Sulfonamide compounds and pharmaceutical compositions thereof for treatment of neurodegenerative disorders

Abstract

Disclosed are compounds according to Formula (I) wherein R1, R2a, R2b, R3, X, Y and subscript n are as defined herein. The present invention relates to compounds for the prevention and / or treatment of diseases involving neurodegenerative disorders by administering a compound of the invention, methods for their production, pharmaceutical compositions comprising said compounds, and methods of treatment using said compounds. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds that can be used to prevent and / or treat 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 may occur sporadically or with a genetic component leading to dementia and is characterized by different clinical symptoms such as a gradual decline in memory, thinking, language and learning abilities.

[0003] A relationship has been established between the accumulation of specific proteins in neurons or brain parenchyma and the development of some specific diseases, which are called proteinopathies, including Alzheimer's disease and Parkinson's disease (T. Bayer, 2012). This accumulation is the result of conformational changes in unstructured proteins, resulting in small oligomers that eventually aggregate into higher-order structures.

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

[0005] The prevalence of cognitive impairment increases exponentially with age, and the incidence of dementia increases dramatically after age 65 and continues to increase thereafter. The incidence of all-cause dementia in individuals aged 65-70 years is approximately 1 in 100 per year, and increases to 4 in 100 per year in individuals aged 80-90 years (Knopman et al. 2021). The global 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] AD is characterized by pathological changes including tau-containing neurofibrillary tangles, Aβ-containing plaques, activated glia, and / or enlarged endosomes. AD also includes loss of synaptic homeostasis, neuronal or neuronal network integrity.

[0007] In AD patients, Aβ-containing extracellular neuritic plaques are widely distributed throughout the cerebral cortex, and tau-containing neurofibrillary tangles initially appear in the medial temporal lobe and then spread to cortical areas such as the temporal, parietal, and frontal lobes.

[0008] The search for a cure is still underway to identify targets that can substantially alter the clinical course of people with AD, and to date no cure has been discovered. Summary of the invention

[0009] The present invention relates to compounds that can be used to prevent and / or treat 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.

[0010] Therefore, in a first aspect of the present invention, there is provided a compound of the present invention having formula (I):

[0011]

[0012] in

[0013] n is 1, 2 or 3;

[0014] One of X and Y is N, and the other is CH;

[0015] R 1 is optionally one or more independently selected R 4 substituted phenyl or pyridyl;

[0016] R 2a and R 2b Independently selected from:

[0017] -H,

[0018] -C 1-4 Alkyl, which is optionally substituted with one or more independently selected halo, -CN or C 1-4 Alkoxy substitution, and

[0019] -C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted with one or more independently selected halo, -CN or C 1-4 Alkoxy substitution;

[0020] or R 2a and R 2b Together with the N atom, it can form optionally one or more independently selected halo, -CN or C 1-4 Alkoxy-substituted 4-7 membered heterocycloalkyl;

[0021] R 3 is H, C optionally substituted by one or more independently selected halo 1-6 alkyl, or C optionally substituted by one or more independently selected halo 3-7 monocyclic cycloalkyl; and

[0022] Each R 4 Selected from:

[0023] --OH,

[0024] - halogenated,

[0025] -C 1-4 Alkyl, the alkyl is optionally substituted with one or more independently selected halogen or C 1-4 Alkoxy substituted, or

[0026] -C 1-4 Alkoxy, the alkoxy is optionally substituted with one or more independently selected halogen or C 1-4 Alkoxy substitution.

[0027] In a specific aspect, the compounds of the present invention are provided for use in preventing and / or treating Alzheimer's disease. In a more specific aspect, the compounds of the present invention are provided for use in treating Alzheimer's disease.

[0028] Furthermore, the compounds of the present invention may show good exposure in the brain, which may result in good efficacy.

[0029] In other aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical carrier, excipient or diluent. In particular aspects, the pharmaceutical composition may further comprise an additional therapeutically active ingredient suitable for use in combination with the compound of the present invention. In more specific aspects, the additional therapeutically active ingredient is a medicament for treating a neurodegenerative disorder.

[0030] Furthermore, the compounds of the invention useful in the pharmaceutical compositions and methods of treatment disclosed herein are pharmaceutically acceptable at the time of preparation and use.

[0031] In a further aspect of the invention, the invention provides a method of treating a mammal, particularly a human, suffering from a condition selected from the conditions listed herein, particularly a neurodegenerative disorder, the method comprising administering an effective amount of a pharmaceutical composition or compound of the invention as described herein.

[0032] The present invention also provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutical carrier, excipient or diluent suitable for use in medicine. In a particular aspect, the pharmaceutical composition is used for preventing and / or treating a neurodegenerative disorder.

[0033] In additional aspects, the present invention provides methods for synthesizing the compounds of the present invention, wherein representative synthetic schemes and routes are disclosed later herein.

[0034] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description. DETAILED DESCRIPTION

[0035] definition

[0036] The following terms are intended to have the meanings presented below, and can be used to understand the description and intended scope of the present invention.

[0037] When describing the present invention, the present invention may include compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, unless otherwise specified, the following terms, if present, have the following meanings. It should also be understood that when described herein, any portion defined below may be substituted with various substituents, and the corresponding definitions are intended to include such substituted portions within their scope as set forth below. Unless otherwise specified, the term "substituted" will be defined as set forth below. It should also be understood that when used herein, the term "group / radical" may be considered interchangeable.

[0038] The articles 'a' and 'an' as used herein may refer to one or to more than one (ie, to at least one) of the grammatical object of the article. As an example, 'analog' means one analog or more than one analog.

[0039] 'Alkyl' means a straight or branched aliphatic hydrocarbon having a specified number of carbon atoms. Specific alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl are attached to a straight alkyl chain. Specific 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 ), isobutyl (-CH 2 -CH(CH 3 ) 2 ), sec-butyl (-CH(CH 3 )-CH 2 -CH 3 ), n-pentyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), n-hexyl (-CH 2 -CH2 -CH 2 -CH 2 -CH 2 -CH 3 ) and 1,2-dimethylbutyl (-CHCH 3 )-C(CH 3 )H 2 -CH 2 -CH 3 ). Certain alkyl groups have 1 to 4 carbon atoms.

[0040] 'Alkoxy' refers to an O-alkyl group, wherein the alkyl group has the specified number of carbon atoms. Specifically, the term refers to -OC 1-6 Alkyl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e. alkoxy groups having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0041] 'Cycloalkyl' refers to a monocyclic, fused polycyclic, bridged polycyclic or spirocyclic non-aromatic hydrocarbon ring structure having a specified number of ring atoms. The cycloalkyl group may have 3 to 12 carbon atoms, particularly 3 to 10 and more particularly 3 to 7 carbon atoms. For example, such cycloalkyl groups include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0042] 'Halo' or 'halogen' refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Specific halo groups are fluorine or chlorine.

[0043] 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 have been replaced by nitrogen, oxygen or sulfur heteroatoms. Heteroatoms can be applied to any of the above hydrocarbon groups, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocycloalkyl), etc., which have 1 to 4, particularly 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms (e.g., a single heteroatom).

[0044] 'Heterocycloalkyl' refers to a monocyclic, fused polycyclic, spirocyclic or bridged polycyclic non-aromatic fully saturated ring structure, which includes one or more heteroatoms independently selected from O, N and S; and the number of ring atoms specified. The heterocycloalkyl ring structure can have 4 to 12 ring members, particularly 4 to 10 ring members and more particularly 4 to 7 ring members. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur and oxygen. Typically, the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more typically up to 2, such as 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.

[0045] Specific examples of monocyclic rings are shown in the following illustrative examples:

[0046]

[0047] wherein each W and Y is independently selected from -CH 2 -, -NH-, -O-, and -S-.

[0048] 'Substituted' refers to a group wherein one or more hydrogen atoms are each independently replaced with the same or different substituents.

[0049] As used herein, the term 'substituted by one or more' refers to one to four substituents. In one embodiment, it refers to one to three substituents. In other embodiments, it refers to one or two substituents. In yet other embodiments, it refers to one substituent.

[0050] Those skilled in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring (whether aromatic or non-aromatic) is determined by the size of the ring, the degree of unsaturation, and the valence of the heteroatoms. In general, a heterocyclic ring can have from one to four heteroatoms, as long as the heteroaromatic ring is chemically feasible and stable.

[0051] 'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or state governments or their counterparts in countries outside the United States or listed in the US Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0052] 'Pharmaceutically acceptable salts' refer to salts of the compounds of the present invention that are pharmaceutically acceptable and have the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or from organic acids such as 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-ethane-disulfonic acid, 2-hydroxyethylsulfonic 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, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion) or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and when the compound contains a basic functional group, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, 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, and the like.

[0053] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0054] 'Prodrugs' refer to compounds having a cleavable group and becoming compounds of the present invention that are pharmaceutically active in vivo through 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.

[0055] 'Solvate' refers to a form of a compound that is associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid, etc. The compounds of the present invention can be prepared, for example, in a crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. 'Solvate' encompasses both liquid phases and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0056] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.

[0057] 'Effective amount' refers to the amount of the compound of the invention which, when administered to a subject to treat a disease, is sufficient to effect such treatment of the disease. The "effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0058] 'Preventing' or 'prevention' refers to reducing the risk of acquiring or developing a disease or condition (ie, preventing at least one clinical symptom of a disease from developing in a subject who may have been exposed to the causative agent or who is otherwise susceptible to the disease prior to onset of the disease).

