Sulfonamide compounds for the treatment of neurodegenerative disorders and pharmaceutical compositions thereof

Abstract

The present invention discloses a compound of formula (I) (wherein R 1 , R 2a , R 2b , R 3 , X, Y, and the subscript n are as defined herein). The present invention relates to compounds, methods for producing them, pharmaceutical compositions containing them, and methods of treatment using them for preventing and / or treating diseases associated with neurodegenerative diseases by administering the compounds of the present invention. 【Chemical 1】 JPEG2025517627000059.jpg3681

Description

Technical Field

[0001] The present invention relates to compounds that may be useful for the prevention and / or treatment of neurodegenerative disorders. The present invention also provides methods for producing the compounds of the present invention, pharmaceutical compositions comprising the compounds of the present invention, and methods for preventing and / or treating neurodegenerative disorders by administering the compounds of the present invention.

Background Art

[0002] Alzheimer's disease (AD) is a neurodegenerative disease that occurs sporadically or due to genetic factors and causes dementia. Dementia is characterized by different clinical symptoms such as progressive decline in memory, thinking ability, language ability, learning ability, etc.

[0003] The relationship between the onset of some specific diseases known as proteinopathies, including Alzheimer's disease and Parkinson's disease, and the accumulation of specific proteins within neurons or in the brain parenchyma has been established (T. Bayer, 2012). This accumulation results from conformational changes of unstructured proteins that lead to small oligomers that ultimately aggregate into higher-order structures.

[0004] AD is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles and is a common cause of acquired cognitive impairment in middle and late life.

[0005] The prevalence of cognitive impairment increases exponentially with age, and the incidence of dementia increases rapidly after the age of 65 and continues to increase thereafter. The incidence of dementia due to all causes in individuals aged 65 - 70 is approximately 1 per 100 per year, and increases to 4 per 100 per year in those aged 80 - 90 (Knopman et al. 2021). The worldwide prevalence of all types of dementia is expected to increase from 50 million in 2010 to 113 million by 2050. (Knopman et al. 2021).

[0006] The pathology of AD is characterized by lesions including tau-containing neurofibrillary tangles, Aβ-containing plaques, activated glia, and / or enlarged endosomes. Furthermore, AD also involves the loss of synaptic homeostasis and the integrity of neurons or neuronal networks.

[0007] In AD patients, extracellular senile plaques containing Aβ are found to be widely distributed throughout the cerebral cortex, and tau-containing neurofibrillary tangles are initially found in the medial temporal lobe and then spread throughout the neocortical regions of the temporal, parietal, and frontal lobes.

[0008] Efforts to identify a treatment are still focused on finding targets that can substantially change the clinical course of AD patients, and currently no treatment has been identified. SUMMARY OF THE INVENTION

[0009] The present invention relates to compounds that may be useful for the prevention and / or treatment of neurodegenerative disorders. The present invention also provides methods for producing the compounds of the present invention, pharmaceutical compositions containing the compounds of the present invention, and methods for preventing and / or treating neurodegenerative disorders by administering the compounds of the present invention.

[0010] Accordingly, in a first aspect of the present invention, a compound of the present invention having the formula I,

Chemical formula

[0011] In certain embodiments, the compounds of the present invention are provided for use in the prevention and / or treatment of Alzheimer's disease. In more specific embodiments, the compounds of the present invention are provided for use in the treatment of Alzheimer's disease.

[0012] Furthermore, the compounds of the present invention may exhibit good exposure in the brain and may result in good efficacy.

[0013] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical carrier, excipient, or diluent. In certain aspects, the pharmaceutical composition may further comprise additional therapeutic active ingredients suitable for use in combination with the compound of the present invention. In a more specific aspect, the additional therapeutic active ingredient is an agent for treating neurodegenerative disorders.

[0014] Furthermore, the compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein are pharmaceutically acceptable when prepared and used.

[0015] In a further aspect of the present invention, the present invention provides a method of treating a mammal (particularly a human) suffering from a condition (particularly a neurodegenerative disorder) selected from those listed herein, the method comprising administering an effective amount of a pharmaceutical composition or compound of the present invention as described herein.

[0016] The present invention also provides a pharmaceutical composition comprising a compound of the present invention and a suitable pharmaceutical carrier, excipient, or diluent for use in medicine. In certain aspects, the pharmaceutical composition is for use in the prevention and / or treatment of neurodegenerative disorders.

[0017] In an additional aspect, the present invention provides a method for synthesizing a compound of the present invention using the representative synthetic protocols and routes disclosed herein later.

[0018] Other objects and advantages will be apparent to those skilled in the art upon consideration of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

[0019] Definitions The following terms are intended to have the meanings presented below and are useful for understanding the description and intended scope of the present invention.

[0020] When describing the present invention, which may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, where present and unless otherwise indicated, have the following meanings. Also, as described herein, any of the moieties defined below may be optionally substituted with various substituents, and each definition is intended to include such substituted moieties within the scope of those described below. Unless otherwise defined, the term "substituted" is defined as shown below. Further, it should be understood that the terms "group" and "radical" may be considered interchangeable as used herein.

[0021] The articles "a" and "an" may be used herein to refer to one or more (i.e., at least one) of the grammatical objects of the article. By way of example, "analog" means one analog or a plurality of analogs.

[0022] "Alkyl" means a straight-chain or branched-chain aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched-chain means that one or more alkyl groups, such as methyl, ethyl, or propyl, are attached to the straight-chain alkyl chain. Particular alkyl groups are methyl (-CH 3 ), ethyl (-CH 2 -CH 3 ), n-propyl (-CH 2 -CH 2 -CH 3 ), isopropyl (-CH(CH 3 )) 2 ), n-butyl (-CH 2 -CH 2 -CH 2 -CH 3 ), tert-butyl (-C(CH 3 )) 3 ), iso-butyl (-CH 2 -CH(CH 3 )) 2 ), sec-butyl (-CH(CH 3 )-CH2 -CH 3 ), n-pentyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), n-hexyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), and 1,2-dimethylbutyl (-CHCH 3 )(-C(CH 3 ))H 2 -CH 2 -CH 3 ). Specific alkyl groups have 1 to 4 carbon atoms.

[0023] "Alkoxy" refers to the group O-alkyl, and the alkyl group has the specified number of carbon atoms. In particular, this term refers to -O-C 1-6 alkyl group. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, iso-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy, that is, having 1 to 6 carbon atoms. Further specific alkoxy groups have 1 to 4 carbon atoms.

[0024] "Cycloalkyl" refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic having the specified number of ring atoms. Cycloalkyl can have 3 to 12 carbon atoms, particularly 3 to 10, more specifically 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0025] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). Specific halo groups are either fluoro or chloro.

[0026] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group are replaced by nitrogen, oxygen, or sulfur heteroatoms. Hetero can apply to any of the above hydrocarbyl groups having from 1 to 4, particularly from 1 to 3, more typically 1 or 2 heteroatoms, for example, an alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocycloalkyl), etc. having a single heteroatom.

[0027] "Heterocycloalkyl" means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, which independently includes one or more heteroatoms selected from O, N, and S, as well as the specified number of ring atoms. The heterocycloalkyl ring structure can have from 4 to 12 ring members, particularly from 4 to 10 ring members, more specifically from 4 to 7 ring members. Each ring can typically contain up to 4 heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, the heterocycloalkyl ring contains up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2 heteroatoms, for example, a single heteroatom. Examples of heterocycles include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, and 3-pyrrolidinyl), tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl), tetrahydrothiophenyl (e.g., 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl, and 3-tetrahydrothiophenyl), piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), tetrahydropyranyl (e.g., 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g., 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0028] Specific examples of monocyclic rings are shown in the following exemplary examples, [Chem.] In the formula, each W and Y is independently selected from -CH 2 -, -NH-, -O-, and -S-.

