 equiv.) followed by DMAP (0.1 equiv.). The reaction mixture was stirred for 10 min, then cooled to 0° C. and trifluoroacetic anhydride (1.6 equiv.) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature. After consumption of the starting material (by TLC), the reaction mass was diluted with water and the precipitate formed was filtered and dried under vacuum to give 3 (0.28 g, 61%) as a light brown fluffy solid. Mass: 270 [-ve]. Synthesis of 2,2,2-trifluoro-N-(2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzofuran-3-yl)acetamide 4:

[0467] To a stirred solution of 3 (1.0 g, 1.0 equiv.) in THF (3.0 mL) at 20° C. was added TMSCF3 (3.0 equiv.) and CsF (2.0 equiv.). The reaction mixture was stirred at room temperature for 6 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0° C., quenched with cold water, and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 4 (0.34 g, 27%) as a light brown solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.66 (d, 1H), 7.46 (m, 1H), 7.42 (m, 1H), 7.33 (m, 1H), 7.19 (s, H), 1.77 (s, 3H); Mass: 340[+ve]. Synthesis of I-20:

[0468] To a stirred solution of 4 (0.3 g, 1.0 equiv.) in MeOH (5.0 mL) in a sealed tube at room temperature was added methanolic ammonia (3 mL, 7% solution). The reaction mixture was stirred at 60° C. for 6 h. After consumption of the starting material (by TLC), the solvent was evaporated under reduced pressure to give I-20 (0.12 mg, 56%) as a brown solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.68 (dd, 1H), 7.39 (d, 1H), 7.24 (m, 1H), 7.17 (t, 1H), 6.99 (s, 1H), 4.67 (s, 2H), 1.72 (s, 3H);LCMS:246[+ve]. Synthesis of 2-(5-aminobenzofuran-6-yl)propan-2-ol (I-22): [ka] Synthesis of 4-bromo-5-fluoro-2-nitrobenzoic acid 2:

[0469] To a stirred solution of 4-bromo-3-fluorobenzoic acid (5.0 g, 1.0 equiv.) in H2SO4 (33 mL) at room temperature was added nitric acid (3 equiv.) and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mass was poured onto crushed ice and stirred at room temperature for 30 min, and the resulting solid was filtered and dried to give 2 (5.4 g, 90%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 8.51 (d, 1H), 7.90 (d, 1H). Synthesis of methyl 4-bromo-5-fluoro-2-nitrobenzoate 3:

[0470] To a stirred solution of 2 (5.4 g, 1.0 equiv.) in methanol (54 mL) was added H2SO4 (1 mL, 0.5 equiv.) at 0° C. The reaction mixture was heated to 80° C. for 16 h. After consumption of the starting material (by TLC), the reaction mass was cooled to room temperature and methanol was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution followed by brine solution. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 3 (4.5 g, 90%) as a colorless liquid. 1 H NMR (CDCl3, 400 MHz): δ 8.20 (d, 1H), 7.47 (d, 1H), 3.94 (s, 3H). Synthesis of methyl 5-fluoro-2-nitro-4-((trimethylsilyl)ethynyl)benzoate 4:

[0471] A mixture of 3 (300 mg, 1.0 equiv.), copper iodide (0.05 equiv.) and TEA (3 equiv.) in THF (5 mL) was degassed with nitrogen for 20 min, then Pd(PPh3)2Cl2 (0.05 equiv.) was added at room temperature, followed by trimethylsilylacetylene (2.2 equiv.). The reaction mass was stirred for 6 h. After consumption of the starting material (by TLC), the reaction mass was diluted with ethyl acetate. The organic layer was washed with ice-cold water (3×20 mL) and then with a brine solution. The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography eluted with (ethyl acetate:hexane, 2:98) and the pure fractions were distilled to give 4 (190 mg, 59%) as a thick syrup. 1 H NMR (CDCl3, 400 MHz): δ 8.03 (d, 1H), 7.40 (d, 1H), 3.93 (s, 3H), 0.28 (s, 9H). Synthesis of methyl 5-nitrobenzofuran-6-carboxylate 5:

[0472] A mixture of 4 (190 mg, 1.0 equiv.) and sodium acetate (4.0 equiv.) in DMF (2 mL) was heated to 100° C. and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mixture was added with water at room temperature and extracted with MTBE. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography eluted with (ethyl acetate:hexane, 10:90) and the pure fractions were distilled to give 5 (100 mg, 70%) as an off-white solid. 1 H NMR (CDCl3, 400 MHz): δ 8.20 (s, 1H), 7.88-7.86 (m, 2H), 6.95-6.94 (m, 1H), 3.92 (s, 3H). Synthesis of methyl 5-aminobenzofuran-6-carboxylate 6:

[0473] To a solution of 5 (140 mg, 1.0 equiv.) in methanol (5 mL) was added Pd / C (20 mg, 10 mol%) at room temperature under nitrogen atmosphere. The reaction was stirred at room temperature under hydrogen atmosphere for 12 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a Celite pad and washed twice with ethyl acetate (20 mL). The filtrate was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography eluted with (ethyl acetate:hexane, 5:95) and the pure fractions were distilled to give 6 (50 mg, 58%) as an off-white solid. 1 H NMR (CDCl3, 400 MHz): δ 8.01 (s, 1H), 7.63 (d, 1H), 6.81 (s, 1H), 6.58-6.57 (m, 1H), 5.53 (bs, 2H), 3.90 (s, 3H). Synthesis of I-22:

[0474] To a solution of 6 (150 mg, 1 equiv.) in THF (10 mL) under nitrogen atmosphere was added methylmagnesium bromide (2 M solution, 5 equiv.) at 0° C. for 10 min. The reaction mass was allowed to warm to room temperature and stirred for 4 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:5) to give I-22 (30 mg, 18%) as a thick syrup. 1 H NMR (CDCl3, 400 MHz): δ 7.74 (d, 1H), 7.23 (s, 1H), 6.78 (s, 1H), 6.67-6.66 (m, 1H), 5.25 (bs, 2H), 1.55 (s, 6H). Synthesis of 2-(5-amino-2,3-dihydrobenzofuran-6-yl)propan-2-ol (I-23): [ka] Synthesis of methyl 5-amino-2,3-dihydrobenzofuran-6-carboxylate 2:

[0475] To a solution of 1 (0.7 g, 1.0 equiv.) in methanol (10 mL) was added Pd / C (70 mg, 10 mol%) at room temperature under nitrogen atmosphere. The reaction was stirred at room temperature under hydrogen atmosphere for 24 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a Celite pad and washed twice with ethyl acetate (50 mL). The filtrate was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography eluted with (ethyl acetate:hexane, 5:95) and the pure fractions were distilled to give 2 (200 mg, 30%) as an off-white solid. 1 H NMR (CDCl3, 400 MHz): δ 7.22 (s, 1H), 6.57 (s, 1H), 5.44 (bs, 2H), 4.48 (t, 2H), 3.84 (s, 3H), 3.16-3.11 (m, 2H). Synthesis of I-23:

[0476] To a solution of 2 (100 mg, 1 equiv.) in THF (10 mL) under nitrogen atmosphere was added methylmagnesium bromide (2 M solution, 7 equiv.) at 0° C. for 10 min. The reaction mass was allowed to warm to room temperature and stirred for 4 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:5) to give I-23 (20 mg, 20%) as a thick syrup. 1 H NMR (CDCl3, 400 MHz): δ 6.64 (s, 1H), 6.59 (s, 1H), 4.48 (t, 2H), 3.13-3.09 (m, 2H), 1.64 (s, 6H). Synthesis of 2-(3-amino-5-(trifluoromethyl)pyridin-2-yl)propan-2-ol (I-24): [ka] Synthesis of 2-bromo-3-nitro-5-(trifluoromethyl)pyridine 2:

[0477] To a stirred solution of 1 (1.0 g, 1.0 equiv) in DMF (5 mL) under nitrogen was added phosphorus oxybromide (1.2 equiv) in small portions at 0° C. The reaction mixture was heated to 80° C. and stirred at 80° C. for 2 h. After consumption of the starting material (by TLC), the reaction mass was diluted with water and the precipitated solid was filtered, washed with water and dried to give 2 (0.6 g, 46%) as a light brown solid. LCMS: 273 [+ve]. Synthesis of 2-bromo-5-(trifluoromethyl)pyridin-3-amine 3:

[0478] To a stirred solution of 2 (0.6 g, 1.0 equiv.) in ethanol (12 mL), water (3 mL) was added iron powder (10.0 equiv.), concentrated HCl (0.3 mL) and the reaction mass was stirred at 80° C. for 2 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was then evaporated under reduced pressure to give a residue, which was dissolved in water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 3 (0.45 g, 84%) as a pale yellow solid. LCMS: 242 [+ve]. Synthesis of I-24:

[0479] To a stirred solution of 3 (2 g, 1.0 equiv.) in THF (50 mL) under nitrogen was added n-butyllithium (5.0 equiv., 1.6 M solution) at -70°C. After stirring for 30 min, acetone (10.0 equiv.) was added at -50°C and the reaction mixture was stirred at room temperature for 2 h. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:5) to give I-24 (160 mg, 8.8%) as a white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.98 (s, 1H), 7.24 (d, 1H), 6.00 (bs, 2H), 5.62 (s, 1H), 1.49 (s, 6H). Synthesis of 2-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-1,1,1-trifluoropropan-2-ol (I-25): [ka] Synthesis of 2-bromo-3-nitro-5-(trifluoromethyl)pyridine 2:

[0480] To a stirred solution of 1 (1.0 g, 1.0 equiv) in DMF (5 mL) under nitrogen was added phosphorus oxybromide (1.2 equiv) in small portions at 0° C. The reaction mixture was heated to 80° C. and stirred at 80° C. for 2 h. After consumption of the starting material (by TLC), the reaction mass was diluted with water and the precipitated solid was filtered, washed with water and dried to give 2 (0.6 g, 46%) as a light brown solid. LCMS: 273 [+ve]. Synthesis of 2-bromo-5-(trifluoromethyl)pyridin-3-amine 3:

[0481] To a stirred solution of 2 (0.6 g, 1.0 equiv.) in ethanol (12 mL), water (3 mL), iron powder (10.0 equiv.), concentrated HCl (0.3 mL) were added and the reaction mass was stirred at 80° C. for 2 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was then evaporated under reduced pressure and the residue was added with water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 3 (0.45 g, 84%) as a pale yellow solid. LCMS: 242 [+ve]. Synthesis of I-25: To a stirred solution of 3 (1 g, 1.0 equiv.) in THF (50 mL) under nitrogen was added n-butyllithium (5.0 equiv., 1.6 M solution) at -70°C. After stirring at -70°C for 30 min, trifluoroacetone (10.0 equiv.) was added at -70°C and the reaction mixture was stirred at 0°C for 2 h. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (1:5 ethyl acetate:hexane) to give I-25 (12 mg, 1.1%) as a pale yellow solid. 1 H NMR (CD3OD, 400 MHz): δ 8.01 (d, 1H), 7.27 (d, 1H), 1.81 (s, 3H). Synthesis of 2-(7-amino-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-2-ol (I-26): [ka] Synthesis of 1-(7-nitro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethenone 2:

[0482] To a solution of 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethenone 1 (5 g, 1.0 equiv.) in acetic acid (35 mL) was added fuming nitric acid (15 mL) at 10-15° C. The reaction mixture was stirred at room temperature for 6 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0° C., poured into ice-cold water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 2 (2.8 g, 45%) as a yellow solid. LCMS: 224[+ve]. Synthesis of 1-(7-amino-2,3-dihydrobenzo[b]1,4]dioxin-6-yl)ethenone (3):

[0483] To a solution of 2 (1.8 g, 1.0 equiv.) in ethyl acetate (10 mL) and methanol (10 mL) under nitrogen atmosphere was added Pd / C (200 mg, 10 mol%) at room temperature. The reaction was stirred under hydrogen atmosphere at room temperature for 12 h. After consumption of starting material (by TLC), the reaction mixture was filtered through a celite pad and washed twice with ethyl acetate (50 mL). The filtrate was evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography to give 3 (1 g, 64%) as a pale yellow solid. LCMS: 194[+ve]. Synthesis of I-26:

[0484] To a solution of 3 (1 g, 1 equiv.) in THF (20 mL) under nitrogen atmosphere was added methylmagnesium bromide (2 M solution, 5 equiv.) at 0° C. for 10 min. The reaction mass was warmed to room temperature and stirred for 3 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:5) to give I-26 (120 mg, 15%) as an off-white solid. 1 H NMR (CDCl3, 400 MHz): δ 6.68 (s, 1H), 6.20 (s, 1H), 4.21-4.16 (m, 4H), 1.62 (s, 6H). Synthesis of 2-(2-amino-4,5-difluorophenyl)propan-2-ol (I-27): [ka] Synthesis of 4,5-difluoro-2-iodoaniline 2:

[0485] A mixture of 3,4-difluoroaniline 1 (2.5 g, 1.0 equiv.), sodium bicarbonate (3.15 g, 1.5 equiv.) and iodine (8.25 g, 1.3 equiv.) in water (125 mL) was stirred at room temperature for 30 min. After consumption of the starting material (by TLC), the reaction mass was diluted with ethyl acetate (100 mL). The organic layer was separated and washed with saturated sodium thiosulfate solution (3×50 mL). The ethyl acetate layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 2 (6 g, 95%) as a brown liquid. LC-MS: 256 [+ve]. Synthesis of 4,5-difluoro-2-((trimethylsilyl)ethynyl)aniline 3:

[0486] A mixture of 4,5-difluoro-2-iodoaniline 2 (500 mg, 1.0 equiv.), copper iodide (68 mg, 0.3 equiv.) in TEA (5 mL) was degassed with nitrogen for 20 min, then Pd(pph3)2Cl2 (0.05 equiv.) was added at room temperature, followed by trimethylsilylacetylene (3 equiv.). The reaction mixture was slowly heated to 40° C. and stirred for 16 h. After consumption of the starting material (by TLC), the reaction mass was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with water (3×5 mL). The ethyl acetate layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography eluted with (ethyl acetate:hexane, 1:99) and the pure fractions were distilled to give 3 (250 mg, 56%) as a thick syrup. 1 H NMR (CDCl3, 400 MHz): δ 7.18-7.05 (m, 1H), 6.48-6.44 (m, 1H), 4.17 (bs, 2H), 0.25 (s, 9H). Synthesis of 4,5-difluoro-2-((trimethylsilyl)ethynyl)aniline 4:

[0487] A mixture of 4,5-difluoro-2-((trimethylsilyl)ethynyl)aniline 3 (250 mg, 1.0 equiv.), PTSA.H2O (1 equiv.) in water (1 mL):ethanol (5 mL) was heated to 80° C. and stirred for 8 h. After consumption of the starting material (by TLC), the reaction mass was cooled to room temperature and the ethanol was evaporated under reduced pressure. The crude compound was diluted with ethyl acetate and washed with water. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography eluted with (ethyl acetate:petroleum ether, 5:95) and the pure fractions were distilled to give 4 (130 mg, 68%) as an off-white solid. 1 H NMR (CDCl3, 400 MHz): δ 7.52-7.47 (m, 1H), 6.43-6.38 (m, 1H), 2.52 (s, 3H). Synthesis of I-27:

[0488] To a stirred solution of 4 (130 mg, 1.0 equiv.) in THF (5 mL) under nitrogen was added methylmagnesium bromide (5.0 equiv., 2 M solution) at -10 °C. The reaction mixture was stirred at -10 °C for 1 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 10:90) to give I-27 (60 mg, 42%) as a thick syrup. 1 H NMR (CD3OD, 400 MHz): δ 7.35 (bs, 1H), 6.94-6.89 (m, 1H), 6.43-6.38 (m, 1H), 4.60 (bs, 2H), 1.63 (s, 6H). Synthesis of 2-(2-amino-4,5-dichlorophenyl)propan-2-ol (I-28): [ka] Synthesis of 1-(2-amino-4,5-dichlorophenyl)ethenone 2:

[0489] To a stirred solution of BCl3 (2.23 g, 1.03 equiv.) in heptane solution under nitrogen atmosphere was added 3,4 dichloroaniline (3 g, 1 equiv.) in acetonitrile (30 mL) dropwise at 0° C. for 10 min. AlCl3 was added portionwise to the reaction mixture under nitrogen. The reaction mixture was heated to 80° C. and stirred for 8 h. After consumption of starting material (by TLC), the reaction mass was cooled to 0° C., 4N HCl (30 mL) was added, heated to 100° C. and stirred for 2 h. The volatiles were removed under reduced pressure and extracted with DCM. The organic layer was separated, washed with 2N HCl, dried over Na2SO4 and evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography silica gel eluted with (ethyl acetate:petroleum ether, 1:99) and the pure fractions were distilled to give 2 (700 mg, 19%) as an off-white solid. 1 H NMR (CDCl3, 400 MHz): δ 7.75 (s, 1H), 6.77 (s, 1H), 6.29 (bs, 2H), 2.54 (s, 3H). Synthesis of I-28:

[0490] To a stirred solution of 2 (150 mg, 1.0 equiv.) in THF (5 mL) under nitrogen was added methylmagnesium bromide (5.0 equiv., 2M solution) at -10°C. The reaction mass was stirred at -10°C for 1 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:9) to give I-28 (90 mg, 55%) as a colorless liquid. 1 H NMR (CD3OD, 400 MHz): δ 7.14 (s, 1H), 6.78 (s, 1H), 1.56 (s, 6H). Synthesis of 2-(6-aminobenzo[d][1,3]dioxol-5-ylpropan-2-ol (I-29): [ka] Synthesis of I-29:

[0491] To a stirred solution of 1-(6-aminobenzo[d][1,3]dioxol-5-yl)ethanone 1 (0.5 g, 1.0 equiv.) in THF (15 mL) under nitrogen was added methylmagnesium bromide (4.0 equiv., 2 M solution) at 0° C. The reaction was stirred at 0° C. for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:9) to give I-29 (300 mg, 55%) as a gummy syrup. 1 H NMR (CDCl3, 400 MHz): δ 6.66 (s, 1H), 6.23 (s, 1H), 5.83 (s,2H), 1.62 (s, 6H). Synthesis of 2-(2-amino-4-(trifluoromethyl)phenyl)propan-2-ol (I-30): [ka] Synthesis of I-30:

[0492] To a stirred solution of 1 (1 g, 1.0 equiv.) in THF (10 mL) under nitrogen atmosphere was added n-butyllithium (5.0 equiv., 1.6 M solution) at -70°C. After stirring for 30 min, acetone (3.0 equiv.) was added at -70°C, and the reaction mixture was stirred at room temperature for 1 h. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:5) to give I-30 (200 mg, 22%) as a thick colorless syrup. 1H NMR (CD3OD, 400 MHz): δ 7.24 (d, 1H), 6.92 (d, 1H), 6.83-6.80 (m, 1H), 1.61 (s, 6H). Synthesis of 2-(2-amino-4-(trifluoromethyl)phenyl)propan-2-ol (I-31): [ka] Synthesis of 2-bromo-5-(methylsulfonyl)aniline 2:

[0493] To a stirred solution of 2 (1.0 g, 1.0 equiv.) in ethanol (3.6 mL), iron powder (3.0 equiv.), concentrated HCl (0.54 mL) were added and the reaction mixture was stirred at 70° C. for 16 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature and ethanol was evaporated under reduced pressure. The resulting residue was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 3 (0.82 g, 92%) as a light brown solid. LCMS: 252 [+ve].

[0494] Synthesis of 5-(methylsulfonyl)-2-((trimethylsilyl)ethynyl)aniline 3: To a stirred solution of 2 (0.1 g, 1.0 equiv.) in diisopropylamine (2.0 mL) in a sealed tube, copper iodide (0.02 equiv.), bis(triphenylphosphine)palladium(II) dichloride (0.04 equiv.) were added, the contents were degassed, and TMS acetylene (3.0 equiv.) was added. The reaction mixture was stirred at 60° C. for 12 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 3 (0.06 g, 56%) as a pale yellow solid. LCMS: 268[+ve]. Synthesis of 1-(2-amino-4-(methylsulfonyl)phenyl)ethanone 4:

[0495] To a stirred solution of 3 (0.8 g, 1.0 equiv.) in ethanol (3.2 mL), water (0.8 mL) was added PTSA (1.0 equiv.). The reaction mixture was stirred at 70° C. for 48 h. After consumption of the starting material (by TLC), water was added and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 4 (0.483 g, 64%) as a pale yellow solid. LCMS: 214 [+ve]. Synthesis of I-31:

[0496] To a stirred solution of 4 (0.3 g, 1.0 equiv.) in THF (3.0 mL) under nitrogen at -70°C was added methylmagnesium bromide (4.0 equiv., 2 M solution). After addition, the reaction mixture was allowed to reach room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (ethyl acetate:hexane, 3:7) to give I-31 (90 mg, 28%) as a pale yellow solid. 1 H NMR (CD3OD, 400 MHz): δ 7.32 (d, 1H), 7.18 (d, 1H), 7.08 (dd, 1H), 3.03 (s, 3H), 1.60 (s, 6H). Synthesis of 2-(3-amino-5-methylpyridin-2-yl)propan-2-ol (I-32): [ka] Synthesis of 2-bromo-5-methylpyridin-3-amine 2:

[0497] To a solution of iron powder (4.3 equiv.) in acetic acid (25.0 mL) was added 1 (5 g, 1.0 equiv.) at 80° C. under nitrogen. The reaction mixture was stirred at 80° C. for 1 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through Celite. The filtrate was evaporated under reduced pressure, and the resulting residue was neutralized with NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 2 (3.7 g, 86%) as a brown solid. LCMS: 187 [+ve]. Synthesis of 2-(3-amino-5-methylpyridin-2-yl)propan-2-ol I-32: To a stirred solution of 2 (1 g, 1.0 equiv.) in THF (20.0 mL) under nitrogen was added n-butyllithium (5.0 equiv., 1.6 M solution) at -70°C. After stirring for 30 min, acetone (10.0 equiv.) was added at 0°C and the reaction mixture was stirred at room temperature for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution at 0°C and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (ethyl acetate:hexane, 1:5) to give I-32 (20 mg, 1.69%) as a pale yellow solid. 1 H NMR (CD3OD, 400 MHz): δ 7.59 (d, 1H), 6.89 (d, 1H), 2.20 (s, 3H), 1.58 (s, 6H);LCMS:167[+ve] Synthesis of 2-(2-amino-4-(trifluoromethyl)phenyl)-1,1,1-trifluoropropan-2-ol) (I-33): [ka] Synthesis of I-33:

[0498] To a stirred THF solution of 1 (1.0 g, 1.0 equiv.) under nitrogen atmosphere was added n-butyllithium (5.0 equiv., 1.6 M solution) at -70°C. After stirring for 30 min, trifluoroacetone (5.0 equiv.) was added at -70°C and the reaction temperature was slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography to give I-33 (15.0 mg, 1.5%) as an off-white solid. 1 H NMR (CD3OD, 400 MHz): δ 7.79 (d, 1H), 7.66-7.65 (m, 1H),7.54 (s, 1H), 1.92 (s, 3H). 3-(4-amino-3-(2-hydroxypropan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid methyl ester . Synthesis of HCl. (I-34A): [ka] Synthesis of 1-(2-amino-5-bromophenyl)ethanone 9:

[0499] To a stirred solution of 8 (20.0 g, 1.0 equiv.) in acetonitrile (160 mL) under nitrogen, NBS solution (27.56 g in 150 mL acetonitrile) was added slowly dropwise over 1 h at 0° C. The reaction mixture was allowed to warm slowly to room temperature and stirred for 3 h. After consumption of the starting material (by TLC), the volatiles were evaporated under reduced pressure to give the crude compound. The crude compound was dissolved in ethyl acetate and washed with water. The organic layer was separated and evaporated to give 9 (29.0 g, 92%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.80 (s, 1H), 7.33 (d, 1H), 6.55 (d, 1H), 6.29 (bs, 2H), 2.55 (s, 3H); Mass: m / z 214.17(+ve). Synthesis of 2-(2-amino-5-bromophenyl)propan-2-ol 10:

[0500] Under nitrogen atmosphere, 2M methylmagnesium bromide (5.0 equiv) solution was slowly added dropwise to a stirred solution of 9 (10.0 g, 1.0 equiv) in THF (100 mL) at 0° C. over 1 h. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and evaporated under reduced pressure to give the crude compound. The crude compound was purified by column chromatography to give 10 (9.5 g, 88%) as a brown solid (low melting point solid). 1 H NMR (CDCl3, 500 MHz): δ 7.20 (d, 1H), 7.14-7.12 (m, 1H), 6.51 (d, 1H), 4.69 (bs, 2H), 1.64 (s, 6H). Synthesis of (R)-methyl 2-amino-3-hydroxypropanoate 2:

[0501] To a stirred solution of D-serine 1 (20 g, 190 mmol) in methanol (192 mL) was slowly added dropwise over 15 min at 10 °C. The reaction mass was warmed to room temperature and stirred for 2 h. The reaction mass was then further heated to 80 °C and stirred at 80 °C for 8 h. After consumption of the starting material (by TLC), the reaction mass was cooled to room temperature and the volatiles were evaporated under reduced pressure to give 29 g of 2·HCl as an off-white solid. The crude compound was used directly in the next reaction without further purification. Synthesis of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate 3:

[0502] To a stirred suspension of 2 (29 g, 243 mmol, 1.0 equiv) in DCM (290 mL) was slowly added dropwise triethylamine (5.0 equiv) over 20 min at room temperature. Boc anhydride (1.1 equiv) was then slowly added to the reaction mass at room temperature for 30 min. The reaction mixture was stirred for 3 h at room temperature. Then, after consumption of the starting material (by TLC), 1N sodium bisulfite solution was added to the reaction mixture. The organic layer was separated and washed with 5% NaHCO3 and 10% citric acid solutions. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 3 (37 g, 70%) as a syrup in nature. 1 H NMR (CDCl3, 400 MHz): δ 5.63 (bs, 1H), 4.38 (bs, 1H), 3.97-3.88 (m, 2H), 3.77 (s, 3H), 2.07 (s, 1H), 1.45 (s, 9H). Synthesis of methyl 2-((tert-butoxycarbonyl)amino)acrylate 4:

[0503] To a stirred solution of 3 (5.0 g, 24.1 mmol) in DCM (50 mL) under nitrogen, mesyl chloride (1.3 equiv.) was added dropwise over 5-10 min at -50 °C. The reaction mixture was stirred at -50 °C for 40 min, then TEA (3.0 equiv.) was added dropwise over 10 min at the same temperature. The reaction mass was allowed to warm to room temperature and stirred for 2 h. Then, after consumption of the starting material (by TLC), the reaction mixture was diluted with ice-cold water. The organic layer was separated and evaporated to give the crude compound. The crude compound was purified by column chromatography to give 4 (4.0 g, 87%) as a colorless liquid. 1 H NMR (CDCl3, 400 MHz): δ 7.01 (bs, 1H), 6.16 (bs, 1H), 5.73 (bs, 1H), 3.83 (s, 3H), 1.49 (s, 9H); Mass: m / z 200.1(-ve). Synthesis of (E)-methyl 3-(4-amino-3-(2-hydroxypropan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)acrylate 5:

[0504] A stirred solution of 10 (2.0 g, 8.60 mmol, 1.0 equiv) and 4 (1.3 equiv) in DMF (20 mL) in a sealed tube was degassed with nitrogen for 30 min, then palladium acetate (0.1 equiv), tri-O-tolylphosphine (0.2 equiv) and triethylamine (1.5 equiv) were added to the reaction mixture. The reaction mixture was heated to 100° C. and stirred for 8 h. After consumption of the starting material (by TLC), the reaction mass was cooled to room temperature and filtered through a celite pad. The filtrate was diluted with ice-cold water and extracted with diethyl ether. The organic layer was separated and evaporated under vacuum to give the crude compound. The crude compound was purified by column chromatography using neutral alumina to give 5 (0.8 g, 26%) as a pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz): δ 8.20 (bs, 1H), 7.52 (s, 1H), 7.29-7.02 (m, 2H), 6.59 (d, 1H), 6.00 (s, 2H), 5.31 (s, 1H), 3.67 (s, 3H), 1.49-1.28 (m, 15H); Mass: m / z 349.29(-ve). Synthesis of methyl 3-(4-amino-3-(2-hydroxypropan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propionate 6:

[0505] A suspension of 5 (1.3 g, 1.0 equiv.) and magnesium (10.0 equiv.) in methanol (26.0 mL) was heated to 80° C. and stirred for 4 h. After consumption of the starting material (by TLC), MeOH was evaporated and the crude was dissolved in ethyl acetate. The organic layer was washed with water, separated and evaporated to give the crude compound. The crude compound was purified by column chromatography to give 6 (1.0 g, 77%) as an off-white solid. 1H NMR (DMSO-d6, 500 MHz): δ 7.15 (d, 1H), 6.87-6.76 (m, 2H), 6.51 (d, 1H), 5.33 (bs, 2H), 5.17 (bs, 1H), 4.05-4.00 (m, 1H), 3.59 (s, 3H), 2.28-2.66 (m, 2H), 1.46 (s, 6H), 1.34 (s, 9H). Synthesis of 3-(4-amino-3-(2-hydroxypropan-2-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid 7:

[0506] To a stirred solution of 6 (1.0 g, 1.0 equiv.) in THF (16 mL) was added lithium hydroxide solution (0.357 g in 4.0 mL water) slowly at 0° C. for 5 min. The reaction mixture was warmed to room temperature and stirred for 4 h. After consumption of the starting material (by TLC), the reaction mixture was diluted with water and acidified to pH ∼5 with 20% potassium hydrogen sulfate solution. The aqueous layer was extracted with ethyl acetate and evaporated to give 7 (0.85 g, 88%) as an off-white solid. 1 H NMR (DMSO-d6, 400 MHz): δ 6.87 (s, 1H), 6.79-6.77 (m, 2H), 6.49 (d, 1H), 5.20 (bs, 1H), 3.96-3.90 (m, 1H), 2.84-2.64 (m, 2H), 1.47 (s, 6H), 1.29 (s, 9H); Mass: m / z 349.29(-ve). Synthesis of I-34A:

[0507] To a stirred solution of 7 (0.85 g, 2.51 mmol) in 1,4-dioxane (8.5 mL) at 0° C. was added 4N HCl (10.0 equiv.) in 1,4-dioxane slowly dropwise. The reaction mass was allowed to warm to room temperature and stirred for 4 h. After consumption of the starting material (by TLC), evaporation of the volatiles gave the crude product which was triturated with ethyl acetate to give I-34A (0.54 g, 79%) as a grey solid. 1H NMR (D2O, 400 MHz): δ 7.41 (s, 1H), 7.35-7.34 (m, 2H), 4.26 (t, 1H), 3.32-3.26 (m, 2H), 1.64 (s, 6H); mass: m / z 237.15(+ve). Synthesis of 2-(3-aminobenzofuran-2-yl)-1,1,1-trifluoropropan-2-ol (I-35): [ka] Synthesis of 1-(3-aminobenzofuran-2-yl)ethanone 2:

[0508] To a stirred solution of 2-hydroxybenzonitrile 1 (1.0 g, 1.0 equiv.) in acetonitrile (16 mL) in a sealed tube at room temperature was added potassium carbonate (1.5 equiv.) followed by chloroacetone (1.0 equiv.). The reaction mixture was stirred at 70° C. for 8 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature and diluted with water. The formed precipitate was filtered and dried under vacuum at 40° C. to give a brown solid (0.8 g, 54%). 1 H NMR (DMSO-d6, 400 MHz): δ 7.97 (d, 1H), 7.54-7.48 (m, 2 H), 7.27-7.24 (m, 1H), 6.92 (s, 2H), 2.37 (s, 3H); mass: 176[+ve]. Synthesis of N-(2-acetylbenzofuran-3-yl)-2,2,2-trifluoroacetamide 3:

[0509] To a stirred solution of 2 (0.3 g, 1.0 equiv.) in THF (3 mL) at room temperature was added TEA (2 equiv.) followed by DMAP (0.1 equiv.). The reaction mixture was stirred for 10 min, then cooled to 0° C. and trifluoroacetic anhydride (1.6 equiv.) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature. After consumption of the starting material (by TLC), the reaction mass was diluted with water and the precipitate formed was filtered and dried under vacuum to give 3 (0.28 g, 61%) as a light brown fluffy solid. Mass: 270 [-ve]. Synthesis of 2,2,2-trifluoro-N-(2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzofuran-3-yl)acetamide 4:

[0510] To a stirred solution of 3 (1.0 g, 1.0 equiv.) in THF (3.0 mL) at 20° C. was added TMSCF3 (3.0 equiv.) and CsF (2.0 equiv.). The reaction mixture was stirred at room temperature for 6 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to 0° C., quenched with cold water, and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give 4 (0.34 g, 27%) as a light brown solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.66 (d, 1H), 7.46 (m, 1H), 7.42 (m, 1H), 7.33 (m, 1H), 7.19 (s, H), 1.77 (s, 3H); mass: 340[+ve]. Synthesis of I-35:

[0511] To a stirred solution of 4 (0.3 g, 1.0 equiv.) in MeOH (5.0 mL) in a sealed tube at room temperature was added methanolic ammonia (3 mL, 7% solution). The reaction mixture was stirred at 60° C. for 6 h. After consumption of the starting material (by TLC), the solvent was evaporated under reduced pressure to give I-35 (0.12 mg, 56%) as a brown solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.68 (dd, 1H), 7.39 (d, 1H), 7.24 (m, 1H), 7.17 (t, 1H), 6.99 (s, 1H), 4.67 (s, 2H), 1.72 (s, 3H);LCMS:246[+ve]. Synthesis of 2-(3-amino-5-chloropyridin-2-yl)propan-2-ol (I-36): [ka] Synthesis of 3-amino-5-chloropicolinonitrile 2:

[0512] Under nitrogen atmosphere, 1 (2 g, 1.0 equiv.) was added to a solution of iron powder (5.5 equiv.) in acetic acid (20.0 mL) at 80° C. The reaction mixture was stirred at 80° C. for 30 min. After consumption of the starting material (by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (ethyl acetate:hexane, 3:7) to give 2 (0.64 g, 38%) as a pale yellow solid. LCMS: 152[-ve]. Synthesis of 1-(3-amino-5-chloropyridin-2-yl)ethanone 3:

[0513] To a stirred solution of 2 (0.4 g, 1.0 equiv.) in THF (4.0 mL) under nitrogen at 0° C. was added methylmagnesium bromide (4.0 equiv., 2 M solution). After addition, the reaction mixture was brought to room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (ethyl acetate:hexane, 1:5) to give 3 (180 mg, 41%) as a light brown solid. 1 H NMR (CD3OD, 400 MHz): δ 7.80 (d, 1H), 7.21 (d, 1H), 2.59 (s, 3H); LCMS: 171[+ve]. Synthesis of I-36:

[0514] To a stirred solution of 3 (0.18 g, 1.0 equiv.) in THF (3.6 mL) under nitrogen atmosphere was added methylmagnesium bromide (3.0 equiv., 2 M solution) at 0° C. After addition, the reaction mixture was brought to room temperature and stirred for 3 h. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution at 0° C. and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:5) to give I-36 (70 mg, 36%) as a pale yellow solid. 1 H NMR (CD3OD, 400 MHz): δ 7.66 (d, 1H), 7.02 (d, 1H), 1.56 (s, 6H); LCMS:186[-ve]. Synthesis of 2-(3-amino-5-bromopyridin-2-yl)propan-2-ol (I-37) [ka] Synthesis of 1-(5-bromo-3-fluoropyridin-2-yl)ethanone 2:

[0515] To a stirred solution of 1 (2.0 g, 1.0 equiv.) in THF (20.0 mL) under nitrogen was added methylmagnesium bromide (3.0 equiv., 2M solution) at 0° C. After addition, the reaction mixture was brought to room temperature and stirred for 2 h. After consumption of starting material (by TLC), the reaction mixture was quenched with NH4Cl solution at 0° C. and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column chromatography (ethyl acetate:hexane, 1:5) to give 2 (730 mg, 34%) as a light brown solid. LCMS: 218 [+ve]. Synthesis of 1-(3-amino-5-bromopyridin-2-yl)ethanone 3:

[0516] To a stirred solution of 2 (0.73 g, 1.0 equiv.) in ethanol (20.0 mL) in a sealed tube, aqueous ammonia (20.0 mL) was added. The reaction mixture was stirred at 80° C. for 12 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to room temperature and ethanol was evaporated. Water was added to the residue and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 1:5) to give 3 (0.15 g, 21%) as a yellow solid. LCMS: 215 [+ve]. Synthesis of I-37:

[0517] To a stirred solution of 1 (150 mg, 1.0 equiv.) in THF (3.0 mL) under nitrogen was added methylmagnesium bromide (3.0 equiv., 2 M solution) at 0° C. After the addition, the reaction mixture was allowed to reach room temperature and stirred for 2 h. After consumption of the starting material (by TLC), the reaction mixture was quenched with NH4Cl solution at 0° C. and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give the crude compound, which was purified by silica gel column (ethyl acetate:hexane, 3:7) to give I-37 (50 mg, 43%) as a pale yellow solid. 1 H NMR (CD3OD, 400 MHz): δ 7.74 (d, 1H), 7.17 (d, 1H), 1.56 (s, 6H); LCMS:230[+ve]. Example 5 Experimental conditions used in the initial capture experiment

[0518] The reactivity of each of compounds I-1 to I-13 (0.01 mol) was tested using 4-hydroxynonenal (4-HNE) (0.006 mol) as a model aldehyde. The experimental compounds were dissolved in a 20% solution of Captisol in phosphate buffer (1 mL, pH=7.2). To this solution was then added 4-HNE (10 mg / mL solution) in ethanol. The ensuing reaction was monitored by HPLC analysis. After approximately 24 hours, the reaction was completed by adding excess formic acid to obtain the final product:starting material composition. The relative ratio of the experimental compound / 4-HNE adduct to the final composition was plotted against time to provide an indication of the reaction rate and the level of reaction completion. The results are shown in Figures 31 and 32. Example 6 Experimental conditions used for additional capture experiments

[0519] The reactivity of each of the compounds ADX-102, I-32, I-8, I-29 and I-31 (0.01 mole) was tested using 4-hydroxynonenal (4-HNE) (1.5 equivalents) as a model aldehyde. ADX-102 is also known as Reproxalap. Each compound was dissolved in a 20% solution of Captisol in phosphate buffer (1 mL, pH=7.2). To this solution was then added 4-HNE (10 mg / mL solution) in ethanol. The ensuing reaction was monitored by LCMS analysis. The relative ratio of the experimental compound / 4-HNE adduct to the final composition was plotted against time to provide an indication of the reaction rate and the level of reaction completion. The results are shown in Figure 33, which shows the rate of formation of the aldehyde adduct over a 24 hour period. All samples were found to be conjugated (positive increase in the HPLC peak of the product over time). I-29 was demonstrated to be the best bind, followed by I-31, which demonstrated slightly better binding than I-32. Example 7 Evaluation of preventive anti-inflammatory activity of test compounds in acute LPS-induced sepsis in C57BL / 6 mice summary

[0520] The primary objective of this study was to obtain plasma samples from lipopolysaccharide (LPS)-challenged C57BL / 6 mice following administration of test compounds to obtain cytokine profiles affected by prophylactic treatment. This study models acute sepsis, a systemic inflammatory syndrome initiated by gram-negative and gram-positive bacteria and fungi that infect the lungs, abdomen, bloodstream, and renal or genitourinary tract. Patients with sepsis ultimately die from multiple organ failure caused by widespread tissue hypoxia due to ongoing microvascular leakage, disseminated intravascular coagulation, defective energy production, and metabolic alterations. Sepsis is characterized by an early systemic inflammatory response phase marked by symptoms such as tachycardia, fever, hyperventilation, and activation of complement and coagulation cascades. However, it is now recognized that this is followed by a compensatory anti-inflammatory response phase characterized by neuroendocrine-mediated immunosuppression. Because these processes are the result of interactions between inflammatory cells and organs, investigations into the treatment of this syndrome require the use of intact animal models. The use of 10 mice per group allows for useful statistical modeling of the results.

[0521] For the data presented in Table 2A, 103 mice (female, 18-22 grams, C57BL / 6) were purchased from ENVIGO. Mice were housed in 20 cages of 5 mice per cage with 1 extra cage of 3 mice. The cages had filter and sterilized bedding on top and animals were kept in a quarantine area for daily visual inspection. Treatment groups are detailed in Table 2A below. Ten mice were included in each group. Mice were dosed by oral gavage (PO) at 10 ml / kg according to the table below. MC=methylcellulose. [Table 2A-1]

[0522] For the data presented in Table 2B, 185 mice (female, 18-22 grams, C57BL / 6) were purchased from ENVIGO. Mice were housed in 37 cages with 5 mice per cage. The cages had filter-topped and sterilized bedding and animals were kept in a quarantine area for daily visual inspection. Treatment groups are detailed in Table 2B below. Ten mice were included in each group. Mice were dosed by oral gavage (PO) at 10 ml / kg according to the table below. MC=methylcellulose.

[0523] [Table 2A-2] procedure

[0524] At time T=0, mice were administered one of the test compounds listed in the table above.

[0525] At T=0.5 hours, mice were injected IP with 1.5 mg / kg MPS (Sigma).

[0526] At T=6.5 hours, all mice were anesthetized and exsanguinated into pre-chilled EDTA-treated tubes. Blood was processed to plasma, which was stored at -80°C in labeled 0.5 polypropylene snap-top tubes (0.5 mL, Eppendorf Safe-Lock Tubes (Fisher Scientific)).

[0527] Vehicle preparation: 1.0 gram of methylcellulose (Sigma) was dissolved in 200 mL of water (USP, purified) to make a solution of 0.5% methylcellulose in water. LPS solution preparation: 6 mg of LPS (from Escherichia Coli, 055:B5, Cat# L2880, Sigma Lot# 057m4013) was dissolved in 20 ml of saline to give a 0.3 mg / ml LPS solution. All mice were injected with 5 ml / kg (1.5 mg / kg) at scheduled times via intraperitoneal injection. Cytokine Panel Summary

[0528] A 32-plex cytokine panel was obtained from Eve Technologies. Each cytokine was evaluated based on a 7-point curve range in duplicate. Means of two replicate analyses were used for statistics. Unpaired t-tests were performed using Excel™ to compare vehicle with each treatment group. Column plots of treatment groups against each cytokine are shown in the figures. One star indicates P<0.05. Two stars indicate P<0.01. Three stars indicate P<0.001. Four stars indicate P<0.0001. Most, but not all, statistically significant results are indicated with a star.