[0059] The term 'prophylaxis' is related to 'prevention' and refers to a measure or procedure intended to prevent rather than treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk of thrombosis, for example due to immobilization; and the administration of anti-malarial agents such as chloroquine prior to visiting geographical areas where malaria is endemic or where the risk of contracting malaria is high.

[0060] In one embodiment, 'treating' or 'treatment' any disease or condition refers to ameliorating the disease or condition (i.e., arresting the disease or reducing the manifestation, extent, or severity of at least one clinical symptom thereof). In another embodiment, 'treating' refers to improving at least one physical parameter that may not be discernible by the subject. In yet another embodiment, 'treating' refers to modulating the disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In additional embodiments, "treating" involves slowing the progression of a disease.

[0061] As used herein, the term neurodegenerative disease refers to Protein diseases, or the disease related to the atrophy of the affected center or peripheral structure of the nervous system. Specifically, the term refers to the disease characterized by the accumulation of specific proteins in neurons or brain parenchyma or the atrophy of the affected center or peripheral structure of the nervous system. More specifically, the term refers to Alzheimer's disease and other dementias, brain cancer, degenerative neurological diseases, encephalitis, epilepsy, hereditary brain diseases, head and brain malformations, hydrocephalus, apoplexy, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, Lewy body disease, prion disease, tau protein disease, frontotemporal lobar degeneration, British and Danish dementias, and autosomal dominant cerebral arteriopathy (CADASIL) with subcortical infarction and leukoencephalopathy. More specifically, the term refers to Alzheimer's disease.

[0062] 'Compounds of the invention' and equivalent expressions are meant to include compounds of formula (e) as described herein, including pharmaceutically acceptable salts and solvates (e.g. hydrates) and solvates of pharmaceutically acceptable salts where the context permits. Similarly, references to intermediates (whether or not they are themselves claimed) are meant to include salts and solvates thereof where the context permits.

[0063] When referring to a range herein, for example but not limited to C 1-8 Alkyl, the recitation of a range should be considered as a representation of each member of the range.

[0064] Other derivatives of the compounds of the invention are active in both their acid and acid derivative forms, but the acid-sensitive form generally provides advantages in solubility, tissue compatibility or delayed release in mammalian organisms (Bundgaard 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the 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 side groups 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. Specific such prodrugs are C 1-8 Alkyl, C 2-8 Alkenyl, C 6-10 Optionally substituted aryl and (C 6-10 Aryl)-(C 1-4 alkyl) esters.

[0065] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether (i) a form in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that predominates in nature (referred to herein as a "natural isotopic form"), or (ii) a form in which one or more atoms are replaced by atoms having the same atomic number but a mass number different from the atomic mass number that predominates in nature (referred to herein as a "non-natural variant isotopic form"). It should be understood that atoms may exist naturally in the form of a mixture of mass numbers. The term "non-natural variant isotopic form" also includes embodiments in which 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 relative to the naturally occurring proportion, for example, to a level of >20%, >50%, >75%, >90%, >95% or >99% of the number of atoms of that atomic number (the latter embodiment is referred to as an "isotopically enriched variant form"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of uncommon isotopes is reduced relative to the naturally occurring proportion. Isotopic forms may include radioactive forms (ie, they incorporate a radioactive isotope) and non-radioactive forms. Radioactive forms are typically isotopically enriched variants.

[0066] Thus, a non-naturally occurring isotopic form of a compound may contain one or more artificial or unusual isotopes, such as 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( 125 I), or may contain a higher proportion of said isotope than the proportion that predominates in nature in one or more atoms.

[0067] For example, non-natural variant isotopic forms containing radioactive isotopes may be used in drug and / or substrate tissue distribution studies. 3 H) and the radioactive isotope carbon-14 (i.e.14 C) is particularly useful for this purpose due to its ease of incorporation and readily available means of detection. 2 Non-naturally occurring isotopic variants of isotopes such as H or D may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Further, compounds incorporating positron emitting isotopes such as 11 C. 18 F. 15 0 and 13 N), and the non-natural variant isotopic form will be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy.

[0068] It will also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.

[0069] Stereoisomers that are not mirror images of each other are termed 'diastereomers', while stereoisomers that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog, or by the way that the molecules rotate the plane of polarized light and are designated as right- or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as a mixture thereof. A mixture containing equal proportions of enantiomers is termed a 'racemic mixture'.

[0070] 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure with variations in the displacement of hydrogen atoms and electrons. Thus, two structures can remain in equilibrium via the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with acid or base. Another example of tautomerism is the acidic and nitro forms of phenylnitromethane, also formed by treatment with acid or base.

[0071] Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0072] The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds may be produced as individual (R)-stereoisomers or (S)-stereoisomers or as mixtures thereof.

[0073] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.Methods for determining stereochemistry and separation of stereoisomers are known in the art.

[0074] It will be appreciated that the compounds of the invention may be metabolized to produce biologically active metabolites.

[0075] The present invention

[0076] The present invention relates to compounds that can be used to prevent and / or treat 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.

[0077] Therefore, in a first aspect of the present invention, there is provided a compound of the present invention having formula (I):

[0078]

[0079] in

[0080] n is 1, 2 or 3;

[0081] One of X and Y is N, and the other is CH;

[0082] R 1 is optionally one or more independently selected R 4 substituted phenyl or pyridyl;

[0083] R 2a and R 2b Independently selected from:

[0084] -H,

[0085] -C 1-4 Alkyl, which is optionally substituted with one or more independently selected halo, -CN or C 1-4 Alkoxy substitution, and

[0086] -C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted with one or more independently selected halo, -CN or C 1-4 Alkoxy substitution;

[0087] or R 2a and R 2b Together with the N atom, it can form optionally one or more independently selected halo, -CN or C 1-4 Alkoxy-substituted 4-7 membered heterocycloalkyl;

[0088] R3 is H, C optionally substituted by one or more independently selected halo 1-6 alkyl, or C optionally substituted by one or more independently selected halo 3-7 monocyclic cycloalkyl; and

[0089] Each R 4 Selected from:

[0090] --OH,

[0091] - halogenated,

[0092] -C 1-4 Alkyl, the alkyl group is optionally substituted with one or more independently selected halogen or C 1-4 Alkoxy substituted, or

[0093] -C 1-4 Alkoxy, the alkoxy is optionally substituted with one or more independently selected halogen or C 1-4 Alkoxy substitution.

[0094] In one embodiment, the compound of the invention is according to Formula I, wherein subscript n is 1, 2, or 3. In a specific embodiment, subscript n is 2 or 3. In a further specific embodiment, subscript n is 1.

[0095] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 It is pyridyl.

[0096] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 is selected by one, two or three independent R 4 In more specific embodiments, R 1 is an R 4 Substituted pyridinyl.

[0097] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 It is phenyl.

[0098] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 is one or more independently selected R 4 In certain embodiments, R 1 is selected by one, two or three independent R 4 In more specific embodiments, R 1 is an R 4 Substituted phenyl.

[0099] In one embodiment, the compounds of the present invention are according to Formula I, wherein R1 is one or more independently selected R 4 Substituted phenyl, wherein one or more R 4 It is -OH.

[0100] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 is one or more independently selected R 4 Substituted phenyl, wherein one or more R 4 In certain embodiments, one or more R 4 are independently selected from F, Cl and Br. In more specific embodiments, one or more R 4 It's F.

[0101] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 is one or more independently selected R 4 Substituted phenyl, wherein one or more R 4 Independently selected from C 1-4 Alkyl, the alkyl group is optionally substituted with one or more independently selected halogen or C 1-4 In certain embodiments, one or more R 4 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 halogen or C 1-4 In another specific embodiment, one or more R 4 Independently selected from C 1-4 Alkyl, the alkyl group is optionally replaced by one or more independently selected F, Cl, -OCH 3 、-OCH 2 CH 3 In more specific embodiments, one or more R 4 Independently selected from -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 and -C(CH 3 ) 3 , each of which is optionally replaced by one or more independently selected F, Cl, -OCH 3 or -OCH 2 CH 3 In more specific embodiments, one or more R4 Independently selected from -CH 3 and -CF 3 .

[0102] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 is one or more independently selected R 4 Substituted phenyl, wherein one or more R 4 Independently selected from C 1-4 Alkoxy, the alkoxy is optionally substituted with one or more independently selected halogen or C 1-4 In certain embodiments, one or more R 4 Independently selected from -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 halogen or C 1-4 In another specific embodiment, one or more R 4 Independently selected from C 1-4 Alkoxy, the alkoxy optionally being replaced by one or more independently selected F, Cl, -OCH 3 、-OCH 2 CH 3 In more specific embodiments, one or more R 4 Independently selected from -OCH 3 、-OCH 2 CH 3 、-OCH(CH 3 ) 2 and -OC(CH 3 ) 3 , each of which is optionally replaced by one or more independently selected F, Cl, -OCH 3 or -OCH 2 CH 3 In more specific embodiments, one or more R 4 Independently selected from -OCH 3 、-OCH 2 CH 2 OCH 3 and-OCF 3 .

[0103] In one embodiment, the compounds of the present invention are according to Formula I, wherein R 1 is composed of one or more independently selected -OH, F, -CH 3, -CF 3 、-OCH 3 、-OCH 2 CH 2 OCH 3 and-OCF 3 In certain embodiments, R 1 is replaced by one or two independently selected -OH, F, -CH 3 , -CF 3 、-OCH 3 、-OCH 2 CH 2 OCH 3 and-OCF 3 Substituted phenyl.