[0029] "Substituted" refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituents.

[0030] As used herein, the term "substituted with one or more" refers to 1 to 4 substituents. In one embodiment, this refers to 1 to 3 substituents. In a further embodiment, this refers to 1 or 2 substituents. In an even further embodiment, this refers to 1 substituent.

[0031] One of ordinary skill in organic synthesis will understand that, whether aromatic or non-aromatic, the maximum number of heteroatoms in a stable chemically feasible heterocyclic ring is determined by the ring size, degree of unsaturation, and valence of the heteroatoms. Generally, a heterocyclic ring can have 1 to 4 heteroatoms as long as the heteroaromatic ring is chemically feasible and stable.

[0032] "Pharmaceutically acceptable" means approved or sanctioned by the regulatory authorities of the federal or state governments of countries other than the United States or the corresponding agencies, or being included in the United States Pharmacopeia or other generally recognized pharmacopeias for use in animals, more specifically humans.

[0033] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. In particular, such salts can be non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include the following: (1) acid addition salts (formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucic acid, etc.); or (2) salts formed when the acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion), or when coordinated with an organic base (ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). The salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc. When the compound contains a basic functional group, it includes salts of non-toxic organic acids or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion for an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc.

[0034] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier administered together with a compound of the present invention.

[0035] "Prodrug" refers to a compound that has a cleavable group and becomes pharmaceutically active in vivo by solvolysis or under physiological conditions, including derivatives of the compounds of the present invention. Such examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like.

[0036] "Solvate" generally refers to a form of a compound that associates with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid, and the like. The compounds of the present invention can be prepared, for example, in crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, a solvate can be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both the solution phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0037] "Subject" includes humans. The terms "human", "patient", and "subject" are used interchangeably herein.

[0038] "Effective amount" means an amount of a compound of the present invention that is sufficient to effect such treatment of a disease when administered to a subject for treating the disease. The "effective amount" can vary depending on the compound, the disease being treated and its severity, as well as age, weight, and the like.

[0039] "Preventing" or "prevention" refers to a decrease in the risk of acquiring or developing a disease or disorder (i.e., preventing at least one of the clinical symptoms of the disease from occurring in a subject who may be exposed to an agent that causes the disease or who may be predisposed to the disease prior to the onset of the disease).

[0040] The term "prophylaxis" is related to "prevention" and refers to measures or procedures aimed at preventing rather than treating or curing a disease. Non-limiting examples of prophylactic measures can include administration of a vaccine, for example, administration of low molecular weight heparin to hospital patients at risk of thrombosis due to immobility, and administration of an antimalarial agent such as chloroquine prior to travel to a geographical area where malaria is endemic or where there is a high risk of contracting malaria.

[0041] "Treating" or "treatment" of any disease or disorder, in one embodiment, refers to an improvement of the disease or disorder (i.e., halting of the disease, or reduction in the signs, degree, or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be recognizable by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0042] As used herein, the term neurodegenerative disease refers to a disease associated with proteinopathy, or atrophy of affected central or peripheral structures of the nervous system. In particular, the term refers to disorders characterized by the accumulation of specific proteins within neurons or in the brain parenchyma, or atrophy of affected central or peripheral structures of the nervous system. More specifically, the term refers to Alzheimer's disease and other dementias, brain cancer, neurodegenerative diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease, prion disease, tauopathy, frontotemporal lobar degeneration, the British and Danish types of dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Most specifically, the term refers to Alzheimer's disease.

[0043] The "compounds of the invention" and equivalent expressions mean, to the extent the context permits, the compounds of formula (e) described herein, including pharmaceutically acceptable salts, and solvates, such as hydrates, and solvates of pharmaceutically acceptable salts. Similarly, references to intermediates, whether or not themselves claimed, mean, to the extent the context permits, their salts and solvates.

[0044] When ranges are referred to herein (e.g., but not limited to, C 1 - 8 alkyl), the recitation of the range should be considered to be a recitation of each member of the range.

[0045] Other derivatives of the compounds of the invention are active in both their acid form and acid derivative forms, but in the acid-sensitive form often provide advantages in solubility, tissue compatibility, or sustained release in mammalian organisms (Bundgaard 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reaction of a parent acid with a suitable alcohol, or amides prepared by reaction of a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of the invention are particularly useful prodrugs. In some cases, it is desirable to prepare double-ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Such prodrugs in particular are the C 1 - 8 alkyl, C 2 - 8 alkenyl, C 6 - 10 optionally substituted aryl, and (C 6 - 10 aryl)-(C 1-4 alkyl) esters of the compounds of the invention.

[0046] This disclosure includes all isotopic forms of the compounds of the invention provided herein, regardless of whether (i) all atoms of a given atomic number are in a form having the mass number (or mixture of mass numbers) that is predominant in nature (referred to herein as the "natural isotopic form"), or (ii) one or more atoms have the same atomic number but a mass number different from that of the atoms that are predominant in nature (referred to herein as the "non-natural variant isotopic form"). It should be understood that atoms can exist naturally as a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments where the proportion of atoms of a given atomic number having a mass number that is less common in nature (referred to herein as "uncommon isotopes") is increased, for example, to levels of >20%, >50%, >75%, >90%, >95%, or >99% relative to what exists naturally, compared to the atoms of that atomic number (the latter embodiments are referred to as "isotope-enriched variant forms"). The term "non-natural variant isotopic form" also includes embodiments where the proportion of uncommon isotopes is decreased compared to what exists naturally. Isotopic forms can include radioactive forms (i.e., incorporating radioactive isotopes) and non-radioactive forms. Radioactive forms are typically isotope-enriched variant forms.

[0047] Thus, non-natural variant isotopic forms of a compound can have one or more atoms with deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulfur-35 ( 35 S), chlorine-36 ( 36 Cl), chlorine-37 ( 37 Cl), fluorine-18 ( 18 F), iodine-123 ( 123 I), iodine-125 ( 125It may contain one or more artificial isotopes or non - common isotopes such as I), or it may contain an increased proportion of such isotopes compared to the proportion that is dominant in nature in one or more atoms.

[0048] Non - natural variant isotopic forms containing radioisotopes can be used, for example, in tissue distribution studies of drugs and / or substrates. Tritium (i.e., 3 H) and carbon - 14 (i.e., 14 C) are particularly useful for this purpose in view of the ease of their incorporation and the ease of detection means. Non - natural variant isotopic forms incorporating deuterium (i.e., 2 H or D) can provide certain therapeutic advantages resulting from greater metabolic stability, e.g., an increase in in - vivo half - life or a decrease in dosage requirements, and are thus, in some situations, preferably used. Further, 11 C, 18 F, 15 0, and 13 Non - natural variant isotopic forms incorporating positron - emitting isotopes such as N can be prepared and would be useful in positron emission topography (PET) studies for examining substrate receptor occupancy.

[0049] Also, it should be understood that compounds having the same molecular formula but differing in the nature or sequence of the bonds of their atoms, or in the arrangement of those atoms in space, are called "isomers". Isomers that differ in the arrangement of atoms in space are called "stereoisomers".

[0050] Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups and a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the Cahn and Prelog R- and S-rules of precedence, or in a manner in which the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., as the (+) or (-) isomer, respectively). Chiral compounds can exist as either individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0051] "Tautomers" are alternative forms of a particular compound structure and refer to compounds that differ in the substitution of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enol and ketone are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or a base.

[0052] Tautomeric forms can be relevant to the achievement of the optimal chemical reactivity and biological activity of the compound of interest.

