TW202313619A - Fused bicyclic heterocyclic compounds and uses thereof - Google Patents

Abstract

The present disclosure provides compounds that are inhibitors of PIKfyve kinase and are therefore useful for the treatment of neurological diseases treatable by inhibition of PIKfyve kinases. Also provided are pharmaceutical compositions containing such compounds, and methods of treatment of neurological diseases using such compounds.

Description

Fused bicyclic heterocyclic compounds and uses thereof

The present invention provides compounds that are phosphoinositide kinase inhibitors, in particular phosphoinositide kinase ("PIKfyve") inhibitors containing the FYVE-type designation, and are therefore useful in the treatment of central nervous system disorders. Pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided.

Phosphoinositide kinase (PIK) catalyzes the phosphorylation of phosphatidylinositol, a component of eukaryotic cell membranes, and a related phospholipid called phosphoinositide. Phosphoinositides are involved in various cellular processes, including regulation of cell proliferation, survival, cytoskeletal organization, vesicle migration, glucose transport, and platelet function. Fruman et al., "Phosphoinositide Kinases", Ann. Review. Biochem. 1998, 67, 481-507. Phosphorylated derivatives of phosphatidylinositol regulate cytoskeletal function, membrane migration, and receptor signaling by recruiting protein complexes to cell and endosomal membranes.

Phosphoinositide kinase containing FYVE-type fingers (PIKfyve; also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII) is a widely expressed PIK with both lipid and protein kinase activities. In its ability to act as a lipid kinase, the enzyme phosphorylates endosomal phosphatidylinositol and phosphatidylinositol-3-phosphate (PI3P) at the D-5 position to generate the corresponding 5-phosphophospholipid analogs. Shisheva et al., Cell Biol. Int. 2008, 32(6), 591. PI3P is found in cell membranes and plays a role in protein migration, protein degradation and autophagy. Nascimbeni et al., FEBS J. 2017, 284, 1267-1278. PIKfyve regulates inner membrane homeostasis and plays a role in the biosynthesis of endosomal carrier vesicles from early endosomes. Enlarged endosomal/lysosomal structures were observed in cells expressing PIKfyve dominant negative or siRNA. Ikonomov et al., J. Biol. Chem. 2001, 276(28), 26141-26147; Rutherford et al., J. Cell Sci. 2006, 119, 3944-3957. Inhibition of PIKfyve activity increases PI3P levels, thereby stimulating autophagy and improving motor neuron health. Phosphorylated inositol phospholipids produced by PIKfyve localize to various processes involved in endolysosomal transport, inner membrane homeostasis, and biosynthesis of endosomal carrier vesicle (ECV) bodies/multivesicular bodies (MVBs) from early endosomes PIKfyve functions in a variety of cell membranes and organelles. In addition, PIKfyve is required for the endocytosis-vacuole pathway and for nuclear migration. Thus, PIKfyve helps maintain the proper morphology of endosomes and lysosomes.

In mammalian cells, PI3P levels are regulated by the reciprocal activities of PIKfyve and the phosphatase FIG4 phosphoinositide 5-phosphatase (FIG4). Zolov et al., "In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P", Proc. Natl. Acad. Sci. USA 2012, 109(43), 17472 -17477. Typically, FIG4 is localized on the cytoplasmic surface of endolysosomal vesicles in the complex. Inhibition of PIKfyve mimics overexpression of FIG4, thereby increasing PI3P levels, stimulating autophagy and improving motor neuron health. A variety of diseases are associated with FIG4 deficiency (such as deleterious FIG4 mutations or reduced FIG4 function) and are therefore suitable targets for PIKfyve inhibitor therapy, including amyotrophic lateral sclerosis (ALS), primary Primary lateral sclerosis (PLS), Charcot-Marie-Tooth (including type 4J (CMT4J)) and Yunis-Varon syndrome. Mutations in PIKfyve are associated with corneal macular dystrophy, an autosomal dominant disorder characterized by numerous white spots in all layers of the corneal stroma.

Exemplary diseases associated with FIG4 deficiency are amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charmadoux disease (including type 4J (CMT4J)), Uris- Valen syndrome, polymicrogyria (including polymicrogyria with seizures), temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease Parkinson's disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, fronto-temporal dementia ), diseases of neuronal nuclear inclusions of polyglutamine and intranuclear inclusion bodies, disease of Marinesco and Hirano bodies, AZ Haimer's disease, neurodegeneration, cavernous neurodegeneration, autophagy, peripheral neuropathy, leukoencephalopathy, motor neuropathy, sensory neuropathy. Bharadwaj et al., Hum. Mol. Genet. 2016, 25(4), 682-692.

PIKfyve inhibitors are indicated for a range of neurological disorders such as tauopathies (including but not limited to Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal lobe mental retardation and chronic traumatic encephalopathy), traumatic brain injury (TBI), cerebral ischemia, ALS, frontotemporal dementia (FTD), Guillain-Barré Syndrome, chronic inflammatory dementia Chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, CMT, lysosomal storage disease (including but not limited to Fabry's disorder, Gaucher's disease (Gaucher's disorder), Niemann Pick C (Niemann Pick C), Tay-Sachs and Type IV mucolipidosis) and certain types of neuropathy. Other therapeutic targets for intervention with PIKfyve inhibitors include Huntington's disease and psychiatric disorders (such as ADHD, schizophrenia, mood disorders including but not limited to major depressive disorder, bipolar I and bipolar II). Gardiner et al., "Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts", JAMA Neurol. 2019, 76(6), 650-656; PCT Publication No. WO2016/210372; US Publication Case No. US2018/0161335.