[0104] In one embodiment, the compound of the invention is according to any one of Formula IIa, IIb, IIc or IId:

[0105]

[0106] Where R 2a , R 2b and R 3 As mentioned above.

[0107] In one embodiment, the compound of the present invention is according to any one of Formula I-IId, wherein R 3 It's H.

[0108] In one embodiment, the compound of the present invention is according to any one of Formula I-IId, wherein R 3 It is C 1-6 In certain embodiments, R 3 Yes-CH 3 、-CH 2 CH 3 or -CH 2 CH(CH 3 ) 2 In more specific embodiments, R 3 Yes-CH 3 or -CH 2 CH(CH 3 ) 2 In a most specific embodiment, R 3 Yes-CH 3 .

[0109] In one embodiment, the compound of the present invention is according to any one of Formula I-IId, wherein R 3 is C substituted with one or more independently selected halogenated 1-6 In certain embodiments, R 3 Yes-CH3 、-CH 2 CH 3 or -CH 2 CH(CH 3 ) 2 , wherein each is substituted with one or more independently selected halo. In a more specific embodiment, R 3 Yes-CH 3 、-CH 2 CH 3 or -CH 2 CH(CH 3 ) 2 , wherein each is substituted with one, two or three independently selected halo. In further specific embodiments, R 3 Yes-CH 3 、-CH 2 CH 3 or -CH 2 CH(CH 3 ) 2 , wherein each is substituted by one, two or three independently selected F, Cl or Br. In even more specific embodiments, R 3 Yes-CH 3 、-CH 2 CH 3 or -CH 2 CH(CH 3 ) 2 , wherein each is substituted by one, two or three independently selected F or Cl. In the most specific embodiment, R 3 Yes-CH 3 、-CH 2 CH 3 or -CH 2 CH(CH 3 ) 2 , wherein each is substituted with one, two or three F. In a further most specific embodiment, R 3 Yes - CF 3 .

[0110] In one embodiment, the compound of the present invention is according to any one of Formula I-IId, wherein R 3 is C substituted with one or more independently selected halogenated 3-7 In certain embodiments, R 3 is cyclopropyl, cyclobutyl or cyclopentyl, each of which is substituted with one, two or three independently selected halo. In more specific embodiments, R 3 is cyclopropyl, cyclobutyl or cyclopentyl, each of which is substituted with one, two or three independently selected F, Cl or Br. In further specific embodiments, R3 is cyclopropyl, cyclobutyl or cyclopentyl, each of which is substituted with one, two or three independently selected F or Cl. In even more specific embodiments, R 3 is cyclopropyl, cyclobutyl or cyclopentyl, each of which is substituted by one, two or three Fs.

[0111] In one embodiment, the compound of the present invention is according to any one of Formula I-IId, wherein R 3 It is C 3-7 In certain embodiments, R 3 is cyclopropyl, cyclobutyl or cyclopentyl. In certain embodiments, R 3 It is cyclopropyl.

[0112] In one embodiment, the compound of the invention is according to any of Formula IIIa, IIIb, IIIc, IIId, IIIe or IIIf:

[0113]

[0114] Where R 2a and R 2b As mentioned above.

[0115] In one embodiment, the compound of the invention is according to any one of Formulas I-IIIf, wherein each R 2a and R 2b All are H.

[0116] In one embodiment, the compound of the invention is according to any one of Formulas I-IIIf, wherein each R 2a and R 2b Independently selected from H, C 1-4 Alkyl and C 3-6 In certain embodiments, each R 2a and R 2b are independently selected from H, -CH 3 、-CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 In another specific embodiment, R 2a is H, and R 2b Selected from H, -CH 3 、-CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 , cyclopropyl, cyclobutyl and cyclopentyl. In certain embodiments, each R 2aand R 2b Independently selected from -CH 3 、-CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 In the most specific embodiment, R 2a and R 2b All -CH 3 .

[0117] In one embodiment, the compound of the invention is according to any one of Formula I-IIIf, wherein R 2a and R 2b Together with the N atom, it can form a 4-7 membered heterocycloalkyl group. 2a and R 2b Together with the N atom, they can form an azetidinyl, pyrrolidinyl or piperidinyl ring. In more specific embodiments, R 2a and R 2b Together with N atoms

[0118] In one embodiment, the compound of the present invention is selected from the group consisting of:

[0119] N,N-dimethyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0120] N,N-dimethyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-3-sulfonamide,

[0121] N,N-dimethyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)piperidine-3-sulfonamide,

[0122] N-isopropyl-N-methyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0123] N-cyclopropyl-N-methyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0124] 1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0125] 1-(2-(4-methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0126] 1-(2-(4-methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide,

[0127] 1-(2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0128] 1-(2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide,

[0129] 1-(2-(3-methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0130] 1-(2-(3-methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide,

[0131] N,N-dimethyl-1-(2-(4-(trifluoromethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0132] 1-(2-(2-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0133] 1-(2-(2-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylpyrrolidine-3-sulfonamide,

[0134] N,N-dimethyl-1-(2-(4-(trifluoromethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)pyrrolidine-3-sulfonamide,

[0135] 1-(2-(2-methoxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0136] N,N-dimethyl-1-(2-(o-tolyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0137] 1-(2-(2-methoxy-6-methylphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0138] 1-(2-(2,6-dimethylphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0139] N,N-dimethyl-1-(3-methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0140] 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,

[0141] 1-(2-(4-hydroxyphenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0142] 1-(2-(4-(2-methoxyethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0143] 1-(2-(4-fluorophenyl)-3-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0144] 1-(2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0145] 1-(2-(2-(2-methoxyethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0146] 1-(2-(3-(2-methoxyethoxy)phenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0147] 1-(2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N-methylazetidine-3-sulfonamide,

[0148] N-methyl-1-(2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0149] N-methyl-1-(3-methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0150] 1-(3-methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0151] 1-(3-cyclopropyl-2-phenyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0152] 1-(2-(4-fluorophenyl)-3-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N-methylazetidine-3-sulfonamide,

[0153] 1-(2-(4-fluorophenyl)-3-methyl-2H-pyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide,

[0154] 1-(3-cyclopropyl-2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0155] 1-(2-(4-fluorophenyl)-3-isopropyl-2H-pyrazolo[4,3-c]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0156] 6-(3-(azetidin-1-ylsulfonyl)azetidin-1-yl)-2-phenyl-2H-pyrazolo[4,3-c]pyridine,

[0157] 6-(3-(azetidin-1-ylsulfonyl)azetidin-1-yl)-2-(4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridine,

[0158] N,N-dimethyl-1-(2-phenyl-2H-pyrazolo[3,4-b]pyridin-6-yl)azetidine-3-sulfonamide,

[0159] 1-(2-(4-fluorophenyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-N,N-dimethylazetidine-3-sulfonamide,

[0160] N-methyl-1-(2-phenyl-2H-pyrazolo[3,4-b]pyridin-6-yl)azetidine-3-sulfonamide, and

[0161] 1-(2-Phenyl-2H-pyrazolo[3,4-b]pyridin-6-yl)azetidine-3-sulfonamide.

[0162] In one embodiment, the compounds of the invention are provided in natural isotopic forms.

[0163] In one embodiment, the compounds of the invention are provided in non-natural variant isotopic forms. In specific embodiments, non-natural variant isotopic forms are those in which deuterium (i.e. 2 In one embodiment, the compounds of the present invention are in the form of isotopes having no radioactivity. In one embodiment, the compounds of the present invention are in the form of isotopes having radioactivity. Suitably, the radioactive isotopes are stable isotopes. Suitably, non-natural variant isotopes are pharmaceutically acceptable forms.

[0164] In one embodiment, compounds of the invention are provided, wherein individual atoms of the compound exist in non-natural variant isotopic forms. In another embodiment, compounds of the invention are provided, wherein two or more atoms exist in non-natural variant isotopic forms.

[0165] Non-natural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein (e.g., 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 labeling) reagents in place of the normal reagents used as examples in the illustrative examples.

[0166] In one aspect, the compound of the invention according to any one of the embodiments described herein exists in the free base form.

[0167] In one aspect, the compound of the invention according to any one of the embodiments described herein is a pharmaceutically acceptable salt.

[0168] In one aspect, the compound of the invention according to any one of the embodiments described herein is a solvate of said compound.

[0169] In one aspect, the compound of the invention according to any one of the embodiments described herein is a solvate of a pharmaceutically acceptable salt of the compound.

[0170] Although the specified groups of each embodiment are listed individually above in general, the compounds of the present invention include compounds in which several or each embodiment in the above formula and other formulas presented herein is selected from one or more specific members or groups specified for each variable, respectively. Therefore, the present invention is intended to include all combinations of such embodiments within its scope.

[0171] Although the above generally lists the specified groups of each embodiment individually, the compounds of the present invention can be such compounds, one or more of which variables (e.g., R groups) are selected from one or more embodiments according to any one of the above listed formula (e). Therefore, the present invention is intended to include all combinations of variables from any disclosed embodiment within its scope.

[0172] Alternatively, the present invention also contemplates excluding one or more specified variables from a group or embodiment or combination thereof.

[0173] In certain aspects, the present invention provides prodrugs and derivatives of compounds according to the above formula. Prodrugs are derivatives of compounds of the present invention, which have metabolically cleavable groups and become compounds of the present invention that are pharmaceutically active in vivo by solvolysis or under physiological conditions. Such examples include, but are not limited to, choline ester derivatives, N-alkyl morpholine esters, etc.