[0053] The compounds of the present invention may have one or more asymmetric centers. Thus, such compounds can be produced as individual (R) or (S) stereoisomers or as mixtures thereof.

[0054] Unless otherwise indicated, the description or naming of a particular compound in this specification and the claims is intended to include both the individual enantiomers and their racemic or other mixtures. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art.

[0055] It should be understood that the compounds of the present invention can be metabolized to produce biologically active metabolites.

[0056] The present invention The present invention relates to compounds that may be useful for the prevention and / or treatment of neurodegenerative disorders. The present invention also provides methods for producing the compounds of the present invention, pharmaceutical compositions comprising the compounds of the present invention, and methods for preventing and / or treating neurodegenerative disorders by administering the compounds of the present invention.

[0057] Accordingly, in a first aspect of the present invention, there is provided a compound of the present invention having the formula I,

Chemical formula

[0058] In one embodiment, the compound of the present invention is a compound according to formula I, wherein the subscript n is 1, 2, or 3. In certain embodiments, the subscript n is 2 or 3. In further certain embodiments, the subscript n is 1.

[0059] In one embodiment, the compound of the present invention is a compound according to formula I, wherein R 1 is pyridyl.

[0060] In one embodiment, the compound of the present invention is a compound according to formula I, wherein R 1 is pyridyl substituted with 1, 2, or 3 independently selected R 4 . In a more specific embodiment, R 1 is pyridyl substituted with one R 4 .

[0061] In one embodiment, the compound of the present invention is a compound according to formula I, wherein R 1 is phenyl.

[0062] In one embodiment, the compound of the present invention is a compound according to formula I, and R 1 is phenyl substituted with one or more independently selected R 4 . In certain embodiments, R 1is phenyl substituted with 1, 2, or 3 independently selected R 4 In a more specific embodiment, R 1 is phenyl substituted with one R 4 .

[0063] In one embodiment, the compound of the present invention is a compound of formula I, wherein R 1 is phenyl substituted with one or more independently selected R 4 , and one or more R 4 are -OH.

[0064] In one embodiment, the compound of the present invention is a compound of formula I, wherein R 1 is phenyl substituted with one or more independently selected R 4 , and one or more R 4 are halo. In certain embodiments, one or more R 4 are independently selected from F, Cl, and Br. In a more specific embodiment, one or more R 4 are F.

[0065] In one embodiment, the compound of the present invention is a compound of formula I, and R 1 is phenyl substituted with one or more independently selected R 4 , and one or more R 4 are independently selected from one or more independently selected halo or C 1-4 alkyl optionally substituted with alkoxy. In certain embodiments, one or more R 1-4 are independently selected from -CH 4 , -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , and -C(CH 3 ) 3 , each of which is optionally substituted with one or more independently selected halo or C 1-4 alkoxy. In another certain embodiment, one or more R 4is independently selected from one or more independently selected F, Cl, -OCH 3 , -OCH 2 CH 3 optionally substituted C 1-4 alkyl. In a more specific embodiment, one or more R 4 are independently selected from -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , and -C(CH 3 ) 3 , each of which is optionally substituted with one or more independently selected F, Cl, -OCH 3 , or -OCH 2 CH 3 . In a more specific embodiment, one or more R 4 are independently selected from -CH 3 and -CF 3 .

[0066] In one embodiment, the compound of the present invention is a compound according to formula I, wherein R 1 is phenyl substituted with one or more independently selected R 4 , and one or more R 4 are independently selected from one or more independently selected halo or C 1-4 alkoxy optionally substituted with C 1-4 alkoxy. In a particular embodiment, one or more R 4 are independently selected from -OCH 3 , -OCH 2 CH 3 , -OCH(CH 3 ) 2 , and -OC(CH 3 ) 3 , each of which is substituted with one or more independently selected halo or C 1-4 alkoxy. In another particular embodiment, one or more R 4 are independently one or more independently selected F, Cl, -OCH 3 , -OCH 2 CH3 C optionally replaced with 1-4 selected from alkoxy. In a more specific embodiment, one or more R 4 are independently -OCH 3 -OCH 2 CH 3 -OCH(CH 3 ) 2 and -OC(CH 3 ) 3 each of which is optionally substituted with one or more independently selected F, Cl, -OCH 3 or -OCH 2 CH 3 . In a more specific embodiment, one or more R 4 are independently -OCH 3 -OCH 2 CH 2 OCH 3 and -OCF 3 .

[0067] In one embodiment, the compound of the present invention is a compound according to formula I, and R 1 is phenyl substituted with one or more independently selected -OH, F, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 2 OCH 3 and -OCF 3 . In a particular embodiment, R 1 is phenyl substituted with one or two independently selected -OH, F, -CH 3 , -CF 3 , -OCH 3 , -OCH 2 CH 2 OCH 3 and -OCF 3 .

[0068] In one embodiment, the compound of the present invention is a compound according to any of formulae IIa, IIb, IIc, or IId,

Chemical formula

[0069] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I to IId, wherein R 3 is H.

[0070] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I to IId, wherein R 3 is C 1-6 alkyl. In a specific embodiment, R 3 is -CH 3 , -CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 is. In a more specific embodiment, R 3 is -CH 3 or -CH 2 CH(CH 3 ) 2 is. In the most specific embodiment, R 3 is -CH 3 .

[0071] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I to IId, wherein R 3 is C 1-6 alkyl substituted with one or more independently selected halos. In a specific embodiment, R 3 is -CH 3 , -CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 and each of these is substituted with one or more independently selected halos. In a more specific embodiment, R 3 is -CH 3 , -CH 2 CH 3 , or -CH 2 CH(CH 3 )2 and each of these is substituted with one, two, or three independently selected halos. In a further specific embodiment, R 3 is -CH 3 , -CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 and each of these is substituted with one, two, or three independently selected F, Cl, or Br. In a more specific embodiment, R 3 is -CH 3 , -CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 and each of these is substituted with one, two, or three independently selected F or Cl. In the most specific embodiment, R 3 is -CH 3 , -CH 2 CH 3 , or -CH 2 CH(CH 3 ) 2 and each of these is substituted with one, two, or three Fs. In a further most specific embodiment, R 3 is -CF 3 .

[0072] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I to IId, wherein R 3 is a C 3-7 monocyclic cycloalkyl substituted with one or more independently selected halos. In a specific embodiment, R 3 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected halos. In a more specific embodiment, R 3 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected F, Cl, or Br. In a further specific embodiment, R 3is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected F or Cl. In a further particular embodiment, R 3 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with 1, 2, or 3 Fs.

[0073] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I - IId, wherein R 3 is C 3-7 monocyclic cycloalkyl. In a particular embodiment, R 3 is cyclopropyl, cyclobutyl, or cyclopentyl. In a particular embodiment, R 3 is cyclopropyl.

[0074] In one embodiment, the compound of the present invention is a compound according to any of IIIa, IIIb, IIIc, IIId, IIIe, or IIIf,

Chemical formula

[0075] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I - IIIf, each R 2a and R 2b both being H.

[0076] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I - IIIf, each R 2a and R 2b being independently selected from H, C 1-4 alkyl, and C 3-6 cycloalkyl. In a particular embodiment, each R 2a and R 2b is independently H, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH3 ) 2 , selected from cyclopropyl, cyclobutyl, and cyclopentyl. In another specific embodiment, R 2a is H, and R 2b is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , selected from cyclopropyl, cyclobutyl, and cyclopentyl. In a specific embodiment, each R 2a and R 2b is independently -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , selected from cyclopropyl, cyclobutyl, and cyclopentyl. In the most specific embodiment, R 2a and R 2b are both -CH 3 .