其中 Y ¹為N或C-R ¹； Y ²為N或C-R ²； X為N或CH； 其限制條件為當Y ¹為N時，Y ²為C-R ²，且當Y ²為N時，Y ¹為C-R ¹；R ¹為H或各自視情況經1至3個R ^s取代之C _3-8芳基、C _3-8雜芳基、C _3-8環烷基或C _3-8雜環基； R ²為H或各自視情況經1至3個R ^s取代之C _3-8芳基、C _3-8雜芳基、C _3-8環烷基或C _3-8雜環基； R ⁴為各自視情況經1至3個R ^s取代之C _3-8芳基、C _3-8雜芳基、C _3-8環烷基或C _3-8雜環基，或-C(O)NR ^xR ^y； R ^s為H、鹵基、胺基、OH、OC _1-6烷基、C _1-6烷基、C _1-6伸烷基-OH或C _1-6伸烷基-NR ^pR ^q； R ^x為H或視情況經R ^o取代之C _1-4烷基； R ^y為H、各自視情況經1至3個R ^o取代基取代之C _1-4烷基、-O-C _1-4烷基、-SO ₂-C _1-4烷基、C _1-4烷基-SO ₂-R ^r、環烷基、-C _1-4伸烷基-環烷基、雜環基或-O-雜環基；或R ^x及R ^y與其所連接之氮一起形成視情況經C _1-4烷基取代之雜環基； 各R ^r為C _1-4烷基或-NR ^pR ^q； 各R ^o取代基獨立地為C _1-4烷基、-OH、-OC _1-4烷基、鹵基、氰基或-NR ^pR ^q； R ^p及R ^q各獨立地為H或C _1-4烷基；或R ^p及R ^q與其所連接之氮一起形成雜環基；且 R ⁵為H、C _1-6烷基、鹵基、-OH或-OC _1-6烷基。 Embodiment 1 is a compound of formula (I):

Wherein Y ¹ is N or CR ¹ ; Y ² is N or CR ² ; X is N or CH; the restriction is that when Y ¹ is N, Y ² is CR ² , and when Y ² is N, Y ¹ is CR ¹ ; R ¹ is H or C _3-8 aryl, C _3-8 heteroaryl, C _3-8 cycloalkyl or C _3-8 heterocycle substituted by 1 to 3 R ^s as appropriate R ² is H or C _3-8 aryl, C _3-8 heteroaryl, C _3-8 cycloalkyl or C _3-8 heterocyclyl substituted by 1 to 3 R ^s as appropriate; R ⁴ is C _3-8 aryl, C 3-8 heteroaryl _{, C 3-8 cycloalkyl or C 3-8 heterocyclyl ,} each optionally substituted by 1 to 3 R ^s , or -C( O) NR ^x R ^y ; R ^s is H, halogen, amino, OH, OC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkylene-OH or C _1-6 alkylene -NR ^p R ^q ; R ^x is H or C _1-4 alkyl optionally substituted by R ^o ; R ^y is H, C _1-4 alkane each optionally substituted by 1 to 3 R ^o substituents radical, -OC _1-4 alkyl, -SO ₂ -C _1-4 alkyl, C _1-4 alkyl-SO ₂ -R ^r , cycloalkyl, -C _1-4 alkylene-cycloalkyl , heterocyclyl or -O-heterocyclyl; or R ^x and R ^y together with the nitrogen to which they are attached form a heterocyclyl optionally substituted by C _1-4 alkyl; each R ^r is C _1-4 alkyl Or -NR ^p R ^q ; Each R ^o substituent is independently C _1-4 alkyl, -OH, -OC _1-4 alkyl, halo, cyano or -NR ^p R ^q ; R ^p and R ^q Each is independently H or C _1-4 alkyl; or R ^p and R ^q form a heterocyclic group together with the nitrogen to which they are attached; and R ⁵ is H, C _1-6 alkyl, halo, -OH or - OC _1-6 alkyl.

Embodiment 2 is the compound of embodiment 1, wherein Y ¹ is N, and Y ² is CR ² .

Embodiment 3 is the compound of embodiment 1, wherein Y ² is N, and Y ¹ is CR ¹ .

Embodiment 4 is the compound of embodiment 1, wherein Y ¹ is CR ¹ and Y ² is CR ² .

Embodiment 5 is the compound of embodiment 1 wherein Y ¹ is CR ¹ and Y ² is CR ² , and wherein one of R ¹ and R ² is other than H.

Embodiment 6 is the compound of embodiment 1, wherein X is N.

Embodiment 7 is the compound of embodiment 1, wherein X is N, and one of ^Y1 and ^Y2 is N.

Embodiment 8 is the compound of embodiment 1 wherein X is N, Y ¹ is CR ¹ , and Y ² is CR ² .

Embodiment 9 is the compound of embodiment 1 wherein X is N, Y ¹ is CR ¹ , and Y ² is CR ² , and wherein one of R ¹ and R ² is not H.

Embodiment 10 is the compound of Embodiment 1 wherein X is CH.

Embodiment 11 is the compound of embodiment 1 wherein X is CH, and one of ^Y1 and ^Y2 is N.

Embodiment 12 is the compound of embodiment 1 wherein X is CH, and ^Y1 and ^Y2 are N.

Embodiment 13 is the compound of any one of embodiments 1 to 12, wherein Y ^is CR ^and R ^is H or phenyl or C _3-8 heteroaryl each optionally substituted with 1 to 3 R ^s .

Embodiment 14 is the compound of any one of embodiments 1 to 13, wherein R ¹ is phenyl or pyridyl, pyrimidinyl or pyrazolyl, each optionally substituted with 1 or 2 R ^s .

Embodiment 15 is the compound of any one of embodiments 1 to 13, wherein R ¹ is phenyl, pyridyl or pyrazolyl, each of which is optionally substituted with 1 R ^s .

Embodiment 16 is the compound of any one of embodiments 1 to 15, wherein Y ² is CR ² and R ² is H or phenyl or C _3-8 heteroaryl each optionally substituted with 1 to 3 R ^s .

Embodiment 17 is the compound of any one of embodiments 1 to 16, wherein R ² is phenyl or pyridyl, pyrimidinyl or pyrazolyl, each optionally substituted with 1 or 2 R ^s .

Embodiment 18 is the compound of any one of embodiments 1 to 16, wherein R ² is phenyl, pyridyl or pyrazolyl, each of which is optionally substituted with 1 R ^s .

Embodiment 19 is the compound of any one of Embodiments 1 to 18, wherein ^R4 is phenyl, pyridyl, pyrimidinyl or pyrazolyl, each optionally substituted with 1 to 2 ^Rs .

Embodiment 20 is the compound of any one of Embodiments 1 to 18, wherein R ⁴ is phenyl, pyridyl or pyrazolyl, each optionally substituted with 1 R ^s .

Embodiment 21 is the compound of any one of embodiments 1 to 20, wherein R ^s is H, F, Cl, Br, NH ₂ , OH, OC _1-6 alkyl, C _1-6 alkyl, OC _{1- 4} alkyl, C _1-4 alkyl, C _1-4 alkylene-OH or C _1-4 alkylene-NR ^p R ^q , wherein R ^p and R ^q are independently H or C _1-4 alkane base.

Embodiment 22 is the compound as any one of embodiments 1 to 20, wherein R ^s is H, Cl, OH, methyl, ethyl, propyl, methylene-OH, ethylidene-OH, propylidene -OH, methylene-N(CH ₃ ) ₂ , ethylidene-N(CH ₃ ) ₂ , propylidene-N(CH ₃ ) ₂ .