[0174] Other derivatives of the compounds of the present invention are active in both their acid and acid derivative forms, but generally provide advantages in solubility, tissue compatibility or delayed release in mammalian organisms in the acid-sensitive form (Bundgard, H, 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the 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 side groups on the compounds of the present invention are preferred prodrugs. In some cases, it is desirable to prepare double ester prodrugs, such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy) alkyl esters. Particularly useful are C of the compounds of the present invention. 1 To C 8 Alkyl, C 2 -C 8 Alkenyl, aryl, C 7 -C 12 Substituted aryl and C 7 -C 12 Arylalkyl esters.

[0175] Pharmaceutical composition

[0176] When used as a drug, the compounds of the present invention are generally administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical field and include at least one active compound of the present invention according to Formula I. Typically, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compounds of the present invention actually administered will generally be determined by a physician based on relevant circumstances, including the condition to be treated; the selected route of administration; the actual compounds of the present invention administered; the age, weight and response of individual patients; the severity of patient symptoms, etc.

[0177] The pharmaceutical composition of the present invention can be used by a variety of routes, including oral, rectal, transdermal, subcutaneous, intraarticular, intravenous, intramuscular and intranasal. Depending on the intended delivery route, the compound of the present invention is preferably formulated as an injectable or oral composition, or an ointment, lotion or patch for transdermal administration.

[0178] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions exist in unit dosage forms for accurate administration. The term 'unit dosage form' refers to physically discrete units suitable as single doses for human subjects and other mammals, each unit containing a predetermined amount of active materials and suitable pharmaceutical excipients, vehicles or carriers calculated to produce the desired therapeutic effect. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or include pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound of the present invention according to Formula I is usually a minor component (about 0.1% by weight to about 50% by weight or preferably about 1% by weight to about 40% by weight), wherein the remainder is various vehicles or carriers and processing aids that contribute to the formation of the desired form of administration.

[0179] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles with buffers, suspending and dispensing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients or compounds of the invention having similar properties: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint or orange flavoring.

[0180] Injectable compositions are usually based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As previously mentioned, the active compound of the invention according to Formula I in such compositions is usually a minor component (usually about 0.05% to 10% by weight), with the remainder being an injectable carrier, etc.

[0181] Transdermal compositions are usually formulated as topical ointments or creams containing active ingredients, and the range of the amount of the active ingredient is usually from about 0.01% by weight to about 20% by weight, preferably from about 0.1% by weight to about 20% by weight, preferably from about 0.1% by weight to about 10% by weight, and more preferably from about 0.5% by weight to about 15% by weight. When formulated as an ointment, usually the active ingredient will be combined with a paraffin ointment base or a water miscible ointment base. Alternatively, the active ingredient can be formulated in an emulsifiable paste with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art, and usually include additional ingredients to enhance the skin penetration stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope of the present invention.

[0182] The compounds of the invention may also be administered by transdermal means. Thus, transdermal administration may be accomplished using patches of either the reservoir or porous membrane type or of the solid matrix variety.

[0183] The above components for orally administrable, injectable or topically administrable compositions are representative only. Other materials, processing techniques, etc. are described in Part 8 of Remington's Pharmaceutical Sciences, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0184] The compounds of the invention may also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0185] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0186] Formulation 1 - Tablet

[0187] The compound of the present invention according to formula I can be mixed with a dry gelatin binder in a weight ratio of about 1:2 in a dry powder form. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 240-270 mg tablets (80-90 mg active compound of the present invention according to formula I per tablet) in a tablet press.

[0188] Formulation 2 - Capsules

[0189] The compound of the invention according to formula I can be mixed in dry powder form 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 invention according to formula I per capsule).

[0190] Formulation 3 - Liquid

[0191] The compound of the present invention (125mg) according to formula I can be mixed with sucrose (1.75g) and xanthan gum (4mg), and the resulting mixture can be blended, passed through 10 mesh U.S. sieves, and then mixed with pre-prepared microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) solution in water. Sodium benzoate (10mg), spices and pigment can be diluted with water, and added under agitation. Then enough water can be added under agitation. Then enough water can be further added to produce a cumulative volume of 5mL.

[0192] Formulation 4 - Tablets

[0193] The compound of the present invention according to Formula I can be mixed in a dry powder form with a dry gelatin binder in a weight ratio of about 1:2. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 450-900 mg tablets (150-300 mg according to the active compound of the present invention of Formula I) in a tablet press.

[0194] Formulation 5 - Injection

[0195] The compounds of the invention according to Formula I can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg / mL.

[0196] Preparation 6 - Topical

[0197] Stearyl alcohol (250 g) and white petrolatum (250 g) can be melted at about 75° C., then a mixture of a compound of the present invention according to Formula I (50 g), methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) can be added, and the resulting mixture can be stirred until it coagulates.

[0198] Treatment

[0199] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in medicine.

[0200] 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 preventing and / or treating a neurodegenerative disease. Specifically, the term neurodegenerative disease refers to Protein diseases , or atrophy of the affected center or peripheral structure of the nervous system. More specifically, the term neurodegenerative disease refers to Alzheimer's disease and other dementias, brain cancer, degenerative neurological 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, tau disease, frontotemporal lobar degeneration, British and Danish dementias, and autosomal dominant cerebral arteriopathy (CADASIL) with subcortical infarcts and leukoencephalopathy. More specifically, the term neurodegenerative disease refers to Alzheimer's disease.

[0201] In another embodiment, the present invention provides the use of the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention in the manufacture of a medicament for preventing and / or treating a neurodegenerative disease. Specifically, the term neurodegenerative disease refers to Protein diseases , or atrophy of the affected center or peripheral structure of the nervous system. More specifically, the term neurodegenerative disease refers to Alzheimer's disease and other dementias, brain cancer, degenerative neurological 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, tau disease, frontotemporal lobar degeneration, British and Danish dementias, and autosomal dominant cerebral arteriopathy (CADASIL) with subcortical infarcts and leukoencephalopathy. More specifically, the term neurodegenerative disease refers to Alzheimer's disease.

[0202] In another aspect of the method of treatment, the present invention provides a method of preventing and / or treating a mammal suffering from a neurodegenerative disease, the method comprising administering an effective amount of a compound of the present invention or one or more pharmaceutical compositions described herein to treat or prevent the condition. Specifically, the term neurodegenerative disease refers to Protein diseases , or atrophy of the affected center or peripheral structure of the nervous system. More specifically, the term neurodegenerative disease refers to Alzheimer's disease and other dementias, brain cancer, degenerative neurological 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, tau disease, frontotemporal lobar degeneration, British and Danish dementias, and autosomal dominant cerebral arteriopathy (CADASIL) with subcortical infarcts and leukoencephalopathy. More specifically, the term neurodegenerative disease refers to Alzheimer's disease.

[0203] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, another therapeutic agent is a neurodegenerative disease therapeutic agent. Specifically, the term neurodegenerative disease refers to protein disease, 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 neurological 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, tau protein disease, frontotemporal lobar degeneration, British and Danish dementia, and autosomal dominant cerebral arteriopathy (CADASIL) with subcortical infarction and leukoencephalopathy. More 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.

[0204] The range of injection dosage levels is about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all for about 1 to about 120 hours, especially 24 to 96 hours. A pre-loading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For a 40 to 80 kg human patient, the maximum total dose is not expected to exceed about 1 g / day.

[0205] For the prevention and treatment of long-term conditions, such as degenerative conditions, treatment regimens usually last for months or years, so oral administration is preferred for the convenience and tolerance of patients. In the case of oral administration, one to four (1-4) conventional administrations per day, especially one to three (1-3) conventional administrations per day, typically one to two (1-2) conventional administrations per day, and most typically one (1) conventional administration per day are representative regimens. Alternatively, for long-acting drugs, in the case of oral administration, once every other week, once a week, and once a day are representative regimens. Specifically, the dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0206] Using these modes of administration, each dose provides from about 1 to about 1000 mg of a compound of the invention, with specific doses each providing from about 10 to about 500 mg, particularly from about 30 to about 250 mg.

[0207] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injected doses.

[0208] When used to prevent the onset of a condition, the compounds of the invention will generally be administered to patients at risk of developing the condition at the above dosage levels as recommended and under the supervision of a physician. Patients at risk of developing a particular condition generally include patients with a family history of the condition, or patients who have been identified by genetic testing or screening as being particularly susceptible to the risk of developing the condition.

[0209] The compounds of the present invention can be administered as the sole active agent, or the compounds of the present invention can be administered in combination with other therapeutic agents, including other compounds of the present invention that exhibit the same or similar therapeutic activity and are determined to be safe and effective for such combined administration. In specific embodiments, the co-administration of two (or more) agents allows the dose of each agent to be used to be significantly reduced, thereby reducing the side effects seen.

[0210] In one embodiment, the compound of the invention or the pharmaceutical composition comprising the compound of the invention is administered as a medicament. In a specific embodiment, the pharmaceutical composition further comprises another active ingredient.

[0211] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of a neurodegenerative disease, specific agents include, but are not limited to, amantadine, apomorphine, aducanumab, baclofen, carbidopa, carbidopa, dantrolene, donepezil, entacapone, galantamine, levodopa, memantine, pramipexole, rasagiline, riluzole, rivastigmine, ropinirole, selegiline, tacrine, tetrabenazine, tizanidine, and tolcapone.