[0077] In one embodiment, the compound of the present invention is a compound according to any one of Formulas I to III f, and R 2a and R 2b can form a 4- to 7-membered heterocycloalkyl together with the N atom. In a specific embodiment, R 2a and R 2b can form an azetidinyl, pyrrolidinyl, or piperidinyl ring together with the N atom. In a more specific embodiment, R 2a and R 2b together with the N atom are [Chemical formula] .

[0078] In one embodiment, the compound of the present invention is a compound according to Formula I and is selected from the following: N,N-dimethyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, N,N-Dimethyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-3-sulfonamide, N,N-Dimethyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-3-sulfonamide, N-Isopropyl-N-methyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, N-Cyclopropyl-N-methyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(2-Phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(2-(4-Methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-Methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide, 1-(2-(3-Methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(3-Methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide, N,N-Dimethyl-1-(2-(4-(trifluoromethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(2-(2-Fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(2-Fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide, N,N-Dimethyl-1-(2-(4-(trifluoromethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-3-sulfonamide, 1-(2-(2-Methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, N,N-Dimethyl-1-(2-(o-tolyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(2-(2-Methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(2,6-Dimethylphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, N,N-Dimethyl-1-(3-methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, N,N-Dimethyl-1-(2-(4-(trifluoromethyl)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, N,N-Dimethyl-1-(2-(p-tolyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(2-(4-Hydroxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-(2-Methoxyethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-3-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(2-(2-(2-Methoxyethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(3-(2-Methoxyethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N-methylazetidine-3-sulfonamide, N-Methyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, N-Methyl-1-(3-methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(3-Methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(3-Cyclopropyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-3-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N-methylazetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-3-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide, 1-(3-Cyclopropyl-2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-3-isopropyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, 6-(3-(Azetidin-1-ylsulfonyl)azetidin-1-yl)-2-phenyl-2H-pyrazolo[4,3-c]pyridine, 6-(3-(Azetidin-1-ylsulfonyl)azetidin-1-yl)-2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine, N,N-Dimethyl-1-(2-phenyl-2H-pyrazolo[3,4-b]pyridin-6-yl)azetidine-3-sulfonamide, 1-(2-(4-Fluorophenyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide, N-Methyl-1-(2-phenyl-2H-pyrazolo[3,4-b]pyridin-6-yl)azetidine-3-sulfonamide, and 1-(2-Phenyl-2H-pyrazolo[3,4-b]pyridin-6-yl)azetidine-3-sulfonamide.

[0079] In one embodiment, the compounds of the present invention are provided in natural isotopic forms.

[0080] In one embodiment, the compounds of the present invention are provided in non-natural variant isotopic forms. In certain embodiments, the non-natural variant isotopic forms are those in which deuterium (i.e., 2 H or D) is incorporated, and hydrogen is specified in the chemical structure at one or more atoms of the compounds of the present invention. In one embodiment, the atoms of the compounds of the present invention are in non-radioactive isotopic forms. In one embodiment, one or more atoms of the compounds of the present invention are in radioactive isotopic forms. Preferably, the radioactive isotope is a stable isotope. Preferably, the non-natural variant isotopic forms are in pharmaceutically acceptable forms.

[0081] In one embodiment, there are provided compounds of the present invention in which a single atom of the compound is in a non-natural variant isotopic form. In another embodiment, there are provided compounds of the present invention in which two or more atoms are in non-natural variant isotopic forms.

[0082] Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by the processes described herein (e.g., by processes similar to those described in the accompanying examples for preparing natural isotopic forms). Thus, non-natural isotopic variant forms can be prepared by using appropriate isotopic variant (or labeled) reagents in place of the normal reagents used as exemplary examples in the examples.

[0083] In one aspect, a compound of the invention described in any one of the embodiments described herein exists as a free base.

[0084] In one aspect, a compound of the invention described in any one of the embodiments described herein is a pharmaceutically acceptable salt.

[0085] In one aspect, a compound of the invention described in any one of the embodiments described herein is a solvate of the compound.

[0086] In one aspect, a compound of the invention described in any one of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of the compound.

[0087] The groups designated for each embodiment are generally listed separately above, but the compounds of the invention include those in which some or each of the above-described embodiments, as well as other formulas presented herein, are selected from one or more of the specific members or groups designated for each variable. Thus, the invention is intended to include all combinations of such embodiments within its scope.

[0088] The specific groups for each embodiment are generally listed separately above, but the compounds of the invention can be those in which one or more variables (e.g., R groups) are selected from one or more embodiments according to any of the formulas (e) listed above. Thus, the invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0089] Alternatively, it is contemplated by the present invention to exclude one or more of the designated variables from a group or embodiment, or a combination thereof.

[0090] In certain embodiments, the present invention provides prodrugs and derivatives of the compounds described in the above formula. A prodrug is a derivative of a compound of the present invention that has a metabolically cleavable group and becomes pharmaceutically active in vivo by solvolysis or under physiological conditions. Examples of such include, but are not limited to, N-alkylmorpholine esters such as choline esters.

[0091] Other derivatives of the compounds of the present invention are active in both their acid and acid derivative forms, and the acid-sensitive forms often provide advantages in solubility, tissue compatibility, or delayed release in mammalian organisms (Bundgard, H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reaction of a parent acid with a suitable alcohol, or amides prepared by reaction of a parent acid compound with a substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds of the present invention are preferred prodrugs. In some cases, it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly useful are C 1 -C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 -C 12 substituted aryl, and C 7 -C 12 arylalkyl esters.

[0092] Pharmaceutical Compositions When used as a medicament, the compounds of the present invention are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and contain at least one active compound of the present invention according to formula I. Generally, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compound of the present invention actually administered will typically be determined by the physician in light of relevant circumstances including the condition being treated, the route of administration selected, the actual compound of the present invention being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0093] The pharmaceutical compositions of the present invention can be administered by various routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds of the present invention are preferably formulated either as an injectable or oral composition, or as an ointment, lotion, or patch for transdermal administration.

[0094] Compositions for oral administration can take the form of a bulk liquid solution or suspension, or a bulk powder. However, more commonly, the compositions are presented in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient, vehicle, or carrier. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules, and the like. In such compositions, the compounds of the present invention according to formula I are usually minor components (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder consists of various vehicles or carriers and processing aids useful for forming the desired dosage form.

[0095] Suitable liquid forms for oral administration may include suitable aqueous or non-aqueous vehicles containing buffers, suspending and compounding agents, coloring agents, flavors, and the like. Solid forms may include, for example, the following components: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; flow promoters such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint orange flavor, or compounds of similar nature may be included.

[0096] Injectable compositions are typically based on sterile saline for injection or phosphate-buffered saline for injection or other injectable carriers known in the art. As described above, the active compounds of the present invention according to formula I in such compositions are typically minor components, often about 0.05 to 10% by weight, and the remainder is an injectable carrier or the like.

[0097] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient, generally in an amount in the range of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, more preferably about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with either a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated, for example, into a cream having an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional ingredients to enhance skin penetration of the active ingredient or formulation stability. All such known transdermal formulations and ingredients are included within the scope of the present invention.

[0098] The compounds of the present invention can also be administered by a transdermal device. Thus, transdermal administration can be achieved using a patch of either the reservoir or porous membrane type, or the solid matrix type.

[0099] The above ingredients for the oral administration composition or the topical administration composition are merely representative. Other materials, as well as processing techniques, etc., are described in Part 8 of Remington’s Pharmaceutical Sciences, 17 th edition, 1985, Mack Publishing Company, Easton, Pennsylvania (incorporated herein by reference).