Embodiment 23 is the compound of any one of embodiments 1-20, wherein R ^s is H or methyl.

Embodiment 24 is the compound of any one of embodiments 1 to 23, wherein R ⁴ is -C(O)NR ^x R ^y .

Embodiment 25 is the compound of any one of Embodiments 1 to 24 wherein ^Rx is H, or methyl or ethyl optionally substituted with one ^Ro .

Embodiment 26 is the compound of any one of Embodiments 1-24 wherein ^Rx is H or methyl.

Embodiment 27 is the compound of any one of embodiments 1 to 24, wherein R ^y is C _1-4 alkyl, -OC _1-4 alkyl, -SO ₂ -C _1-4 alkyl, C _1-4 Alkyl-SO ₂ -R ^r , cycloalkyl, -C _1-4 alkyl(cycloalkyl), heterocyclyl, -O-heterocyclyl, each optionally substituted by 1 to 3 R ^o replace.

Embodiment 28 is the compound of any one of embodiments 1 to 24, wherein R ^y is C _1-4 alkyl optionally substituted with one, two or three R ^o substituents.

Embodiment 29 is the compound of any one of embodiments 1 to 24, wherein ^Ry is methyl, ethyl, propyl or isopropyl, each optionally substituted by one, two or three ^R substituents .

Embodiment 30 is a compound as any one of embodiments 1 to 24, wherein ^Ry is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropyl, (dimethylamino) Ethyl or (dimethylamino)butyl.

Embodiment 31 is the compound of any one of Embodiments 1-24 wherein ^Ry is methoxy.

Embodiment 32 is the compound of any one of embodiments 1 to 24, wherein ^Ry is _-SO2 -methyl.

Embodiment 33 is a compound as in any one of embodiments 1 to 24, wherein R ^y is cycloalkyl or -C _1-2 alkyl (cycloalkyl), each optionally passed through one, two or three R ^o Substituent substitution.

Embodiment 34 is the compound of any one of embodiments 1 to 24, wherein R ^y is monocyclic cycloalkyl optionally substituted with one, two or three R ^o substituents.

Embodiment 35 is the compound of any one of embodiments 1 to 24, wherein R ^y is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted by one, two or three R ^o base substitution.

Embodiment 36 is a compound as any one of embodiments 1 to 24, wherein ^Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropyl ethyl, cyclobutylmethyl or cyclopentylmethyl.

Embodiment 37 is the compound of any one of embodiments 1 to 24, wherein ^Ry is heterocyclyl or -O-heterocyclyl optionally substituted with one, two, or three R ^o substituents.

Embodiment 38 is the compound of any one of embodiments 1 to 24, wherein ^Ry is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, Linyl, piperyl or oxetanyloxy, each optionally substituted with one, two or three R ^o substituents.

Embodiment 39 is the compound of any one of Embodiments 1 to 24, wherein ^Rx is H and ^Ry is methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopentyl.

Embodiment 40 is the compound of any one of Embodiments 1-24 wherein ^Rx is H and ^Ry is isopropyl.

Embodiment 41 is the compound of any one of embodiments 1 to 24, wherein R ^x and R ^y together with the nitrogen to which they are attached form an optionally C _1-4 alkyl substituted heterocyclyl.

Embodiment 42 is a compound of any one of embodiments 1 to 24, wherein R ^x and R ^y together with the nitrogen to which they are attached form an optionally C _1-4 alkyl substituted heterocycloalkyl.

Embodiment 43 is the compound of any one of embodiments 1 to 24 wherein R ^x and R ^y together with the nitrogen to which they are attached form an optionally methyl substituted monocyclic heterocyclyl.

Embodiment 44 is the compound of any one of embodiments 1 to 24, wherein R ^x and R ^y together form the nitrogen to which they are attached azetidinyl, pyrrolidinyl, piperidinyl, piperoxyl, oxalinyl , thio-l-azaspiro[3.3]heptyl, 6-oxa-1-azaspiro[3.3]heptyl, or 2-oxa-6-azaspiro[3.3]heptyl, each of which is optionally substituted with methyl.

Embodiment 45 is the compound of any one of embodiments 1 to 44, wherein each R ^o substituent is independently C _1-4 alkyl, -OH, -OC _1-4 alkyl or -NR ^p R ^q .

Embodiment 46 is the compound of any one of embodiments 1 to 44, wherein each R ^o substituent is C _1-4 alkyl.

Embodiment 47 is the compound of any one of embodiments 1 to 44, wherein each R ^o substituent is -OH.

Embodiment 48 is the compound of any one of Embodiments 1 to 44, wherein each R ^o substituent is -NR ^p R ^q .

Embodiment 49 is the compound of any one of embodiments 1-48, wherein ^Rp and ^Rq are each independently H or methyl.

Embodiment 50 is a compound of any one of embodiments 1 to 48, wherein ^Rp and ^Rq together with the nitrogen to which they are attached form a heterocyclyl.

Embodiment 51 is the compound of any one of embodiments 1 to 48, wherein R ^p and R ^q together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperhexyl, oxalinyl , Thio-thiolinyl 6-oxa-1-azaspiro[3.3]heptyl or 2-oxa-6-azaspiro[3.3]heptyl.

Embodiment 52 is the compound of any one of Embodiments 1 to 51, wherein R ⁵ is H, methyl, ethyl, propyl, Cl, Br, or -OH.

Embodiment 53 is a compound of any one of Embodiments 1-51 wherein R ⁵ is H or methyl.

Embodiment 54 is a compound of any one of Embodiments 1-51 wherein R ⁵ is H.

Embodiment 55 is a compound selected from Table 1 and/or a pharmaceutically acceptable salt thereof.

Embodiment 56 is the compound of any one of Embodiments 1 to 55, wherein one or more hydrogen atoms attached to a carbon atom of the compound are replaced with a deuterium atom.

Embodiment 57 is a pharmaceutical composition, which comprises the compound and/or pharmaceutically acceptable salt or prodrug of any one of Embodiments 1 to 56 and pharmaceutically acceptable excipients.

Embodiment 58 is a method of inhibiting PIKfyve kinase in an individual in need thereof, comprising administering to the individual an effective amount of the compound of any one of embodiments 1-56 or the pharmaceutical composition of embodiment 57.