[0212] 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, specific agents include, but are not limited to, methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5-fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibodies (e.g., Herceptin TM ), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g., Tarceva TM , Erbitux TM ), VEGF inhibitors (e.g., Avastin TM ), proteasome inhibitors (e.g., Velcade TM ), and hsp90 inhibitors (e.g., 17-AAG). In addition, the compounds of the invention according to Formula I may be administered in combination with other therapies, including but not limited to radiation therapy or surgery. In specific embodiments, the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia.

[0213] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and / or prevention of an autoimmune disease, specific agents include, but are not limited to, glucocorticoids, cytostatics (e.g., purine analogs), alkylating agents (e.g., nitrogen mustard (cyclophosphamide), nitrosoureas, platinum compounds of the present invention, etc.), antimetabolites (e.g., methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g., dactinomycin anthracyclines, mitomycin C, bleomycin and mithramycin), antibodies (e.g., anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, and ), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF binding proteins (e.g., infliximab, etanercept, or adalimumab), mycophenolate, fingolimod, and myriocin.

[0214] Co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen, as will be apparent to one skilled in the art. Although the two or more agents can be administered simultaneously in a single formulation (i.e., as a single pharmaceutical composition), this is not required. The agents can be administered in different formulations and at different times.

[0215] Chemical synthesis procedures

[0216] Overview

[0217] The compounds of the present invention can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise indicated. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0218] In addition, 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 particular functional groups and suitable conditions for protection and deprotection are well known in the art ("Greene's Protective Groups in Organic Synthesis", 4th edition | Wiley, 2006).

[0219] The following methods are presented in detail regarding the preparation of the compounds of the invention and comparative examples as defined above.The compounds of the invention can be prepared by those skilled in the art of organic synthesis with known or commercially available starting materials and reagents.

[0220] Unless otherwise stated, all reagents were of commercial grade and were used as received without further purification. Commercially available anhydrous solvents were used for reactions performed under an inert atmosphere. Reagent grade solvents were used in all other cases unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was performed using pre-coated silica gel F-254 plates (thickness: 0.25 mm). Recordings were made on a Bruker DPX 400 NMR spectrometer (400 MHz) or a Bruker Advance 300 NMR spectrometer (300 MHz). 1 H NMR spectra. Chemical shifts (δ) in 1H NMR spectra are relative to tetramethylsilane (δ 0.00) as an internal reference or to an appropriate residual solvent peak, i.e., CHCl 3 (δ 7.27) is reported as parts per million (ppm). Multiplicities are given as singlets (s), doublets (d), triplets (t), quartets (q), quintets (quin), multiplets (m), and broads (br). Electrospray MS spectra were obtained on a Waters platform LC / MS spectrometer or with 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 ID x 50 mm L; Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID x 30 mm L; or Waters Xterra MS 5 μm C18, 100 x 4.6 mm. These methods use MeCN / H 2 O gradient (H 2 O containing 0.1% TFA or 0.1% NH 3 ) or MeOH / H 2 O gradient (H 2 (0 contains 0.05% TFA). Microwave heating was performed using a Biotage Initiator.

[0221] Table I. List of abbreviations used in the experimental section

[0222]

[0223]

[0224] Synthesis and preparation of the compounds of the present invention Example 1. Preparation of intermediates and illustrative compounds of the invention

[0225] 1.1. General method 1: Azide

[0226]

[0227] To a solution of 4,6-dichloropyridine-3-carboxaldehyde or 1-(4,6-dichloro-3-pyridyl)ethanone (1.0 equiv.) in anhydrous DMF cooled at 0 °C or room temperature was added NaN 3 The resulting mixture was stirred at room temperature for 1-2 hours, then EtOAc was added and washed with saturated NaHCO 3 The mixture was washed with aqueous solution and brine. The organic extract was washed with Na 2 SO 4 Dry and concentrate under vacuum to afford the expected intermediate as a crude product.

[0228] Illustrative Example of Method 1, Synthesis of Intermediate 1: 4-Azido-6-chloronicotinaldehyde

[0229]

[0230] To an ice-cold solution of 4,6-dichloropyridine-3-carbaldehyde (528.0 mg, 3.0 mmol, 1.0 equiv) in anhydrous 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 The mixture was washed with aqueous solution and brine. The organic extract was washed with Na 2 SO 4 Drying and concentration in vacuo afforded the desired intermediate.

[0231] Another illustrative example of method 1, synthesis of intermediate 2: 1-(4-azido-6-chloropyridin-3-yl)ethan-1-one

[0232]

[0233] To a solution of 1-(4,6-dichloro-3-pyridyl)ethanone (5.0 g, 26.3 mmol, 1.0 equiv) in anhydrous DMF (50 mL) was added NaN 3 (18.8 g, 28.9 mmol, 1.1 equivalents), and the reaction mixture was stirred at room temperature for 1.5 hours. After complete conversion, the reaction was stopped and quenched by adding water and EtOAc. The aqueous layer was extracted with EtOAc and saturated with NaHCO 3 The mixture was washed with aqueous solution and brine. The organic extract was washed with MgSO 4 Drying and concentration under vacuum provided the crude material which was suspended in MTBE, stirred for 1 hour, filtered and dried to give the desired intermediate.

[0234] 1.2. General method 2: cyclization

[0235] 1.2.1. Method 2-1: Cyclization of aldehydes

[0236]

[0237] A solution of compound 4-azido-6-chloro-pyridine-3-carbaldehyde (1.0 eq.) and appropriate amine (1.0-1.1 eq.) in anhydrous toluene is stirred at 80-100° C. for 1-5 hours. The solvent is evaporated in vacuo and the crude obtained is purified by flash chromatography on silica gel.

[0238] Alternatively, the reaction was carried out by combining 4-azido-6-chloro-pyridine-3-carbaldehyde (1.0 eq.) and the appropriate amine (1.0 eq.) and heated without solvent at 120 °C in a sealed vial for 3-4 hours.

[0239] Illustrative example of method 2-1, synthesis of intermediate 3: 6-chloro-2-phenyl-2H-pyrazolo[4,3-c]pyridine

[0240]

[0241] A solution of 4-azido-6-chloro-pyridine-3-carbaldehyde (2.1 g, 11.5 mmol, 1.0 eq.) and aniline (1.05 mL, 11.5 mmol, 1.0 eq.) in anhydrous toluene (20 mL) was stirred for 42 h at 65° C. The solvent was evaporated in vacuo and the crude obtained was purified by flash chromatography on silica gel under a gradient of hexane / EtOAc (0-50% EtOAc) to afford the desired intermediate.

[0242] 1.2.2. Method 2-2: Cyclization of ketone

[0243]

[0244] To a solution of 1-(4-azido-6-chloro-3-pyridinyl)ethanone (1.0 eq) in anhydrous DCM at 0°C was added an amine (1.0 eq) followed by titanium (IV) chloride (0.6 eq) and TEA (3.0 eq). The resulting mixture was stirred at 0°C for 1 hour and then at room temperature for 3-16 hours. The reaction was stopped and washed with cold NaHCO 3 Quench with saturated aqueous solution. Filter TiO 2 The residue was purified by flash chromatography on silica gel.

[0245] Illustrative example of method 2-2, synthesis of intermediate 17: 6-chloro-3-methyl-2-phenyl-2H-pyrazolo[4,3-c]pyridine

[0246]

[0247] To a solution of 1-(4-azido-6-chloro-3-pyridyl)ethanone (51.7 mg, 0.263 mmol, 1.0 eq) in anhydrous DCM (1 mL) cooled to 0°C was added 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). The resulting mixture was stirred at 0°C for 1 hour and then at room temperature for 3 hours. The reaction was stopped and washed with cold NaHCO 3 Quench with saturated aqueous solution. Filter TiO 2 and the solution was extracted with DCM. The organic layer was washed with brine and water, dried and evaporated. The obtained residue was purified by flash chromatography on silica gel with a gradient of hexane / EtOAc (0-50% EtOAc) to give the desired intermediate.

[0248] 1.3. General method 3: Sulfonamide synthesis

[0249]

[0250] To a solution of a suitable amine (1.0-5.0 equivalents) in a suitable solvent (such as THF or DCM) cooled (ice bath) and stirred with or without the addition of a base (such as TEA (3.0 equivalents)) is added 3-chlorosulfonylazetidine-1-tert-butyl formate (1.0 equivalents). After addition, the reaction mixture is warmed to room temperature and stirred for 2-20 hours. The expected intermediate can be isolated and, if desired, can be further purified by methods known to those skilled in the art.

[0251] Illustrative Example of Method 3, Synthesis of Intermediate 22: tert-Butyl 3-(N,N-dimethylsulfamoyl)azetidine-1-carboxylate

[0252]

[0253] A solution of 3-chlorosulfonylazetidine-1-carboxylic acid tert-butyl ester (25.0 g, 97.8 mmol, 1.0 equivalent) in anhydrous THF (100 mL) was added dropwise to a solution of N-methylmethylamine (2.00 M, 245 mL, 489.0 mmol, 5.0 equivalent) in THF cooled (ice bath) and stirred. After addition, the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was evaporated, and the obtained residue was dissolved in EtOAc (200 mL), washed with water (200 mL), and then saturated with NaHCO 3 The organic layer was washed with anhydrous MgSO 4 Dry, filter and evaporate to dryness to obtain the desired intermediate.