[0100] Also, the compounds of the present invention can be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release substances can be found in Remington’s Pharmaceutical Sciences.

[0101] The following examples of formulations illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0102] Formulation 1 - Tablet The compound of the present invention according to formula I can be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture can be formed into tablets of 240 - 270 mg (80 - 90 mg of the active compound of the present invention according to formula I per tablet) using a tableting machine.

[0103] Formulation 2 - Capsule The compound of the present invention according to formula I can be mixed as a dry powder with a starch diluent in a weight ratio of about 1:1. The mixture can be filled into 250 mg capsules (125 mg of the active compound of the present invention according to formula I per capsule).

[0104] Formulation 3 - Liquid The compound of the present invention according to formula I (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended and passed through a No. 10 mesh US Sieve, and then can be mixed with an aqueous solution of pre-prepared microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavoring agent, and coloring agent can be diluted with water and added with stirring. Then, sufficient water can be added with stirring. Then, further sufficient water can be added to make the total volume 5 mL.

[0105] Formulation 4 - Tablet The compound of the present invention according to formula I can be mixed as a dry powder with a dry gelatin binder at a weight ratio of about 1:2. A small amount of magnesium stearate may be added as a lubricant. The mixture can be formed into tablets of 450 - 900 mg (150 - 300 mg of the active compound of the present invention according to formula I) using a tableting machine.

[0106] Formulation 5 - Injection The compound of the present invention according to formula I can be dissolved or suspended in a buffered sterile physiological saline injection aqueous medium at a concentration of about 5 mg / mL.

[0107] Formulation 6 - Topical Stearyl alcohol (250 g) and white petrolatum (250 g) can be dissolved at about 75°C. Then, a mixture of the compound of the present invention according to formula I (50 g) dissolved in water (about 370 g), methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) can be added, and the resulting mixture can be stirred until it solidifies.

[0108] Treatment Method In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in medicine.

[0109] In certain embodiments, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of neurodegenerative diseases. In particular, the term "neurodegenerative disease" refers to proteinopathy, or atrophy of the central or peripheral structures affected by the nervous system. More specifically, the term "neurodegenerative disease" refers to Alzheimer's disease and other dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease, prion disease, tauopathy, frontotemporal lobar degeneration, British and Danish types of dementia, and autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Most specifically, the term "neurodegenerative disease" refers to Alzheimer's disease.

[0110] In another embodiment, the present invention provides the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention in the manufacture of a medicament for the prevention and / or treatment of neurodegenerative diseases. In particular, the term "neurodegenerative disease" refers to proteinopathy, or atrophy of the central or peripheral structures affected by the nervous system. More specifically, the term "neurodegenerative disease" refers to Alzheimer's disease and other dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease, prion disease, tauopathy, frontotemporal lobar degeneration, British and Danish types of dementia, and autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Most specifically, the term "neurodegenerative disease" refers to Alzheimer's disease.

[0111] In a further aspect of the treatment method, the present invention provides a method for preventing and / or treating a mammal suffering from a neurodegenerative disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein for the treatment or prevention of such condition. In particular, the term neurodegenerative disease refers to proteinopathy, or atrophy of the affected central or peripheral structures of the nervous system. More specifically, the term "neurodegenerative disease" refers to Alzheimer's disease and other dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease, prion disease, tauopathy, frontotemporal lobar degeneration, British and Danish type dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Most specifically, the term neurodegenerative disease refers to Alzheimer's disease.

[0112] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In certain embodiments, the other therapeutic agent is a therapeutic agent for a neurodegenerative disease. In particular, the term neurodegenerative disease refers to proteinopathy, or atrophy of the affected central or peripheral structures of the nervous system. More specifically, the term "neurodegenerative disease" refers to Alzheimer's disease and other dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease, prion disease, tauopathy, frontotemporal lobar degeneration, British and Danish type dementia, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Most specifically, the term neurodegenerative disease refers to Alzheimer's disease. In another embodiment, the other therapeutic agent is selected from aducanumab, galantamine, rivastigmine, donepezil, and memantine.

[0113] The infusion dosage levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 h, particularly 24 to 96 h. Also, a preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may be administered to achieve an appropriate steady-state level. The maximum total dosage is expected not to exceed about 1 g / day in the case of a 40 - 80 kg human patient.

[0114] In the case of prevention and / or treatment of long-term conditions such as altered states, the regimen for treatment is preferably administered orally for the convenience and tolerance of the patient as the treatment regimen is extended over several months or years. For oral administration, regular administration 1 to 4 times a day, particularly 1 to 3 times a day, typically 1 to 2 times a day, and most typically once a day are representative regimens. Alternatively, for drugs with a long-lasting effect, oral administration once every two weeks, once a week, and once a day are representative regimens. In particular, the administration regimen can be every 1 to 14 days, more specifically every 1 to 10 days, even more specifically every 1 to 7 days, and most specifically every 1 to 3 days.

[0115] Using these administration patterns, each dosage provides from about 1 to about 1000 mg of the compound of the present invention, and specific dosages each provide from about 10 to about 500 mg, particularly from about 30 to about 250 mg.

[0116] The transdermal dosage is generally selected to provide blood levels similar to or lower than those achieved using infusion dosages.

[0117] When used to prevent the onset of a condition, the compounds of the present invention are administered at the dosage levels described above, typically to patients at risk of developing the condition, under the advice and supervision of a physician. Patients at risk of developing a particular condition generally include patients with a family history of that condition, or patients specifically identified as being particularly prone to developing that condition by genetic testing or screening.

[0118] The compounds of the present invention can be administered as the sole active agent or in combination with other therapeutic agents (including other compounds of the present invention that exhibit the same or similar therapeutic activity and have been determined to be safe and effective for such combination administration). In certain embodiments, co - administration of two (or more) agents can significantly lower each of the doses used, thereby reducing the side effects seen.

[0119] In one embodiment, the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention is administered as a medicament. In certain embodiments, the pharmaceutical composition further comprises additional active ingredients.

[0120] In one embodiment, the compound of the present invention is co - administered with another therapeutic agent for the treatment and / or prevention of neurodegenerative diseases. Specific agents include, but are not limited to, amantadine, apomorphine, aducanumab, baclofen, carbidopa, dantrolene, donepezil, entacapone, galantamine, levodopa, memantine, pramipexole, rasagiline, riluzole, rivastigmine, ropinirole, selegiline, tacrine, tetrabenazine, tizanidine, and tolcapone.

[0121] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of a proliferative disorder. Particular agents include, but are not limited to, methotrexate, leucovorin, doxorubicin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibodies (e.g., Herceptin™, capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g., Iressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g., Avastin™), proteasome inhibitors (e.g., Velcade™), Glivec®, and hsp90 inhibitors (e.g., 17-AAG). Further, the compounds of the invention according to Formula I can be administered in combination with other therapies including, but not limited to, radiation therapy or surgery. In certain embodiments, the proliferative disorder is selected from cancer, myeloproliferative disease, or leukemia.

[0122] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of autoimmune diseases. Specific agents include, but are not limited to, glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, the platinum compounds of the invention, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin anthracyclines, mitomycin C, bleomycin, and mitramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, Atgam®, and Thymoglobuline®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF-binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate salts, fingolimod, and milcamycin.

[0123] As will be apparent to those skilled in the art, co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. The two or more agents can be co-administered simultaneously as a single formulation, i.e., a single pharmaceutical composition, but this is not required. The agents can be administered in different formulations at different times.

[0124] Chemical synthesis procedures General The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It is to be understood that other process conditions can be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise specified. Optimal reaction conditions can vary depending on the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0125] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The selection of suitable protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art (“Greene’s Protective Groups in Organic Synthesis, 4th Edition|Wiley” 2006).