[0529] Heat maps of significant cytokine changes are shown below in Tables 3A and 3B. [Table 3A-1] [Table 3A-2] [Table 3B-1] [Table 3B-2] conclusion

[0530] For several cytokines, significant changes were observed for treatment groups versus vehicle.

Claims

1. A compound of formula IX: 【Chemical 143】 or a pharmaceutically acceptable salt thereof [wherein, R １ 、 R ２ 、 R ３ and R ４ each of which is independently hydrogen, deuterium, halogen, -NH ２ 、 -CN, -OR, -SR, -S(O)R, -S(O) ２ R or optionally substituted C １～６ is aliphatic, R ａ is C optionally substituted by one, two or three deuterium atoms or halogen atoms, １～４ is aliphatic, R ｂ is C optionally substituted with one, two or three deuterium or halogen atoms; １～４ aliphatic; or R ａ and R ｂ together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and each R is selected from hydrogen, deuterium; and C １～６ aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. R １ is hydrogen, deuterium, halogen, -CN, -OMe, -S(C １～６ alkyl), -S(O)(C １～６ alkyl) or C １～６ alkyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ is -S(O)R or -S(O) ２ R, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R １ and R ４ is H, the compound according to claim 3 or a pharmaceutically acceptable salt thereof.

5. A compound of formula VIII: 【Chemical 137】 or a pharmaceutically acceptable salt thereof [wherein, each of R2, R3, R4 and R5 is independently hydrogen, deuterium, halogen, -NH2, -CN, -OR, -SR, -S(O)R, -S(O)2R, optionally substituted C1-6 aliphatic, or 【Chemical 138】 provided that one of R2, R3, R4 and R5 is -NH2 and another one of R2, R3, R4 and R5 is 【Chemical 139】 wherein the -NH2 and the 【Chemical 140】 are attached to adjacent carbon atoms, R1 and R1' are each independently hydrogen, deuterium or C1-6 alkyl, Ra is C1-4 aliphatic optionally substituted with one, two or three deuterium atoms or halogen atoms, Rb is C1-4 aliphatic optionally substituted with one, two or three deuterium atoms or halogen atoms; or Ra and Rb together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and each R is independently selected from hydrogen, deuterium; and C1-6 aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms each independently selected from nitrogen, oxygen and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms each independently selected from nitrogen, oxygen and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms each independently selected from nitrogen, oxygen and sulfur, selected from optionally substituted groups, n is 1, 2 or 3].

6. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R1 and R1' are H.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R2 is hydrogen, deuterium, halogen, -CN, -OMe, -S(C1-6 alkyl), -S(O)(C1-6 alkyl) or C1-6 alkyl.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R3 is hydrogen, deuterium, halogen, -NH2, -CN, -O(C1-6 alkyl), -S(C1-6 alkyl), -S(O)R, C4-6 cycloalkyl, C1-6 alkyl or 【Chemical 141】 The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R3 is

9. R3 is 【Chemical 142】 The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R3 is

10. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R5 is hydrogen, deuterium, halogen, -CN, -OMe, -S(C1-6 alkyl), -S(O)(C1-6 alkyl) or C1-6 alkyl.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein n is 1.

12. The compound of formula X: 【Chemical 144】 Or a pharmaceutically acceptable salt thereof [wherein, R １ , R ２ , R ３ , R ４ and R ５ each independently represents hydrogen, deuterium, a halogen, -NH ２ , -CN, -OR, -SR, -S(O)R, -S(O) ２ R, optionally substituted C １～６ Aliphatic or 【Chemical 145】 and provided that R １ R ２ R ３ R ４ and R ５ one of is -NH ２ and R １ R ２ R ３ R ４ and R ５ and another one of is 【Chemical 146】 and the -NH ２ and the 【Chemical 147】 Is bonded to adjacent carbon atoms, R ａ is C optionally substituted by one, two or three deuterium atoms or halogen atoms and １～４ is aliphatic, R ｂ is C optionally substituted with one, two or three deuterium or halogen atoms; １～４ aliphatic; or R ａ and R ｂ together with the carbon atom to which they are attached form a 3-8 membered cycloalkyl ring or a heterocyclyl ring containing 1-2 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and each R is selected from hydrogen, deuterium; and C １～６ aliphatic; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8-10 membered bicyclic aryl ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

13. R １ is 【Chemical 148】 and R ２ is —NH ２ The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein

14. R ３ The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein R is hydrogen or halogen.

15. R ４ is hydrogen, deuterium, halogen, -CN, -OMe, -S(C １～６ alkyl), -S(O)(C １～６ alkyl) or C １～６ alkyl, and the compound according to claim 12 or a pharmaceutically acceptable salt thereof.

16. R ５ The compound or a pharmaceutically acceptable salt thereof according to claim 12, wherein R is hydrogen or halogen.

17. The compound of formula I: 【Chemical 149】 Or a pharmaceutically acceptable salt thereof [wherein, W is N or CR ４ wherein X is S, NH or O, Y is N or CR ６ wherein However, when X is S or O, Y is CR ６ and R １ 、 R ２ 、 R ３ 、 R ４ 、 R ５ and R ６ each of which, independently, is hydrogen, deuterium, halogen, -NH ２ , -CN, -OR, -SR, optionally substituted C １～６ aliphatic, or 【Chemical Formula 150】 and provided that R １ R ２ R ３ R ４ R ５ and R ６ one of which is -NH ２ and R １ R ２ R ３ R ４ R ５ and R ６ another one of which is 【Chemical 151】 And R ａ is C optionally substituted by one, two or three deuterium atoms or halogen atoms, １～４ is aliphatic, R ｂ is C optionally substituted by one, two or three deuterium atoms or halogen atoms and １～４ is aliphatic, or Alternatively, R ａ and R ｂ together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl ring or a heterocyclyl ring containing 1 to 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, Each R is hydrogen, deuterium; and C １～６ is independently selected from optionally substituted groups selected from aliphatic; 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic rings; phenyl; 8- to 10-membered bicyclic aryl rings; 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 6-membered monocyclic heteroaryl rings having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic rings having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 8- to 10-membered bicyclic heteroaryl rings having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur].