[0254] Another illustrative example of method 3, synthesis of intermediate 32: tert-butyl 3-(N,N-bis(4-methoxybenzyl)sulfamoyl)azetidine-1-carboxylate

[0255]

[0256] A solution of 1-(4-methoxyphenyl)-N-[(4-methoxyphenyl)methyl]methanamine (2.0 g, 7.77 mmol, 1.0 eq) and TEA (2383 mg, 23.3 mmol, 3.0 eq) in anhydrous DCM (46.6 mL) was cooled to 0 °C, and then tert-butyl 3-chlorosulfonylazetidine-1-carboxylate (2208 mg, 8.55 mmol, 1.1 eq) was added. The resulting mixture was stirred at room temperature for 48 hours. The reaction was diluted with DCM and washed with 5% Na 2 CO 3 Aqueous solution was washed and then 1 N HCl was added. The organic layer was dried and evaporated in vacuo to give the crude product which was purified by flash chromatography on silica gel in a gradient of hexanes / EtOAc (0-20% EtOAc) to give the desired intermediate.

[0257] 1.4. General method 4: Amine deprotection

[0258] 1.4.1. Method 4-1: Boc deprotection

[0259]

[0260] To a solution of the appropriate Boc protected compound (1.0 eq) in DCM, TFA (5.0 eq) was added and the reaction mixture was stirred at room temperature for 1-24 hours to give the corresponding free amine product. The desired product may be isolated and, if desired, further purified by methods known to those skilled in the art.

[0261] Illustrative Example of Method 4-1, Synthesis of Intermediate 21: N,N-Dimethylazetidine-3-sulfonamide

[0262]

[0263] To a solution of tert-butyl 3-(dimethylsulfamoyl)azetidine-1-formate (25.1 g, 94.0 mmol, 1.0 equivalent) in anhydrous DCM (350 mL) was added TFA (57.6 mL, 752.0 mmol, 8.0 equivalents). The resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to obtain a TFA salt in a light yellow oil. The salt was divided into three equal parts. Each part was then applied to an SCX column (preconditioned with MeOH) and eluted with MeOH, followed by elution with MeOH containing 7 M ammonia. Ammonia / MeOH fractions were combined and evaporated to dryness to obtain the desired intermediate.

[0264] 1.4.2. Method 4-2: PMB deprotection

[0265]

[0266] To the solution of the compound (1.0 equivalent) of suitable single PMB or double PMB protection in DCM, add TFA (100-300 equivalent), and at room temperature stir reaction mixture 3-72 hours, to obtain corresponding elementary sulfonamide or monomethylsulfonamide product. Expected product can be separated, and if necessary, the product can be further purified by methods known to persons skilled in the art.

[0267] Illustrative 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

[0268]

[0269] To a solution of N-[(4-methoxyphenyl)methyl]-N-methyl-1-(2-phenylpyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide (46.9 mg, 0.101 mmol, 1.0 eq) in DCM (2.0 mL) was added TFA (2.0 mL, 26.9 mmol, 266.0 eq) and the mixture was stirred at room temperature for 3 hours. The solvent was removed under vacuum to give a crude material which was subjected to preparative HPLC purification to obtain the desired compound.

[0270] Another illustrative example of method 4-2, synthesis of compound 41: 1-[2-(4-fluorophenyl)pyrazolo[4,3-c]pyridin-6-yl]azetidine-3-sulfonamide

[0271]

[0272] To a solution of 1-[2-(4-fluorophenyl)pyrazolo[4,3-c]pyridin-6-yl]-N,N-bis[(4-methoxyphenyl)methyl]azetidine-3-sulfonamide (42.0 mg, 0.0715 mmol, 1.0 equiv) in anhydrous DCM (1.0 mL) was added TFA (1.00 mL, 13.1 mmol, 183.0 equiv). The resulting mixture was stirred over the weekend at room temperature. The reaction mixture was diluted with DCM, water was then added, and the pH was adjusted to 13-14 with 6N NaOH. The layers were separated. The desired product remained in the aqueous layer. The pH of the aqueous layer was adjusted to pH~9 using 1N HCl. The resulting mixture was extracted with DCM and EtOAc. The precipitate was collected by filtration, and the precipitate was combined with DCM and EtOAc extracts, and the solvent was evaporated to dryness to give a crude product, which was subjected to preparative HPLC purification, and the material was purified under acidic conditions. The desired compound was obtained after purification.

[0273] 1.5. General method 5: Buchwald-Hartwig reaction

[0274]

[0275] To a solution of the halogenated aryl derivative (1.0 eq.) in toluene were added the amine derivative (1.0-1.5 eq.), TEA (0.5 eq.) and KO t Bu (3.0 eq.). The reaction mixture is degassed with argon, XPhos Pd G3 (0.1 eq.) is added, and the solution is degassed again by bubbling argon. The reaction mixture is heated to 80° C. and stirred for 0.5-20 hours. The desired product can be isolated and, if desired, further purified by methods known to those skilled in the art.

[0276] Illustrative Example of Method 5, Synthesis of Compound 1: N,N-Dimethyl-1-(2-phenylpyrazolo[4,3-c]pyridin-6-yl)azetidine-3-sulfonamide

[0277]

[0278] To a solution of 6-chloro-2-phenyl-pyrazolo[4,3-c]pyridine (1.84 g, 8.01 mmol, 1 eq) in toluene (80.0 mL) were added N,N-dimethylazetidine-3-sulfonamide (1.32 g, 8.01 mmol, 1 eq), TEA (0.55 ml, 4.01 mmol, 0.5 eq) and KO t To the precipitate of 4-nitro-1-yl pyridine-2 ...

[0279] 1.6. General method 6: SNAr

[0280]

[0281] To a solution of 6-bromo-2-chloro-pyridine-3-carboxaldehyde (1.0 equiv.) in anhydrous DMF, potassium carbonate (1.4-2.0 equiv.) was added, followed by the appropriate azetidine-3-sulfonamide (1.0-1.1 equiv.). The resulting mixture was heated at 60 °C and stirred for 2-5 hours. After complete conversion, the reaction mixture was cooled to room temperature, and then water and EtOAc were added, and saturated NaHCO 3 The mixture was washed with aqueous solution and water. The organic layer was washed with Na 2 SO 4 Drying and concentration under vacuum afforded the crude product which was purified by silica gel flash chromatography.

[0282] Illustrative Example of Method 6, Synthesis of Intermediate 47: 1-(6-chloro-5-formyl-2-pyridinyl)-N,N-dimethyl-azetidine-3-sulfonamide

[0283]

[0284] Potassium carbonate (193 mg, 1.40 mmol, 1.4 equiv) was added to a solution of 6-bromo-2-chloro-pyridine-3-carboxaldehyde (220 mg, 1.00 mmol, 1.0 equiv) in anhydrous DMF (5.00 mL), followed by N,N-dimethylazetidine-3-sulfonamide (164 mg, 1.00 mol, 1.0 equiv). The resulting mixture was heated and stirred at 60 ° C for 2 hours. After complete conversion, the reaction mixture was cooled to room temperature and quenched with water, followed by addition of EtOAc and saturated NaHCO 3 The mixture was washed with aqueous solution and water. The organic extract was washed with Na 2 SO 4 Drying and concentration under vacuum provided the crude product which was purified by flash chromatography on silica gel in a gradient of hexanes / EtOAc (0-50% EtOAc) to give the desired intermediate.

[0285] 1.7. General method 7: Chlorination

[0286]

[0287] To a solution of the appropriate pyrazolo[4,3-c]pyridine (1.0 eq.) in ACN was added N-chlorosuccinimide (1.0 eq.). The reaction mixture was stirred at 50° C. overnight. The reaction was stopped and the solvent was evaporated. The obtained residue was purified by flash chromatography on silica gel.

[0288] Illustrative Example of Method 7, Synthesis of Intermediate 42: 3,6-Dichloro-2-(4-fluorophenyl)pyrazolo[4,3-c]pyridine

[0289]

[0290] To a solution of 6-chloro-2-(4-fluorophenyl)pyrazolo[4,3-c]pyridine (500 mg, 2.02 mmol, 1.0 equiv) in ACN (18.00 mL) was added N-chlorosuccinimide (270 mg, 2.02 mmol, 1.0 equiv). The reaction mixture was stirred at 50 ° C overnight. The reaction was stopped and the solvent was evaporated. The obtained residue was purified by flash chromatography on silica gel under a gradient of hexane / EtOAc (0-50% EtOAc) to give the desired intermediate.

[0291] 1.8. General method 8: Suzuki-Miyaura reaction

[0292]

[0293] To a solution of the appropriate dichloropyrazolo[4,3-c]pyridine (1.0 equiv) in 1,4-dioxane was added the appropriate boronic acid (or boronic ester) (2.0-3.0 equiv) followed by saturated Na 2 CO 3 Aqueous solution and tetrakis(triphenylphosphine)palladium(0) (0.05 equiv.) were added. The reaction mixture was degassed with argon and stirred at 120°C under microwave irradiation for 15 minutes or at 75°C overnight. After complete conversion, the reaction solution was cooled to room temperature, then EtOAc was added, and the reaction solution was washed with brine and water. The organic matter was washed with Na 2 SO 4 Drying and concentration under vacuum afforded the crude product which was purified by silica gel flash chromatography.