[0126] The following methods are presented along with details and comparative examples regarding the preparation of the compounds of the invention as defined above. The compounds of the invention can be prepared by those skilled in organic synthesis from known or commercially available starting materials and reagents.

[0127] All reagents were of commercial grade and were used as received without further purification, unless otherwise specified. Commercially available anhydrous solvents were used for reactions conducted under an inert atmosphere. In all other cases, reagent-grade solvents were used, unless otherwise specified. Column chromatography was performed on silica gel 60 (35 - 70 μm). Thin-layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). 1 1H NMR spectra were recorded on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Advance 300 NMR spectrometer (300 MHz). The chemical shifts (δ) of the 1H NMR spectra were referenced internally to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e., CHCl 3It is reported in parts per million (ppm) compared to (δ 7.27). The multiplicity is given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m), and broad (br). The electrospray MS spectrum was obtained using a Waters platform LC / MS spectrometer or a Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm inner diameter × 50 mm length, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm inner diameter × 30 mm length, or Waters Xterra MS 5 μm C18, 100 × 4.6 mm. This method uses either a MeCN / H 2 O gradient (H 2 O contains either 0.1% TFA or 0.1% NH 3 and) or a MeOH / H 2 O gradient (H 2 O contains 0.05% TFA). Microwave heating was carried out using a Biotage Initiator.

Table 1

[0128] Synthetic preparation of the compounds of the present invention Example 1. Preparation of intermediates and exemplary compounds of the present invention 1.1. General method 1: Azidation

Chemical formula

[0129] Exemplary example of Method 1, synthesis of Intermediate 1: 4-Azido-6-chloronicotinaldehyde [Chemical formula] To an ice-cooled solution of 4,6-dichloropyridine-3-carbaldehyde (528.0 mg, 3.0 mmol, 1.0 equiv) in dry DMF (5.0 mL) was added NaN 3 (204.8 mg, 6.30 mmol, 3.15 equiv), and the reaction mixture was stirred at room temperature. After 1.5 h, EtOAc was added and the mixture was washed with saturated NaHCO 3 aqueous solution and brine. The organic extract was dried over Na 2 SO 4 and concentrated in vacuo to give the desired intermediate.

[0130] Another exemplary example of Method 1, synthesis of Intermediate 2: 1-(4-Azido-6-chloropyridin-3-yl)ethan-1-one [Chemical formula] To a solution of 1-(4,6-dichloro-3-pyridyl)ethanone (5.0 g, 26.3 mmol, 1.0 equiv) in dry DMF (50 mL) was added NaN 3 (18.8 g, 28.9 mmol, 1.1 equiv), and the reaction mixture was stirred at room temperature for 1.5 h. When the conversion was complete, the reaction was quenched by adding water and EtOAc. The aqueous layer was extracted with EtOAc and the mixture was washed with saturated aqueous solution of NaHCO 3 and brine. The organic extract was dried over MgSO 4 and concentrated in vacuo to give a crude material, which was suspended in MTBE, stirred for 1 h, filtered, and dried to give the desired intermediate.

[0131] 1.2. General Method 2: Cyclization 1.2.1. Method 2-1: Cyclization of Aldehydes

Chem.

[0132] Alternatively, the reaction is carried out by combining 4-azido-6-chloro-pyridine-3-carbaldehyde (1.0 equiv) and an appropriate amine (1.0 equiv) and heating at 120 °C for 3 - 4 h in a sealed vial without solvent.

[0133] Exemplary Example of Method 2-1, Synthesis of Intermediate 3: 6-Chloro-2-phenyl-2H-pyrazolo[4,3-c]pyridine

Chem.

[0134] 1.2.2. Method 2-2: Cyclization of Ketones

Chem.

[0135] Exemplary example of Method 2-2, synthesis of Intermediate 17: 6-chloro-3-methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridine [Chemical formula] To a solution of 1-(4-azido-6-chloro-3-pyridyl)ethanone (51.7 mg, 0.263 mmol, 1.0 eq) in dry DCM (1 mL) cooled to 0 °C, aniline (0.0240 mL, 0.263 mmol, 1.0 eq), titanium(IV) chloride (0.0173 mL, 0.158 mmol, 0.6 eq), and TEA (0.110 mL, 0.789 mmol, 3.0 eq) are added. The resulting mixture is stirred at 0 °C for 1 h and then at room temperature for 3 h. The reaction is quenched with cold NaHCO 3 saturated aqueous solution. TiO 2 is filtered off, and the solution is extracted with DCM. The organic layer is washed with brine and water, dried, and evaporated. The resulting residue is purified by flash chromatography on silica gel with a gradient of hexane / EtOAc (0 - 50% EtOAc) to obtain the desired intermediate.

[0136] 1.3. General Method 3: Sulfonamide Synthesis [Chemical formula] In the presence or absence of a base such as TEA (3.0 equivalents), tert-butyl 3-chlorosulfonylazetidine-1-carboxylate (1.0 equivalent) is added to a cooled (ice bath) and stirred solution of an appropriate amine (1.0 - 5.0 equivalents) in a suitable solvent (such as THF or DCM). After the addition, the reaction mixture is warmed to room temperature and stirred for 2 - 20 hours. The expected intermediate can be isolated by methods known to those skilled in the art and, if necessary, further purified.

[0137] Exemplary example of Method 3, synthesis of Intermediate 22: tert-butyl 3-(N,N-dimethylsulfamoyl)azetidine-1-carboxylate

Chemical formula

[0138] Another exemplary example of Method 3, synthesis of Intermediate 32: tert-butyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)azetidine-1-carboxylate

Chemical formula

[0139] 1.4. General method 4: Amine deprotection 1.4.1. Method 4-1: Boc deprotection

Chemical formula

[0140] Exemplary example of Method 4-1, synthesis of Intermediate 21: N,N-dimethylazetidine-3-sulfonamide

Chemical formula

[0141] 1.4.2. Method 4-2: PMB Deprotection

Chemical Structure

[0142] Exemplary Example of Method 4-2, Synthesis of Compound 56: N-Methyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide

Chemical Structure

[0143] Another exemplary example of Method 4-2, synthesis of Compound 41: 1-[2-(4-Fluorophenyl)pyrazolo[4,3-c]pyridin-6-yl]azetidine-3-sulfonamide

Chemical formula

[0144] 1.5. General Method 5: Buchwald-Hartwig Reaction

Chemical formula

[0145] Exemplary Example of Method 5, Synthesis of Compound 1: N,N-Dimethyl-1-(2-phenylpyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide

Chemical Structure

[0146] 1.6. General Method 6: SNAr

Chemical Structure

[0147] Exemplary Example of Method 6, Synthesis of Intermediate 47: 1-(6-Chloro-5-formyl-2-pyridyl)-N,N-dimethyl-azetidine-3-sulfonamide

Chemical Structure

[0148] 1.7. General Method 7: Chlorination

Chemical Structure

[0149] Exemplary Example of Method 7, Synthesis of Intermediate 42: 3,6-Dichloro-2-(4-fluorophenyl)pyrazolo[4,3-c]pyridine

Chemical Structure

[0150] 1.8. General Method 8: Suzuki-Miyaura Reaction

Chemical Structure

[0151] Exemplary Example of Method 8, Synthesis of Intermediate 46: 6-Chloro-2-(4-fluorophenyl)-3-(prop-1-en-2-yl)-2H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0152] 1.9. General Method 9: Hydrogenation

Chemical Structure

[0153] Exemplary Example of Method 9, Synthesis of Intermediate 45: 6-Chloro-2-(4-fluorophenyl)-3-isopropyl-2H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0154] Biological Examples Example 2. In Vitro Assay 2.1. MDCKII-MDR1 2.1.1. Research Principle The purpose of this study is to determine the permeability and efflux ratio of the compounds of the present invention in Madin-Darby canine kidney (MDCKII) cells.