Embodiment 59 is a method of treating a neurological disease associated with PIKfyve activity in an individual in need thereof, comprising administering to the individual an effective amount of the compound of any one of embodiments 1 to 56 or the pharmaceutical combination of embodiment 57 thing.

Embodiment 60 is the method of embodiment 59, wherein the disease is associated with PIKfyve activity.

Embodiment 61 is the method of embodiment 59, wherein the disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charmadoux disease (CMT; including type 4J (CMT4J)) and Uris-Valen syndrome, autophagy, polymicrogyria (including polymicrogyria with seizures), temporal-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease Lewy body disease, Lewy body dementia, Lewy body disease, frontotemporal dementia, polyglutamine and neuronal endosome disease, Marris and Hirano body disease, tauopathies, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic Brain Injury (TBI), Cerebral Ischemia, Guillain-Barr Syndrome, Chronic Inflammatory Demyelinating Polyneuropathy, Multiple Sclerosis, Cytolytic Storage Disease, Fabry Disease, Gaucher Disease, Niemann-Pick type C disease, Tay-Sachs disease and mucolipidosis type IV, neuropathy, Huntington's disease, psychosis, ADHD, schizophrenia, mood disorders, major depressive disorder, depression, bipolar disorder I type or bipolar disorder type II.

Embodiment 62 is the method of embodiment 59, wherein the disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease or CMT.

Embodiment 63 is the method of embodiment 59, wherein the disease is ALS.

Embodiment 64 is the method of embodiment 59, wherein the disease is a tauopathy, such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy .

Embodiment 65 is the method of embodiment 59, wherein the disease is a lysosomal storage disease, such as Fabry disease, Gaucher disease, Niemann-Pick type C disease, Tay-Sachs disease, or type IV Mucolipidosis.

Embodiment 66 is the method of embodiment 59, wherein the disorder is a psychiatric disorder, such as ADHD, schizophrenia, or a mood disorder, such as major depressive disorder, depression, bipolar disorder I or bipolar disorder II.

Embodiment 67 is a compound of any one of embodiments 1 to 56 for use as a medicament.

Embodiment 68 is the compound of embodiment 67, wherein the compound is for use in the treatment of a neurological disease treatable by inhibiting PIKfyve kinase.

Embodiment 69 is the use of a compound according to any one of embodiments 1 to 56 for the manufacture of a medicament for treating a disease in an individual in which PIKfyve causes lesions and/or symptoms of the disease.

Cross References to Related Applications

This application claims priority to U.S. Provisional Application No. 63/195,237, filed June 1, 2021, the disclosure of which is hereby incorporated by reference in its entirety.

Unless otherwise stated, the following terms used in the specification and claims are defined for the purpose of the present invention and have the following meanings.

A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O) _NH2 is attached through a carbon atom. A dash at the front or end of a chemical group is for convenience; a chemical group may be depicted with or without one or more dashes without loss of its ordinary meaning. A wavy or dashed line drawn across a line in a formula indicates a designated point of attachment for a group. Unless chemically or structurally required, the order in which chemical groups are written or presented does not indicate or imply directionality or stereochemistry.

The prefix "C _uv " indicates that the following group has u to v carbon atoms. For example, "C _1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter per se. In certain embodiments, the term "about" includes ±10% of the indicated amount. In certain embodiments, the term "about" includes ±5% of the indicated amount. In certain embodiments, the term "about" includes ±1% of the indicated amount. Additionally, the term "about X" includes descriptions of "X". Further, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "analysis" includes reference to one or more assays known to those skilled in the art and equivalents thereof.

"Alkyl" means a straight-chain saturated monovalent hydrocarbon group with one to six carbon atoms or a branched saturated monovalent hydrocarbon group with three to six carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms) and the like. C _1-x alkyl refers to an alkyl group having 1 to x carbon atoms.

Unless otherwise specified, "alkylene" means a straight chain saturated divalent hydrocarbon group of one to six carbon atoms or a branched chain saturated divalent hydrocarbon group of three to six carbon atoms, such as methylene, ethylene, alkene, Propyl, 1-methylpropylenyl, 2-methylpropylenyl, butyl, pentylene and the like.

"Aryl" refers to an aromatic carbocyclic group having a single ring (eg, monocyclic ring) or multiple rings (eg, bicyclic or tricyclic rings), including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (ie, C _6-20 aryl), 6 to 18 carbon ring atoms (ie, C _6-18 aryl), 6 to 12 carbon ring atoms (ie C _6-12 aryl) or 6 to 10 carbon ring atoms (ie C _6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fenyl and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused to a heterocyclyl group, the resulting ring system is a heterocyclyl group.

"Amino" means -NH ₂ .

"Alkoxy" means an -OR group wherein R is alkyl as defined above, for example methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy group or tertiary butoxy group and similar groups.

"Cycloalkyl" means a cyclic saturated monovalent hydrocarbon group of three to ten carbon atoms, one or two of which may be replaced by a pendant oxy group; for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and its similar groups. C _xy cycloalkyl refers to a cycloalkyl group having x to y carbon atoms in the ring, where x and y are integers.

"Carboxy" means -COOH.

"Halo" means fluorine, chlorine, bromine or iodine; in one embodiment it means fluorine or chlorine.

"Haloalkyl" means an alkyl group as defined above substituted with one or one to five halogen atoms (in one embodiment, fluorine or chlorine), including those substituted with different halogens, for example -CH ₂ Cl, -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -CF ₂ CF ₃ , -CF(CH ₃ ) ₂ and the like. In C _xy haloalkyl, "C _xy " means that the number of carbon atoms in the alkyl ranges from x to y. When an alkyl group is substituted only with fluoro groups, it may be referred to as a fluoroalkyl group in the present invention.

"Heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic group (fused or bridged) of 4 to 10 ring atoms, one or two of which are selected from N, O and S (O) A heteroatom of _n , wherein n is an integer from 0 to 2, and the remaining ring atoms are C. Additionally, one or both ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically, the term heterocyclyl includes, but is not limited to, oxetanyl, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, N-𠰌-olinyl, piper-𠯤-yl, tetrahydropyranyl, N-thio-𠰌-linyl, hexahydropyrrolo[1,2-a]pyrrolo[1,2-a]pyrrolo-6(2H)-one-yl, tetrahydro- 1H-azolo[3,4-a]pyr-3(5H)-one-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a] pyryr-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl and the like. When a heterocyclyl ring is unsaturated, it may contain one or two ring double bonds, provided that the ring is not aromatic. C _xy heterocyclyl refers to a heterocyclyl having x to y carbon atoms in the ring, where x and y are integers.