[0294] Illustrative 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

[0295]

[0296] To a solution of 3,6-dichloro-2-(4-fluorophenyl)pyrazolo[4,3-c]pyridine (56.4 mg, 0.200 mmol, 1.0 equiv) in 1,4-dioxane (2.00 mL) was added 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.0764 mL, 0.400 mmol, 2.0 equiv) followed by the addition of Na 2 CO 3 Saturated aqueous solution (0.250 mL) and tetrakis(triphenylphosphine)palladium(0) (11.6 mg, 0.0100 mmol, 0.05 equiv.) The reaction mixture was degassed with argon and stirred at 120 °C under microwave irradiation for 15 minutes. After complete conversion, the reaction was stopped, EtOAc was added, and washed with brine and water. The organics were washed with Na 2 SO 4 Drying and concentration under vacuum provided the crude material which was purified by flash chromatography on silica gel in a gradient of hexanes / EtOAc (0-50% EtOAc) to give the desired intermediate.

[0297] 1.9. General method 9: Hydrogenation

[0298]

[0299] To a solution of the appropriate dichloropyrazolo[4,3-c]pyridine (1.0 equiv) in anhydrous MeOH was added palladium on carbon (10%) (0.01-0.05 equiv). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After complete conversion, the reaction mixture was filtered through celite and the solvent was evaporated to give the crude material, which was purified by flash chromatography on silica gel.

[0300] Illustrative Example of Method 9, Synthesis of Intermediate 45: 6-Chloro-2-(4-fluorophenyl)-3-isopropyl-2H-pyrazolo[4,3-c]pyridine

[0301]

[0302] To a solution of 6-chloro-2-(4-fluorophenyl)-3-isopropenyl-pyrazolo[4,3-c]pyridine (48.0 mg, 0.167 mmol, 1.0 equivalent) in anhydrous MeOH (0.5 mL) was added palladium on carbon (10%) (10.0%, 1.78 mg, 0.00167 mmol, 0.01 equivalent). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour, and then an additional amount of palladium on carbon (10%) (10.0%, 8.88 mg, 0.00834 mmol, 0.05 equivalent) was added, and the mixture was continued to be stirred at room temperature under a hydrogen atmosphere for 1 hour. After complete conversion, the reaction mixture was filtered through diatomaceous earth, and the solvent was evaporated to obtain a crude material, which was purified by flash chromatography on silica gel under a gradient of hexane / EtOAc (0-50% EtOAc) to obtain the desired intermediate.

[0303] Table II. Intermediates useful in compounds of the invention.

[0304] SM = starting material, Mtd = method, MS Mes'd = measured mass

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312] Table III. Illustrative compounds of the invention

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321] Table IV. NMR data for illustrative compounds of the invention and comparative compounds.

[0322]

[0323]

[0324]

[0325]

[0326]

[0327] Biological Examples

[0328] Example 2. In vitro assay

[0329] 2.1.MDCKII-MDR1

[0330] 2.1.1. Research principles

[0331] The aim of this study was to determine the permeability and efflux rates of the compounds of the invention in Madin-Darby canine kidney (MDCKII) cells.

[0332] 2.1.2. Research plan

[0333] MDCKII-MDR1 cells were cultured at 0.12 x 10 6 The final concentration of 10 cells / well was seeded on Millicell-24 cell culture insert plate assembly. Before the start of the experiment, the cells were cultured in a CO2 incubator for 3-4 days, with the culture medium replaced 24 hours after seeding.

[0334] On the day of the experiment, cells were pre-incubated with Dulbecco's phosphate buffered saline (D-PBS, pH 7.4) containing 1% DMSO for 45 minutes. Compounds were prepared in D-PBS at pH 7.4 and added to the apical or basolateral chambers of the Millicell cell culture insert assembly at a final concentration of 10 μM, with a final DMSO concentration of 1%. Lucifer Yellow was added to all donor buffer solutions to assess the integrity of the cell monolayer by monitoring the penetration of Lucifer Yellow. After incubation at 37°C for 1 hour, aliquots were taken from the apical (A) and basolateral (B) chambers while shaking and added to an ACN: aqueous solution (2: 1) containing an analytical internal standard.

[0335] A sample was also taken from the donor solution at the beginning of the experiment to obtain the initial (C0) concentration. After brief mixing and centrifugation, the supernatant was analyzed by LC-MS / MS. The apparent permeability coefficient (Papp) was calculated according to the following equation: Papp = (dQ / dT)*(1 / C0)*(1 / A), where dQ / dT = permeability; C0 = initial concentration in the donor compartment; A = surface area of ​​the cell monolayer (0.7 cm 2 ). "Concentration" is the ratio of the compound peak area to the internal standard peak area. The Papp value is measured as the rate (x10 -6 cm / s). The outflow ratio was calculated as the Papp from B to A divided by the Papp from A to B. The passive permeability was calculated by the following formula (x10 -6 cm / s): Papp from A to B x (outflow ratio + 1 / 2).

[0336] Example 3. In vivo assay

[0337] 3.1. Alzheimer's disease mouse model using intrahippocampal injection of amyloid β oligomers.

[0338] 3.1.1. Research principles

[0339] Elevated levels of amyloid beta (Aβ) can be found in the brains of AD patients. This is accompanied by the activation of microglia in the AD brain and an increase in the number of microglia, which is called microgliosis. Activated microglia can be found early in the progression of the disease.

[0340] The purpose of this Alzheimer's disease model is to evaluate the effects of test compounds based on the intrahippocampal injection of AβO, which is involved in the pathogenesis of AD (Sakono and Zako 2010) and induces short-term and long-term memory deficits (Calvo-Flores Guzmán et al. 2020). Cognitive dysfunction is closely related to the loss of neurons and the activation of microglia.

[0341] The study evaluated cognitive function in mice after long-term administration of compounds following AβO injury. Plasma and brain samples were also collected for further histological analysis, assessing neurodegeneration and microglial activation by immunochemistry.

[0342] 3.1.2. Research plan

[0343] 3.1.2.1. Overview

[0344] The forced alternation Y-maze test relies on the natural tendency of rodents to explore novel environments and is used to assess short-term spatial memory and exploratory behavior in injured mice.

[0345] 3.1.2.2. Animals

[0346] 18 month old male C57BL6 mice (Janvier Labs) were housed in the Neuro-Sys facility for 1 week of acclimatization and housed under a reversed 12-hour light-dark cycle. Animals were group housed (2-4 animals per cage) and housed in a room with controlled temperature (21-22°C) and humidity (40-60%) and food and water available ad libitum.

[0347] 3.1.2.3. Stereotactic injection of Aβ1-42 preparation

[0348] After one week of acclimation, all mice underwent stereotaxic surgery on the bilateral hippocampus determined relative to bregma according to the mouse brain atlas of Paxinos and Franklin (Yeung et al. 2020).

[0349] The preparation of Aβ1-42 was carried out following the procedure described by Callizot (Callizot et al. 2013). Briefly, Aβ1-42 peptide (Bachem, 1071428, CAS#107761-42-2) was dissolved in vehicle (water (w / v) containing 0.5% methylcellulose) at an initial concentration of 100 μM. The solution was gently stirred in the dark at 37°C for 3 days.

[0350] After stirring, the Aβ1-42 preparation was injected bilaterally into the stratum serratum, striatum pyramidal layer and striatum radiatum at three different depths in the CA1 region of the hippocampus. 2 μL / side of the Aβ1-42 preparation (100 μM, containing ~15 μmol / L oligomers accurately measured by automatic WB) or vehicle (0.2 microliters / minute, using an Elite Nanomite syringe pump) was stereotactically administered bilaterally in the CA1 region of the hippocampus by bilateral injection with a Hamilton syringe.

[0351] Study design

[0352] All treatments started one day before stereotaxic injection of Aβ1-42 and were applied daily until the last day of the experiment, when different tissue samples were collected.

[0353] Test compounds were administered by oral gavage (po).

[0354] Donepezil (DNP) is an inhibitor of acetylcholinesterase that acts as an enhancer of acetylcholine signaling and has been approved by the FDA for the treatment of mild cognitive impairment. DNP is administered intraperitoneally (ip).

[0355] Table V. Study Groups and Duration

[0356]

[0357] Formulations containing vehicle 1: Weigh the required amount of test compound and place it in a glass vial. Dissolve the compound in water (w / v) containing 0.5% methylcellulose corresponding to 100% of the final volume and vortex. Place the formulation (glass vial) in an ultrasonic bath for 30 minutes. Aliquot the formulation into tubes protected from light and store at 4°C.

[0358] Preparation containing vehicle 2: Weigh the required amount of test compound and place it in a glass tube. Dissolve the compound in a certain volume of PEG200 corresponding to 25% of the final volume (at 4x concentration). The preparation is aliquoted into light-proof tubes and stored at 4°C. Before application, a certain volume of MC (0.5%, w / v, in sterile water) corresponding to 75% of the final volume (for 1x concentration) is added to the preparation and vortexed. The preparation (glass vial) is placed in an ultrasonic bath for homogenization. The glass vial containing the preparation is kept under stirring and protected from light until application.

[0359] 3.1.2.5. Assessment of short-term spatial memory - Y-maze

[0360] The Y-maze is used to assess the short-term memory (working memory) of mice. The spatial reference memory emphasized by the hippocampus is tested by placing the test mice in a Y-maze, in which one arm is closed during training. After the trial interval, the mouse should remember which arm it had not explored previously and should visit that arm more frequently (Kraeuter, Guest and Sarnyai 2019). Behind each arm, some visual cues (stuck on the wall) are placed to allow the animal to make some visual recognition.