[0155] 2.1.2. Research Protocol Seed MDCKII-MDR1 cells on a Millicell-24 cell culture insert plate assembly at a final concentration of 0.12×106 cells / well. Before the start of the experiment, culture the cells in a CO2 incubator for 3 - 4 days and change the medium 24 hours after seeding.

[0156] On the day of the experiment, pre-incubate the cells with Dulbecco's phosphate-buffered saline (D-PBS, pH 7.4) containing 1% DMSO for 45 minutes. Prepare the compounds in D-PBS, pH 7.4 and add them to either the apical or basolateral chamber of the Millicell cell culture insert plate assembly at a final concentration of 10 μM (1% final DMSO concentration). Add Lucifer Yellow to all donor buffers to evaluate the integrity of the cell monolayer by monitoring its permeation. After incubating at 37°C for 1 hour, aliquot samples are taken from both the apical (A) and basolateral (B) chambers with shaking and added to ACN: aqueous solution (2:1) containing an internal standard for analysis.

[0157] Also, to obtain the initial (C0) concentration, a sample is taken from the donor solution at the start of the experiment. After gently mixing and centrifuging, the supernatant is analyzed by LC-MS / MS. The apparent permeability coefficient (Papp) is calculated according to the following formula: Papp = (dQ / dT) * (1 / C0) * (1 / A) (where dQ / dT = permeability rate; C0 = initial concentration in the donor compartment; A = surface area of the cell monolayer (0.7 cm2)). "Concentration" is the ratio of the peak areas of the compound and the internal standard. The Papp value has the dimension of velocity (×10-6 cm / sec). The efflux ratio is calculated as the Papp from B to A divided by the Papp from A to B. The passive permeability (×10-6 cm / sec) is calculated by the following formula: Papp from A to B × (efflux ratio + 1 / 2).

[0158] Example 3. In Vivo Assay 3.1. Alzheimer's Disease Mouse Model Using Intracerebroventricular Injection of Amyloid Beta Oligomers 3.1.1. Research Principle In the brains of AD patients, an increase in the level of amyloid β (Aβ) can be found. This is accompanied by the activation of microglia and an increase in the number of microglia in the AD brain, which is referred to as microgliosis. Activated microglia can be found early in the disease progression.

[0159] The purpose of this Alzheimer's disease model was to evaluate the effect of test compounds based on the intracerebroventricular injection of AβO related to the etiology of AD. (Sakono and Zako 2010), and induce short-term and long-term memory impairment (Calvo-Flores Guzman et al. 2020). Cognitive impairment is related to and well correlated with neuronal loss and activation of microglial cells.

[0160] This study evaluated the cognitive function of mice after chronic administration of the compound after AβO injury. Plasma and brain samples were also taken for further histological analysis and immunohistochemical evaluation of neurodegeneration and activation of microglial cells.

[0161] 3.1.2. Research Protocol 3.1.2.1. Summary The forced alternating Y-maze test relies on the natural tendency of rodents to explore new environments. This was used to evaluate the short-term spatial memory and exploratory behavior of damaged mice.

[0162] 3.1.2.2. Animals Male C57BL6 mice (Janvier Labs) at 18 months of age were housed in the Neuro-Sys facility for 1 week to acclimate and maintained on a 12-hour reversed light-dark cycle. The animals were housed in groups (2 - 4 animals per cage) and maintained in a room with controlled temperature (21 - 22 °C) and humidity (40 - 60%), where food and water were freely available.

[0163] 3.1.2.3. Stereotaxic injection of Aβ1-42 preparation After 1 week of acclimation, all mice were subjected to bilateral hippocampal stereotaxic surgery determined relative to bregma according to the mouse brain atlas of Paxinos and Franklin (Yeung et al. 2020).

[0164] The preparation of Aβ1-42 was performed according to the procedure described by Callizot (Callizot et al. 2013). Briefly, the Aβ1-42 peptide (Bachem, 1071428, CAS number 107761-42-2) was dissolved in a vehicle (0.5% methylcellulose (w / v) in water) at an initial concentration of 100 μM. This solution was gently stirred at 37 °C for 3 days in the dark.

[0165] After stirring, the Aβ1-42 preparation was bilaterally injected into the polymorphic cell layer, pyramidal cell layer, and radiate layer of the CA1 region of the hippocampus at three different depths within the CA1 region. Bilateral stereotaxic administration of 2 μL / side of the Aβ1-42 preparation (containing approximately 15 μmol / L of oligomers accurately measured by automated WB) or vehicle was performed bilaterally into the CA1 region of the hippocampus using a Hamilton syringe (0.2 μL / min using an Elite Nanomite syringe pump).

[0166] 3.1.2.4. Study design All treatments were initiated the day before stereotaxic injection of Aβ1-42 and administered daily until the end of the experiment. On the last day, different tissue samples were collected.

[0167] The test compound was administered by oral gavage (p.o.).

[0168] Donepezil (DNP) is an inhibitor of acetylcholinesterase that functions as an enhancer of acetylcholine signaling and is approved by the FDA for the management of mild cognitive impairment. DNP was administered intraperitoneally (i.p.).

Table 5

[0169] Preparation using Vehicle 1: The required amount of the test compound was weighed and placed in a glass tube. The compound was dissolved in 0.5% methylcellulose in water (w / v) corresponding to 100% of the final volume and vortexed. The formulation (glass vial) was placed in an ultrasonic bath for 30 minutes. The preparation was aliquoted into light-protected tubes and stored at 4°C.

[0170] Preparation using Vehicle 2: The required amount of the test compound was weighed and placed in a glass tube. The compound was dissolved in an amount of PEG200 corresponding to 25% of the final volume (at 4-fold concentration). The preparation was aliquoted into light-protected tubes and stored at 4°C. Before administration, an amount of MC (0.5%, w / v in sterile water) corresponding to 75% of the final volume (1-fold concentration) was added to the preparation and vortexed. The formulation (glass vial) was placed in an ultrasonic bath for homogenization. Until administration, the glass vial containing the preparation was continuously stirred and protected from light.

[0171] 3.1.2.5. Evaluation of Short-Term Spatial Memory - Y-Maze The Y-maze was used to evaluate short-term memory (working memory) in mice. Spatial reference memory (emphasized by the hippocampus) was tested by placing the test mice in a Y-maze with one arm closed during training. After the inter-trial interval, the mice had to remember the arm that they had not explored previously and visit this arm more frequently (Kraeuter, Guest, and Sarnyai 2019). Some visual cues (stuck on the walls) were placed behind each arm to enable visual discrimination by the animals.

[0172] The apparatus consisted of a light grey polyvinyl chloride (PVC) Y-shaped compartment (35 cm arm length × 6 cm × 15 cm arm height) with arms of equal length.

[0173] Prior to surgery, all mice underwent a training session in the Y-maze as a habituation session. The mice were tested again 7 and 14 days after the surgery.

[0174] This test was based on two trials: - 1. The mice were allowed to freely explore two arms of the Y-maze for 5 minutes (300 seconds). The last arm remained closed. At the end of the 5 minutes, the animals were left in an empty cage for 3 minutes. The Y-maze was washed with acetic acid to neutralize the odor. - 2. Then, after 3 minutes, the mice were allowed to freely explore the three arms of the Y-maze for 5 minutes.

[0175] Both trials were automatically recorded by a video camera using the Ethovision system (Noldus). For each animal, the number of entries and the time spent in each arm were automatically determined.