"Heterocyclylalkyl" and "heterocycloalkyl" mean a -(alkylene)-R group wherein R is a heterocyclyl ring as defined above, for example tetrahydrofuranylmethyl, piperoxymethyl group, 𠰌linylethyl group and similar groups.

"Heteroaryl" means a monovalent monocyclic or bicyclic aryl group of 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two or three) ring atoms are selected from N, O and heteroatoms of S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl , quinolinyl, isoquinolyl, pyridyl, pyrimidyl, pyridyl, pyridyl, triazolyl, tetrazolyl, pyrazolopyridyl, indazolyl, fluoropyrimidinyl and similar groups . C _xy heteroaryl refers to a heteroaryl group having x to y carbon atoms, where x and y are integers.

"Mammal" as used herein means domesticated animals (such as dogs, cats, and horses) and humans. In one embodiment, the mammal is a human.

The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like. Organic acids from which salts can be derived include, for example, acetic, propionic, glycolic, pyruvic, oxalic, maleic, malonic, succinic, fumaric, tartaric, citric, benzoic, Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and similar acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, in particular such as iso Propylamine, Trimethylamine, Diethylamine, Triethylamine, Tripropylamine, and Ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium and magnesium salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences , 17th Edition, Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference.

"Pendant oxy" means a =(O) group and "carbonyl" means a >C(O) group.

"Conditioning" or "contingent" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that an alkyl group may but need not be present, and the description includes cases where the heterocyclyl is substituted with an alkyl group and cases where the heterocyclyl is not substituted with an alkyl group .

The phrases "parenteral administration and administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually injection, and include but are not limited to intravenous, intramuscular, Intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

The phrase "pharmaceutically acceptable" is used herein to mean, within the scope of sound medical judgment, suitable for contact with human and animal tissues without undue toxicity, irritation, allergic reaction or other problem or complication, and reasonably consistent with reasonable medical judgment. Those compounds, materials, compositions and/or dosage forms with matching benefit/risk ratio.

The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler , diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives , such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin Alcohols, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution (19) ethanol; (20) phosphate buffered saline; 21) Other non-toxic compatible substances used in pharmaceutical preparations.

"Treating or treatment" of a disease includes: (1) prevention of disease, such as preventing clinical symptoms of disease from developing in mammals that may be exposed to or susceptible to disease but have not yet experienced or exhibited symptoms of disease; (2) Inhibiting the disease, such as arresting or reducing the development of the disease or its clinical symptoms; or (3) Alleviating the disease, such as regressing the disease or its clinical symptoms.

"Therapeutically effective amount" means an amount of a compound of formula (I) (or any of its embodiments described herein) sufficient to treat a disease when administered to a mammal for that disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

In some cases, compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms. Unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, racemic forms in the individual forms and mixtures thereof are within the scope of the invention. Compounds of the invention containing asymmetrically substituted atoms may be isolated in optically active, optically enriched, optically pure or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of the species. Separation of stereoisomers can be performed by chromatography or by formation of diastereomers and separation by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, the disclosure of which is incorporated herein by reference). Stereoisomers may also be obtained by stereoselective synthesis.

Certain compounds of formula (I) (or any of its embodiments described herein) and/or pharmaceutically acceptable salts or prodrugs thereof may be in the form of tautomers and/or geometric isomers exist. All possible tautomers and cis and trans isomers, both in individual forms and in mixtures thereof, are within the scope of the present invention. For example, the pyrazole tautomers shown below are equivalent structures. A description of one such structure is intended to cover both structures.

Additionally, as used herein, the term alkyl includes all possible isomeric forms of the alkyl group, although only a few examples are set forth. Furthermore, when a cyclic group such as heteroaryl, heterocyclyl is substituted, it includes all positional isomers.

Pharmaceutically acceptable salts of compounds of formula (I) (or any of its embodiments described herein) are within the scope of this invention. In addition, the compounds described herein include hydrates and solvates of the compounds or pharmaceutically acceptable salts thereof.

The present invention also includes prodrugs of compounds of formula (I) (or any of its embodiments described herein) and/or pharmaceutically acceptable salts or prodrugs thereof. The term prodrug is intended to mean a covalently bonded carrier capable of releasing the active ingredient of formula (I) (or any of the embodiments thereof described herein) when administered to a mammalian subject. Release of the active ingredient occurs in vivo. Prodrugs can be prepared by techniques known to those skilled in the art. These techniques generally modify appropriate functional groups in a given compound. However, such modifying functional groups regenerate the original functional groups in vivo or by conventional manipulations. Prodrugs of compounds of formula (I) (or any of its embodiments described herein) include compounds in which the hydroxyl, amine, carboxyl or similar groups have been modified. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g. , N, N -dimethylaminocarbonyl) or phosphonate (e.g. -OP(=O)(OH) ₂ ), amides (e.g. trifluoroacetylamino, acetamido and the like) and the like analog. Prodrugs of compounds of formula (I) (or any of its embodiments described herein) and/or pharmaceutically acceptable salts or prodrugs thereof are also within the scope of the present invention.

The present invention also includes polymorphic forms (amorphous and crystalline) of the compound of formula (I) (or any of its embodiments described herein) and/or pharmaceutically acceptable salts or prodrugs thereof and deuterated form.

In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, eg, enriched in ² H, ³ H, ¹¹ C, ¹³ C, and/or ¹⁴ C. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in US Patent Nos. 5,846,514 and 6,334,997. As described in US Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and/or efficacy, thus increasing the duration of drug action.

Unless otherwise stated, structures depicted herein are intended to include compounds differing only by the presence of one or more isotopically enriched atoms. For example, compounds having structures of the invention except for replacement of a hydrogen by deuterium or tritium or replacement of a carbon by ^{a13C or14C} enriched carbon are within the scope of the invention.

The compounds of the present invention optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, compounds may be labeled with isotopes such as deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). ² H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ O, ¹⁷ O, ¹⁴ F, ¹⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, and ¹²⁵ I isotopic substitutions are all considered. All isotopic variations of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.

In certain embodiments, some or all of the ¹ H atoms of the compounds disclosed herein are replaced with ² H atoms. Methods of synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting examples only, the following synthetic methods.