18. R １ and R ６ One of them is -NH ２ or 【Chemical 152】 The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein

19. W is CR ４ The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein W is CR

20. X is S and W is CR ４ The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein:

21. The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein W is N, X is NH and Y is N.

22. R ２ is -CF ３ or hydrogen, the compound according to claim 17 or a pharmaceutically acceptable salt thereof.

23. R ３ is -NH ２ The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein R is -NH

24. R ４ The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein R is hydrogen.

25. R ５ The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein R is hydrogen.

26. R ａ and R ｂ are both methyl, the compound according to claim 17 or a pharmaceutically acceptable salt thereof.

27. R ａ is methyl and R ｂ is -CF ３ and the compound according to claim 17 or a pharmaceutically acceptable salt thereof.

28. The compound as claimed in claim 17, wherein the compound is a compound of formula II-a, II-b, II-c, II-d, II-e, II-f, II-g, II-h, II-i, II-j, III-a, III-b, III-c, III-d, III-e, III-f, III-g, III-h, III-i, III-j, IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, V-a, V-b, V-c, V-d, V-e, V-f, V-g, V-h, V-i, or V-j: 【Chemical 153】 【Chemical 154】 【Chemical 155】 【Chemical 156】 【Chemical 157】 The compound or a pharmaceutically acceptable salt thereof according to claim 17, wherein

29. The compound of formula VI: 【Chemical 158】 or a pharmaceutically acceptable salt thereof [wherein, R ７ 、 R ８ 、 R ９ and R １０ each of which is independently hydrogen, deuterium, halogen, -N(R) ２ , -CN, -OR, -SR or optionally substituted C １～６ is aliphatic, R ｃ is hydrogen or C optionally substituted by one, two or three deuterium or halogen atoms, １～４ is aliphatic, R ｄ is hydrogen or C optionally substituted by one, two or three deuterium atoms or halogen atoms １～４ is aliphatic; or R ｃ and R ｄ together with the carbon atom to which they are attached form a 3- to 8-membered saturated cycloalkyl ring or a heterocyclyl ring containing 1 to 2 heteroatoms each independently selected from nitrogen, oxygen and sulfur Each R is hydrogen, deuterium; and C １～６ aliphatic; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocyclic ring; phenyl; an 8- to 10-membered bicyclic aryl ring; a 3- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 6- to 10-membered bicyclic saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur; and an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur, each independently selected from optionally substituted groups].

30. R ７ The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R is hydrogen.

31. R ８ The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R is -OMe or -CF3.

32. R ９ The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

33. R １０ The compound or a pharmaceutically acceptable salt thereof according to claim 29, wherein R is hydrogen.

34. R ｃ and R ｄ The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein both are hydrogen.

35. The following: 【Chemical 201】 【Chemical 202】 【Chemical 203】 【Chemical 204】 【Chemical 205】 a compound selected from any one of the following, or a pharmaceutically acceptable salt thereof.

36. A pharmaceutical composition comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier or vehicle.

37. The pharmaceutical composition according to claim 36, in combination with an additional therapeutic agent.

38. A composition for treating a subject in need of treating age-related macular degeneration or a retinal disease in which the accumulation of A2E and / or lipofuscin is involved in the etiology thereof, the composition comprising a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, wherein the composition is administered to the subject, whereby the level of A2E accumulation is reduced compared to the level of A2E accumulation in the subject not administered the composition.

39. A composition for treating, preventing or reducing the risk of a disease, disorder, condition or cosmetic sign in which aldehyde toxicity is involved, in a subject in need thereof, the composition comprising a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, characterized in that the composition is administered topically or systemically to the subject. (a) the disease, disorder or condition is an eye disorder selected from dry eye syndrome, cataract, keratoconus, bullous keratopathy and other corneal diseases, Fuchs endothelial dystrophy, ocular cicatricial pemphigoid, states associated with the healing of PRK and other corneal healing, states associated with the breakdown of tear lipids or lacrimal gland dysfunction, uveitis, scleritis, Stevens-Johnson syndrome, and ocular rosacea, diabetic macular edema (DME), atopic keratoconjunctivitis (AKC), vernal keratoconjunctivitis (VKC), age-related macular degeneration (AMD), dry eye disease (DED), allergic conjunctivitis (AC), dry eye disease with allergic conjunctivitis, non-infectious anterior uveitis, posterior uveitis, panuveitis, postoperative eye pain and inflammation; or (b) the disease, disorder or condition is selected from macular degeneration and Stargardt disease; or (c) the disease, disorder or condition is selected from the group consisting of psoriasis, scleroderma, local (discoid) lupus, contact dermatitis, atopic dermatitis, allergic dermatitis, radiation dermatitis, acne vulgaris, Sjogren-Larsson syndrome or other ichthyosis; or (d) the cosmetic sign is selected from the group consisting of solar elastosis / wrinkles, skin tone and elasticity, swelling, eczema, smoking or irritant-induced skin changes, skin incisions and skin conditions related to burns or wounds; or (e) the disease, disorder or condition is a viral infection caused by coronavirus, hepatitis A virus, hepatitis B virus, dengue virus, yellow fever virus, Zika virus, influenza virus, respiratory syncytial virus (RSV), norovirus, herpes virus, human immunodeficiency virus (HIV), Ebola virus, human T-lymphotropic virus (HTLV)-1 and -2, Epstein-Barr virus, Lassa virus or Crimean-Congo hemorrhagic fever virus, and optionally, the coronavirus is 229E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), HKU1 (beta coronavirus), MERS-CoV (Middle East respiratory syndrome, i.e., the beta coronavirus that causes MERS), SARS-CoV (severe acute respiratory syndrome, i.e., the beta coronavirus that causes SARS) or SARS-CoV-2 (coronavirus disease 2019, i.e., COVID-19); or (f) the disease, disorder or condition is acute respiratory distress syndrome (ARDS); or (g) the disease, disorder or condition is an autoimmune, immune-mediated, inflammatory, cardiovascular or neurological disease, or diabetes, metabolic syndrome, or a fibrotic disease, and optionally, the fibrotic disease is fibrosis of the kidney, liver, lung or myocardium; or (h) the disease, disorder or condition is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis (UC), psoriasis, IBS (irritable bowel syndrome or spastic colon), ankylosing spondylitis, osteoporosis, rheumatoid arthritis (RA), psoriatic arthritis, chronic obstructive pulmonary disease (COPD), atherosclerosis, pulmonary arterial hypertension, pyridoxine-dependent epilepsy, atopic dermatitis, hives, multiple sclerosis (MS), systemic lupus erythematosus (SLE), lupus nephritis, sepsis, eosinophilic esophagitis, chronic kidney disease (CKD), renal fibrosis, chronic eosinophilic pneumonia, extrinsic allergic alveolitis, preeclampsia, endometriosis, polycystic ovary syndrome (PCOS), female infertility, decreased sperm viability and motility, cyclophosphamide-induced hemorrhagic cystitis; or light chain deposition disease, IgA nephropathy, end-stage renal disease, gout, pseudogout, diabetic nephropathy, diabetic neuropathy, traumatic brain injury, noise-induced hearing loss, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, primary biliary cirrhosis, primary sclerosing cholangitis, uterine leiomyoma, sarcoidosis, and chronic kidney disease; or (i) the disease, disorder or condition is keratitis or neurotrophic keratitis; or (j) the disease, disorder or condition is a respiratory disease, disorder or condition selected from chronic cough, pneumonia and pulmonary sepsis; or an organ disease, disorder or condition selected from alcoholic hepatitis, minimal change disease and focal segmental glomerulosclerosis (FSGS), composition. **Claim 40**: A composition for reducing the level of one or more toxic aldehydes in a subject in need of reducing the level of one or more toxic aldehydes, the composition comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, characterized in that the composition is administered to the subject, and the toxic aldehyde is selected from formaldehyde, acetaldehyde, acrolein, glyoxal, methylglyoxal, hexadecanal, octadecanal, hexadecenal, succinic semialdehyde, malondialdehyde, 4-hydroxynonenal, 4-hydroxy-2E-hexenal, 4-hydroxy-2E,6Z-dodecadienal, retinaldehyde, leukotriene B4 aldehyde and octadecenal.

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