[0176] Animals that remained in the entry arm throughout the test period (≤200 seconds) were automatically excluded from the analysis.

[0177] Animals that showed freezing (due to excessive anxiety behavior) were excluded from the test.

[0178] 3.1.2.6. Immunohistochemistry (IHC). At the end of the experiment (day 18), mice (n = 5) from groups 1, 2, and 3 were sacrificed under anesthesia, the brains were collected, and fixed with 4% paraformaldehyde (PFA) for 2 hours at room temperature. After 2 hours, the brains were placed in 30% sucrose in Tris phosphate buffered saline (TBS) solution at 4°C overnight.

[0179] Serial coronal sections containing the hippocampal region, 40 μm thick, were cut using a cryostat.

[0180] For immunohistochemistry, floating sections were incubated in TBS containing 0.25% bovine serum albumin, 0.3% Triton X-100, and 1% goat serum for 1 hour at room temperature. This incubation was performed to block non-specific binding sites and permeabilize the tissue.

[0181] 3.1.2.7. Bioassays (ELISA and NGS) At the end of the experiment (day 18), mice (up to 7 from groups 1, 2, 3, and 8) were sacrificed under anesthesia and specific brain regions were collected. Two hemispheres were dissected to generate two cortices (one from each hemisphere) and two hippocampal regions (one from each hemisphere) per animal. These samples were stored at -80°C.

[0182] 3.1.2.8. Pharmacokinetic samples and brain sampling for bioassays (ELISA and NCS) 3.1.2.8.1.1. PK blood sampling: At the end of the experiment (day 8 or 18), for mice (n = 9, 3 samples per time point) (from group 6), blood was collected into EDTA tubes under deep anesthesia 0.5, 1, and 4 hours after the last treatment for PK analysis. 25 μL of blood was transferred to a second EDTA tube containing 25 μL of deionized water and frozen at -80°C. The remaining blood was centrifuged to collect plasma and maintained at -80°C.

[0183] 3.1.2.8.2 Brain sampling: Brains were dissected from the same animals. To generate two cortices (one from each hemisphere) and two hippocampal regions (one from each hemisphere) per animal, the two hemispheres were dissected. These samples were stored at -80 °C.

[0184] 3.1.2.9. Statistical Analysis All values are shown as mean ± SEM (standard error of the mean) per group of animals. Graphs and statistical analyses were performed using GraphPad Prism software version 8.0.2, either one-way or two-way ANOVA, followed by Fisher's test. *p < 0.05 was considered significant. Outliers were identified by Grubbs' test (alpha = 0.2) and abnormal behavior during the Y-maze test (e.g., freezing behavior during the test).

[0185] 3.1.3. Results A significant impairment in short-term spatial memory was found in Aβ1-42 injected mice on the 7th day post-surgery compared to control animals (Table VI). This was demonstrated by the shortened exploration time of the new arm during the forced alternation test in the Y-maze. The abnormality in short-term memory remained significantly changed in the second Y-maze test performed on the 14th day post-surgery compared to the control.

Table 6

[0186] Compound 14 showed a significant beneficial effect on short-term spatial memory on the 7th and 14th day post-surgery compared to Aβ1-42 injected mice and vehicle-treated mice (Group ID2).

[0187] Compound 66 showed a significant beneficial effect on short-term spatial memory on the 7th day compared to Group ID2.

Brief Description of the Drawings

[0188]

Figure 1

[0189] The * symbol at the top of the column indicates that the p-value is < 0.05 for Group ID2 (one-way ANOVA, followed by Fisher's test).

[0190] Finally Those skilled in the art will understand that the foregoing description is illustrative and explanatory in nature and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, those skilled in the art will recognize that obvious modifications and variations can be made without departing from the spirit of the invention. All such modifications within the scope of the appended claims are intended to be included therein. Accordingly, the invention is intended to be defined by the following claims and their equivalents rather than by the above description.

[0191] All publications, including but not limited to patents and patent applications cited herein, are hereby incorporated by reference into this specification as if each individual publication were specifically and individually indicated to be incorporated by reference as if fully set forth herein.

[0192] It should be understood that factors such as differences in the cell permeability of various compounds can contribute to the discrepancies between the activities of compounds in in vitro biochemical assays and cell assays.

[0193] At least a portion of the chemical names of the compounds of the invention provided and described in this application may have been generated on an automated basis using commercially available chemical nomenclature software programs and have not been independently verified. Representative programs that perform this function include the Lexichem naming tool sold by Open Eye Software, Inc., and the Autonom software tool sold by MDL, Inc. If the chemical name shown is different from the structure shown, the structure shown is given precedence. References Bundgaard, Hans. 1985. Design of Prodrugs. Amsterdam; New York; Oxford: Elsevier. Callizot, Noelle, Maud Combes, Remy Steinschneider, and Philippe Poindron. 2013. “Operational Dissection of β-Amyloid Cytopathic Effects on Cultured Neurons.” Journal of Neuroscience Research 91(5): 706-16. https: / / doi.org / 10.1002 / jnr.23193. Calvo-Flores Guzman, Beatriz, SooHyun Kim, Bhavya Chawdhary, Katie Peppercorn, Warren P Tate, Henry J Waldvogel, Richard LM Faull, Johanna Montgomery, and Andrea Kwakowsky. 2020. “Amyloid-Beta1-42 -Induced Increase in GABAergic Tonic Conductance in Mouse Hippocampal CA1 Pyramidal Cells.” Molecules 25(3): 693. https: / / doi.org / 10.3390 / molecules25030693. “Greene’s Protective Groups in Organic Synthesis, 4th Edition | Wiley.” 2006. Wiley.Com. 2006. https: / / www.wiley.com / en-gb / Greene%27s+Protective+Groups+in+Organic+Synthesis%2C+4th+Edition-p-9780470053485. Knopman, David S., Helene Amieva, Ronald C. Petersen, Gael Chetelat, David M. Holtzman, Bradley T. Hyman, Ralph A. Nixon, and David T. Jones. 2021. “Alzheimer Disease.” Nature Reviews. Disease Primers 7(1): 33. https: / / doi.org / 10.1038 / s41572-021-00269-y. Kraeuter, Ann-Katrin, Paul C. Guest, and Zoltan Sarnyai. 2019. “The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice.” In Pre-Clinical Models, edited by Paul C. Guest, 1916:105-11. Methods in Molecular Biology. New York, NY: Springer New York. https: / / doi.org / 10.1007 / 978-1-4939-8994-2_10. Sakono, Masafumi, and Tamotsu Zako. 2010. “Amyloid Oligomers: Formation and Toxicity of Aβ Oligomers.” The FEBS Journal 277(6): 1348-58. https: / / doi.org / 10.1111 / j.1742-4658.2010.07568.x. Thomas Bayer. 2012. “Proteinopathies, a Core Concept for Understanding and Ultimately Treating Degenerative Disorders? | Elsevier Enhanced Reader.” 2012. https: / / doi.org / 10.1016 / j.euroneuro.2013.03.007. Yeung, Jason H.Y., Beatriz Calvo-Flores Guzman, Thulani H. Palpagama, Jayarjun Ethiraj, Ying Zhai, Warren P. Tate, Katie Peppercorn, Henry J. Waldvogel, Richard L.M. Faull, and Andrea Kwakowsky. 2020. “Amyloid-Beta1-42 Induced Glutamatergic Receptor and Transporter Expression Changes in the Mouse Hippocampus.” Journal of Neurochemistry 155(1): 62 - 80. https: / / doi.org / 10.1111 / jnc.15099.

Claims

[Claim 1] Novel products, methods, and methods of manufacture substantially described in this specification.

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