Deuterium-substituted compounds were synthesized using various methods such as those described in: Dean, Dennis C. eds. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Published in: Curr., Pharm. Des ., 2000; 6(10)] 2000, p. 110; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, Evans, E . Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

Deuterated starting materials are readily available and subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

其中 Y ¹為N或C-R ¹； Y ²為N或C-R ²； X為N或CH； 其限制條件為當Y ¹為N時，Y ²為C-R ²，且當Y ²為N時，Y ¹為C-R ¹； R ¹為H或各自視情況經1至3個R ^s取代之C _3-8芳基、C _3-8雜芳基、C _3-8環烷基或C _3-8雜環基； R ²為H或各自視情況經1至3個R ^s取代之C _3-8芳基、C _3-8雜芳基、C _3-8環烷基或C _3-8雜環基； R ⁴為各自視情況經1至3個R ^s取代之C _3-8芳基、C _3-8雜芳基、C _3-8環烷基或C _3-8雜環基，或-C(O)NR ^xR ^y； R ^s為H、鹵基、胺基、OH、OC _1-6烷基、C _1-6烷基、C _1-6伸烷基-OH或C _1-6伸烷基-NR ^pR ^q； R ^x為H或視情況經R ^o取代之C _1-4烷基； R ^y為H、各自視情況經1至3個R ^o取代基取代之C _1-4烷基、-O-C _1-4烷基、-SO ₂-C _1-4烷基、C _{1- 4}烷基-SO ₂-R ^r、環烷基、-C _1-4伸烷基-環烷基、雜環基或-O-雜環基；或R ^x及R ^y與其所連接之氮一起形成視情況經C _1-4烷基取代之雜環基； 各R ^r為C _1-4烷基或-NR ^pR ^q； 各R ^o取代基獨立地為C _1-4烷基、-OH、-OC _1-4烷基、鹵基、氰基或-NR ^pR ^q； R ^p及R ^q各獨立地為H或C _1-4烷基；或R ^p及R ^q與其所連接之氮一起形成雜環基； R ⁵為H、C _1-6烷基、鹵基、-OH或-OC _1-6烷基。 One aspect is a compound of formula (I):

Wherein Y ¹ is N or CR ¹ ; Y ² is N or CR ² ; X is N or CH; the restriction is that when Y ¹ is N, Y ² is CR ² , and when Y ² is N, Y ¹ Is CR ¹ ; R ¹ is H or C _3-8 aryl, C _3-8 heteroaryl, C _3-8 cycloalkyl or C _3-8 heterocycle substituted by 1 to 3 R ^s as appropriate R ² is H or C _3-8 aryl, C _3-8 heteroaryl, C _3-8 cycloalkyl or C _3-8 heterocyclyl substituted by 1 to 3 R ^s as appropriate; R ⁴ is C _3-8 aryl, C 3-8 heteroaryl, C _3-8 cycloalkyl or C _3-8 heterocyclyl, each optionally substituted by ₁ to 3 R ^s , or -C( O) NR ^x R ^y ; R ^s is H, halogen, amino, OH, OC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkylene-OH or C _1-6 alkylene -NR ^p R ^q ; R ^x is H or C _1-4 alkyl optionally substituted by R ^o ; R ^y is H, C _1-4 alkane each optionally substituted by 1 to 3 R ^o substituents radical, _{-OC 1-4} alkyl, -SO ₂ -C _1-4 alkyl, C _1-4 alkyl-SO ₂ -R ^r , cycloalkyl, -C _1-4 alkylene-cycloalkyl , heterocyclyl or -O-heterocyclyl; or R ^x and R ^y together with the nitrogen to which they are attached form a heterocyclyl optionally substituted by C _1-4 alkyl; each R ^r is C _1-4 alkyl Or -NR ^p R ^q ; Each R ^o substituent is independently C _1-4 alkyl, -OH, -OC _1-4 alkyl, halo, cyano or -NR ^p R ^q ; R ^p and R ^q Each is independently H or C _1-4 alkyl; or R ^p and R ^q form a heterocyclic group together with the nitrogen to which they are attached; R ⁵ is H, C _1-6 alkyl, halo, -OH or -OC _1-6 alkyl.

In some embodiments, Y ¹ is N and Y ² is CR ² . In some embodiments, Y ² is N and Y ¹ is CR ¹ . In some embodiments, Y ¹ is CR ¹ and Y ² is CR ² . In some embodiments, Y ¹ is CR ¹ and Y ² is CR ² , and one of R ¹ and R ² is not H.

In some embodiments, X is N. In some embodiments, X is N, and one of ^Y1 and ^Y2 is N. In some embodiments, X is N, Y ¹ is CR ¹ , and Y ² is CR ² . In some embodiments, X is N, Y ¹ is CR ¹ , and Y ² is CR ² , and one of R ¹ and R ² is not H. In some embodiments, X is CH. In some embodiments, X is CH, and ^one of Y and ^Y is N. In some embodiments, X is CH, and ^Y1 and ^Y2 are N.

In some embodiments, Y ¹ is CR ¹ , and R ¹ is H, or phenyl or C _3-8 heteroaryl, each optionally substituted with 1 to 3 R ^s . In some embodiments, ^R is phenyl or pyridyl, pyrimidinyl or pyrazolyl, each optionally substituted with 1 or 2 ^Rs . In some embodiments, R ¹ is phenyl or pyridyl or pyrazolyl, each optionally substituted with 1 R ^s .

In some embodiments, Y ² is CR ² , and R ² is H, or phenyl or C _3-8 heteroaryl, each optionally substituted with 1 to 3 R ^s . In some embodiments, R ^is phenyl or pyridyl, pyrimidinyl or pyrazolyl, each optionally substituted with 1 or 2 ^Rs . In some embodiments, R ² is phenyl, pyridyl, or pyrazolyl, each optionally substituted with 1 R ^s .

In some embodiments, R ⁴ is C _3-8 aryl, _C 3-8 heteroaryl, C _3-8 cycloalkyl, C _3-8 heterocyclyl, C _1-4 alkyl, C _{1- 4} alkyl P(O))(OR ^x ) ₂ , C _1-4 alkylene-C _3-8 aryl, C _1-4 alkylene-C _3-8 heteroaryl, C _1-4 alkylene Alkyl-C _3-8 cycloalkyl or C _1-4 alkylene-C _3-8 heterocyclyl, each optionally substituted by 1 to 3 R ^s , or R ⁴ is C(O)R ^y , -C(O)NR ^x R ^y , NR ^x C(O)R ^y , C _1-4 alkylNR ^x C(O)R ^y or C(O)C _1-4 alkylene-NR ^x C( O) R ^y . In some embodiments, ^R4 is phenyl, pyridyl, pyrimidinyl, or pyrazolyl, each optionally substituted with 1 to 2 ^Rs . In some embodiments, ^R4 is phenyl, pyridyl, or pyrazolyl, each optionally substituted with 1 ^Rs .