[0361] The apparatus consisted of a light grey polyvinyl chloride (PVC) Y-shaped compartment with arms of equal length (35 cm arm length x 6 cm x 15 cm high arms).

[0362] Prior to the day of surgery, all mice underwent a Y-maze training session as an acclimatization session. Mice were tested again seven (7) and fourteen (14) days after surgery.

[0363] The testing is based on two experiments:

[0364] -1. Allow mice to freely explore both arms of the Y-maze for 5 minutes (300 seconds). The last arm remains closed. At the end of 5 minutes, place the animal in an empty cage for 3 minutes. Clean the Y-maze with acetic acid to neutralize any odor.

[0365] -2. After 3 min, the mice were allowed to freely explore the three arms of the Y-maze for 5 min.

[0366] Both trials were automatically recorded by a video camera using the Ethovision system (Noldus). The number of entries and the time spent in each arm were automatically determined for each animal.

[0367] Animals that remained in the entry arm for the entire test duration (≤200 sec) were automatically excluded from the analysis.

[0368] Animals showing immobility (due to excessive anxiety behavior) were excluded from testing.

[0369] 3.1.2.6. Immunostaining (IHC).

[0370] At the end of the experiment (on day 18), mice (n=5) from groups 1, 2, and 3 were sacrificed under anesthesia, and brains were collected and fixed in 4% paraformaldehyde (PFA) for 2 hours at room temperature. After 2 hours, brains were placed in a solution of 30% sucrose in Tris-phosphate saline (TBS) at 4°C overnight.

[0371] Serial coronal sections of 40 μm thickness were cut using a freezing microtome, including the hippocampal region.

[0372] For immunostaining, free-floating sections were incubated for 1 hour at room temperature in TBS containing 0.25% bovine serum albumin, 0.3% Triton X-100, and 1% goat serum. This incubation was to block nonspecific binding sites and permeabilize the tissue.

[0373] 3.1.2.7. Bioassays (ELISA and NGS)

[0374] At the end of the experiment (on day 18), mice (n = maximum 7 for groups 1, 2, 3 and 8) were sacrificed under anesthesia and specific brain regions were collected. The two hemispheres were separated to yield two cortical regions (one in each hemisphere) and two hippocampal regions (one in each hemisphere) per animal. These samples were kept at -80°C.

[0375] 3.1.2.8. Pharmacokinetic samples and brain sampling for bioassays (ELISA and NCS)

[0376] 3.1.2.8.1.1.PK blood sampling:

[0377] At the end of the experiment (on day 8 or day 18), for mice (n=9, 3 samples per time point) (from group 6), blood was collected in EDTA tubes under deep anesthesia at 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 kept frozen at -80°C. The remaining blood was centrifuged and the plasma was collected and kept at -80°C.

[0378] 3.1.2.8.2 Brain sampling:

[0379] Brains from the same animal were dissected. The two hemispheres were separated to yield two cortices (one in each hemisphere) and two hippocampal regions (one in each hemisphere) per animal. The samples were kept at -80°C.

[0380] Statistical analysis

[0381] All values ​​show the mean + / - SEM (standard error of the mean) of each group of animals. GraphPad Prism software version 8.0.2 was used for graphs and statistical analysis by one-way or two-way analysis of variance (ANOVA) followed by Fisher's test, *p<0.05 was considered significant. Outliers were identified by Grubb's test (α=0.2) and abnormal behavior during the Y maze test (e.g., immobility during the test).

[0382] Results

[0383] Compared with control animals, mice injected with Aβ1-42 showed significant impairment of short-term spatial memory 7 days after surgery (Table VI), as evidenced by reduced exploration time in the novel arm in the forced alternation test of the Y-maze. Short-term memory deficits were still significantly altered in a second Y-maze test performed 14 days after surgery compared with controls.

[0384] Table VI. Results of the study groups

[0385]

[0386] NA = Not applicable

[0387] Compound 14 showed significant beneficial effects on short-term spatial memory at days 7 and 14 after surgery compared to mice injected with Aβ1-42 and mice receiving vehicle treatment (ID 2 group).

[0388] Compared with the ID 2 group, compound 66 showed a significant beneficial effect on short-term spatial memory on day 7. BRIEF DESCRIPTION OF THE DRAWINGS

[0389] Figure 1 Describes the average cumulative duration (in seconds) of each mouse group in the novel arm of the Y-maze. Each column of the figure represents the mean time and standard deviation range for each mouse group described in Table V. Column A represents the control group (ID 1 group), Column B represents the ID 2 group, Column C represents the ID 3 group, Column D represents the ID 6 group, and Column E represents the ID 8 group.

[0390] The * symbol at the top of the column indicates a p value < 0.05 compared with the ID 2 group (one-way ANOVA followed by Fisher's test).

[0391] Final Comments

[0392] Those skilled in the art will appreciate that the above description is exemplary and explanatory in nature and is intended to illustrate the present invention and its preferred embodiments. Through routine experimentation, the skilled person will recognize the obvious modifications and changes that can be made without departing from the spirit of the present invention. All such modifications that fall within the scope of the appended claims are intended to be included therein. Therefore, the present invention is not intended to be defined by the above description, but rather by the following claims and their equivalents.

[0393] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication was specifically and individually indicated to be incorporated by reference as if fully set forth.

[0394] It is understood that factors such as the different cell penetration abilities of various compounds may cause differences in compound activity in in vitro biochemical and cellular assays.

[0395] At least some of the chemical names of the compounds of the invention given and described in this application may be generated on an automatic basis using commercially available chemical naming 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. In the case where the indicated chemical name and the depicted structure are different, the depicted structure shall prevail.

[0396] References

[0397] Bundgaard, Hans. 1985. Design of Prodrugs. Amsterdam; New York; Oxford: Elsevier.

[0398] Callizot, Noelle, Maud Combes, Rémy 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.

[0399] Calvo-Flores Guzmán, Beatriz, SooHyun Kim, Bhavya Chawdhary, KatiePeppercorn, Warren P Tate, Henry J Waldvogel, Richard LM Faull, JohannaMontgomery, and Andrea Kwakowsky. 2020. “Amyloid-Beta1-42-Induced Increase in GABAergic TonicConductance in Mouse Hippocampal CA1 Pyramidal Cells.” Molecules 25(3): 693. https: / / doi.org / 10.3390 / molecules25030693.

[0400] "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.

[0401] Knopman,David S.,Helene Amieva,Ronald C.Petersen, Chételat, 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.

[0402] Kraeuter, Ann-Katrin, Paul C. Guest, and Zoltán Sarnyai. 2019. “The Y-Maze for Assessment of Spatial Working and Reference Memory in Mice.” 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.

[0403] 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.

[0404] 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.

[0405] Yeung, Jason HY, Beatriz Calvo-Flores Guzmán, Thulani H. Palpagama, Jayarjun Ethiraj, Ying Zhai, Warren P. Tate, Katie Peppercorn, Henry J. Waldvogel, Richard L. M. Faull, and Andrea Kwakowsky. 2020. “Amyloid-Beta1–42Induced Glutamatergic Receptorand Transporter Expression Changes in the Mouse Hippocampus.” Journal of Neurochemistry 155(1):62–80. https: / / doi.org / 10.1111 / jnc.15099.

Claims

1. A compound according to formula I: in n is 1, 2 or 3; One of X and Y is N, and the other is CH; R 1 is optionally one or more independently selected R 4 substituted phenyl or pyridyl; R 2a and R 2b Independently selected from: -H， -C 1-4 Alkyl, which is optionally substituted with one or more independently selected halo, -CN or C 1-4 Alkoxy substitution, and -C 3-6 Cycloalkyl, the cycloalkyl is optionally substituted with one or more independently selected halo, -CN or C 1-4 Alkoxy substitution; or R 2a and R 2b Together with the N atom, it can form optionally one or more independently selected halo, -CN or C 1-4 Alkoxy-substituted 4-7 membered heterocycloalkyl; R 3 is H, C optionally substituted by one or more independently selected halo 1-6 alkyl, or C 3-7 monocyclic cycloalkyl; and Each R 4 Selected from: -OH, - halogenated, -C 1-4 Alkyl, the alkyl group is optionally substituted with one or more independently selected halogen or C 1-4 Alkoxy substituted, or -C 1-4 Alkoxy, the alkoxy is optionally substituted with one or more independently selected halogen or C 1-4 Alkoxy substitution; or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt of a solvate thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt of a solvate thereof, wherein n is 0.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is one or more independently selected R 4 Substituted phenyl.

4. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 It is phenyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of the present invention is according to any one of Formula IIa, IIb, IIc or IId: Where R 2a , R 2b and R 3 As mentioned above.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 It's H.

7. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 1-6 alkyl.

8. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 3-7 Monocyclic cycloalkyl.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of the present invention is according to any one of Formula IIIa, IIIb, IIIc, IIId, IIIe or IIIf: Where R 2a and R 2b As mentioned above.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein each R 2a and R 2b Independently selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, wherein R 2a It is C 1-4 Alkyl, and R 2b It is H, C 1-4 Alkyl or C 3-6 Cycloalkyl. 12 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, for use in medicine.

14. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, for use in preventing, controlling and / or treating a neurodegenerative disease.

15. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12, for use in preventing and / or treating a neurodegenerative disease, wherein the neurodegenerative disease is selected from Alzheimer's disease and other dementias, brain cancer, degenerative neurological diseases, encephalitis, epilepsy, hereditary brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

16. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, for use in treating Alzheimer's disease.

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