In some embodiments, R ^is pyrazolylmethyl, imidazolylmethyl, N-alphalinylmethyl, piperidinylmethyl, diazolylmethyl, diazolylethyl, Alkylethylenyl, diazanylpropyl, diazanylpropylenyl, cyclohexenyl, cyclopentenyl, dihydropyridyl, each optionally substituted with 1 to 2 ^Rs .

In some embodiments, R ⁴ is C(O)R ^y , -C(O)NR ^x R ^y , NR ^x C(O)R ^y , C _1-4 alkyl NR ^x C(O)R ^y or C(O)C _1-4 alkyl NR ^x C(O)R ^y . In some embodiments, R ⁴ is -C(O)NR ^x R ^y .

In some embodiments, R ^s is H, F, Cl, Br, NH ₂ , OH, OC _1-6 alkyl, or C _1-6 alkyl. In some embodiments, R ^s is OC _1-4 alkyl or C _1-4 alkyl. In some embodiments, R ^s is H, Cl, OH, _methyl , ethyl, propyl, methylene-OH, ethylidene-OH, propylidene-OH, methylene-N(CH ) ₂ , ethylidene-N(CH ₃ ) ₂ , propylidene-N(CH ₃ ) ₂ . In some embodiments, R ^s is H or methyl.

In some embodiments, R ^x is H, or methyl or ethyl optionally substituted with one R ^o . In some embodiments, ^Rx is H or methyl.

In some embodiments, R ^y is C _1-4 alkyl, -OC _1-4 alkyl, -SO ₂ -C _1-4 alkyl, C _1-4 alkyl-SO ₂ -R ^r , cycloalkane radical, -C _1-4 alkyl(cycloalkyl), heterocyclyl, -O-heterocyclyl, each of which is optionally substituted with 1 to 3 ^R substituents. In some embodiments, R ^y is C _1-4 alkyl optionally substituted with one, two, or three R ^o substituents. In some embodiments, ^Ry is methyl, ethyl, propyl, or isopropyl, each of which is optionally substituted with one, two, or three ^Ro substituents. In some embodiments, ^Ry is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropyl, (dimethylamino)ethyl, or (dimethylamino)butyl base. In some embodiments, ^Ry is methoxy. In some embodiments, ^Ry is _-SO2 -methyl. In some embodiments, R ^y is C _1-4 alkyl-R ^r , C _1-4 alkyl, -OC _1-4 alkyl, -SO ₂ -C _1-4 alkyl, C _1-4 alkane -SO ₂ -R ^r , cycloalkyl, (C _1-4 alkyl) cycloalkyl, heterocyclyl, (C _1-4 alkyl) heterocyclyl, O-heterocyclyl, C _3-8 Aryl, (C _1-4 alkyl) C _3-8 aryl, C _3-8 heteroaryl, (C _1-4 alkyl) C _3-8 heteroaryl, each of which is optionally modified by 1 to 3 R ^o substituents are substituted.

In some embodiments, R ^y is cycloalkyl or (C _1-4 alkyl) monocyclic cycloalkyl or -C _1-2 alkyl (cycloalkyl), each of which is optionally modified by one, two or Substituted by three R ^o substituents. In some embodiments, ^Ry is a monocyclic cycloalkyl optionally substituted with one, two, or three ^Ro substituents. In some embodiments, ^Ry is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, cyclohexenyl, or cyclopentenyl, each optionally substituted by one, two, or three ^R replace. In some embodiments, ^Ry is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentyl Methyl, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, cyclohexenylpropyl or cyclopentenylpropyl.

In some embodiments, R ^y is heterocyclyl or -O-heterocyclyl, optionally substituted with one, two, or three R ^o substituents. In some embodiments, Ry ^is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, oxalinyl, piperyl, dioxanyl , pyrazolyl, dihydropyridyl or oxetanyloxy, each of which is optionally substituted with one, two or three R ^o substituents.

In some embodiments, Ry ^is tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, oxetanylmethyl Base, piperylmethyl, dioxanylmethyl, pyrazolylmethyl, dihydropyridylmethyl or oxetanyloxymethyl, tetrahydrofurylpropyl, tetrahydropyranylpropyl , oxetanyl propyl, azetidinyl propyl, pyrrolidinyl propyl, piperidinyl propyl, 𠰌linyl propyl, piper 𠯤 propyl, dioxanyl propyl, pyrazole oxypropyl, dihydropyridylpropyl or oxetanyloxypropyl, each of which is optionally substituted with one, two or three R ^o substituents.

In some embodiments, ^Rx is H and ^Ry is methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopentyl. In some embodiments, ^Rx is H and ^Ry is isopropyl.

In some embodiments, R ^x and R ^y together with the nitrogen to which they are attached form an optionally C _1-4 alkyl substituted heterocyclyl. In some embodiments, R ^x and R ^y together with the nitrogen to which they are attached form an optionally C _1-4 alkyl substituted heterocycloalkyl. In some embodiments, ^Rx and ^Ry together with the nitrogen to which they are attached form an optionally methyl substituted monocyclic heterocyclyl. In some embodiments, R ^x and R ^y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperolyl, stanolyl, thiolnyl, 6-oxa - 1-azaspiro[3.3]heptyl or 2-oxa-6-azaspiro[3.3]heptyl, each of which is optionally substituted with methyl.

In some embodiments, each R ^r is C _1-4 alkyl or -NR ^p R ^q . In some embodiments, R ^r is methyl, ethyl, propyl, or isopropyl or -NR ^p R ^q .

In some embodiments, each R ^o substituent is independently C _1-4 alkyl, -OH, -OC _1-4 alkyl, or -NR ^p R ^q . In some embodiments, each R ^o substituent is C _1-4 alkyl. In some embodiments, each R ^o substituent is -OH. In some embodiments, each R ^o substituent is -NR ^p R ^q .

In some embodiments, R ^p and R ^q are each independently H or methyl.

In some embodiments, ^Rp and ^Rq together with the nitrogen to which they are attached form a heterocyclyl. In some embodiments, R ^p and R ^q are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperolyl, sulphuryl, thiolnyl 6-oxa- 1-azaspiro[3.3]heptyl or 2-oxa-6-azaspiro[3.3]heptyl.

In some embodiments, ^R5 is H, methyl, ethyl, propyl, Cl, Br, or -OH. In some embodiments, R ⁵ is H or methyl.

其中一或多個連接至化合物之碳原子的氫原子經氘原子置換。 In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I) as defined herein:

wherein one or more of the hydrogen atoms attached to the carbon atoms of the compound is replaced by a deuterium atom.

In some embodiments, one or more hydrogen atoms attached to carbon atoms of R ¹ , R ² , R ⁴ and/or R ⁵ are replaced with deuterium atoms.

In some embodiments, one or more hydrogen atoms attached to carbon atoms of R ^o , R ^s , R ^p , R ^q , R ^r , R ^x and/or R ^y are replaced with deuterium atoms.

In some embodiments, one or more hydrogen atoms of one or more _{Ci_4} alkyl groups attached to a carbon atom are replaced with a deuterium atom. In some embodiments, one or more hydrogen atoms attached to a carbon atom of one or more methyl groups are replaced with a deuterium atom.

4-[7-(1-甲基吡唑-3-基)-2-[3-(間甲苯基)吡唑-1-基]吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 2

4-[7-(1-甲基吡唑-3-基)-2-(3-苯基吡唑-1-基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 3

4-(7-(吡啶-3-基)-2-(3-(間甲苯基)-1H-吡唑-1-基)吡唑并[1,5-a][1,3,5]三𠯤-4-基)𠰌啉 4

4-[2-(3-苯基吡唑-1-基)-7-(3-吡啶基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 5

4-[2-[3-(3-甲氧基苯基)吡唑-1-基]-7-(3-甲基-1H-吡唑-5-基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 6

4-[2-[3-(3-甲氧基苯基)吡唑-1-基]-7-(3-吡啶基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 7

4-[2-[3-(間甲苯基)吡唑-1-基]-7-(4-吡啶基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 8

4-[7-(3-甲基-1H-吡唑-5-基)-2-[3-(間甲苯基)吡唑-1-基]吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 9

4-[2-[3-(3-甲氧基苯基)吡唑-1-基]-7-(1H-吡唑-4-基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 10

4-[2-[3-(3-甲氧基苯基)吡唑-1-基]-7-(4-吡啶基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 11

4-[2-[3-(間甲苯基)吡唑-1-基]-7-(1H-吡唑-4-基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 12

   N,N-二甲基-3-[4-[4-N-𠰌啉基-2-[3-(間甲苯基)吡唑-1-基]吡唑并[1,5-a][1,3,5]三𠯤-7-基]吡唑-1-基]丙-1-胺 13

3-[4-[2-[3-(3-甲氧基苯基)吡唑-1-基]-4-N-𠰌啉基-吡唑并[1,5-a][1,3,5]三𠯤-7-基]吡唑-1-基]-N,N-二甲基-丙-1-胺 14

3-[4-[4-N-𠰌啉基-2-[3-(間甲苯基)吡唑-1-基]吡唑并[1,5-a][1,3,5]三𠯤-7-基]吡唑-1-基]丙-1-醇 15

3-[4-[2-[3-(3-甲氧基苯基)吡唑-1-基]-4-N-𠰌啉基-吡唑并[1,5-a][1,3,5]三𠯤-7-基]吡唑-1-基]丙-1-醇 16

4-[2-[3-(3-甲氧基苯基)吡唑-1-基]-7-(2-吡啶基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 17

4-[2-[3-(間甲苯基)吡唑-1-基]-7-(2-吡啶基)吡唑并[1,5-a][1,3,5]三𠯤-4-基]𠰌啉 18

N-異丙基-4-N-𠰌啉基-2-(3-(間甲苯基)-1H-吡唑-1-基)吡唑并[1,5-a][1,3,5]三𠯤-7-甲醯胺 19

N-異丙基-4-N-𠰌啉基-2-(3-苯基-1H-吡唑-1-基)吡唑并[1,5-a][1,3,5]三𠯤-7-甲醯胺 及其醫藥學上可接受之鹽。 治療方法、投與及醫藥組合物 In some embodiments, compounds of formula (I) comprise -D instead of at least one -H, or _-CD3 substituents instead of at least one _CH3 . Table 1 compound structure name 1

4-[7-(1-methylpyrazol-3-yl)-2-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a][1,3, 5] Tri-𠯤-4-yl]𠰌line 2

4-[7-(1-methylpyrazol-3-yl)-2-(3-phenylpyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri 𠯤-4-yl]𠰌line 3

4-(7-(pyridin-3-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5] Tri-(-4-yl)-)- 4

4-[2-(3-Phenylpyrazol-1-yl)-7-(3-pyridyl)pyrazolo[1,5-a][1,3,5]tri-pyrazol-4-yl] 𠰌line 5

4-[2-[3-(3-methoxyphenyl)pyrazol-1-yl]-7-(3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5- a][1,3,5]tri-𠯤-4-yl]𠰌line 6

4-[2-[3-(3-methoxyphenyl)pyrazol-1-yl]-7-(3-pyridyl)pyrazolo[1,5-a][1,3,5] Tris𠯤-4-yl]𠰌line 7

4-[2-[3-(m-Tolyl)pyrazol-1-yl]-7-(4-pyridyl)pyrazolo[1,5-a][1,3,5]trimethanone-4 -yl]𠰌line 8

4-[7-(3-Methyl-1H-pyrazol-5-yl)-2-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a][1 ,3,5]tris𠯤-4-yl]𠰌line 9

4-[2-[3-(3-methoxyphenyl)pyrazol-1-yl]-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a][1, 3,5] Tris𠯤-4-yl]𠰌line 10

4-[2-[3-(3-methoxyphenyl)pyrazol-1-yl]-7-(4-pyridyl)pyrazolo[1,5-a][1,3,5] Tris𠯤-4-yl]𠰌line 11

4-[2-[3-(m-Tolyl)pyrazol-1-yl]-7-(1H-pyrazol-4-yl)pyrazolo[1,5-a][1,3,5] Tris𠯤-4-yl]𠰌line 12

N,N-Dimethyl-3-[4-[4-N-𠰌linyl-2-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a][ 1,3,5]tris-7-yl]pyrazol-1-yl]propan-1-amine 13

3-[4-[2-[3-(3-methoxyphenyl)pyrazol-1-yl]-4-N-𠰌linyl-pyrazolo[1,5-a][1,3 ,5] Tris-7-yl]pyrazol-1-yl]-N,N-dimethyl-propan-1-amine 14

3-[4-[4-N-𠰌linyl-2-[3-(m-tolyl)pyrazol-1-yl]pyrazolo[1,5-a][1,3,5]tri-𠯤 -7-yl]pyrazol-1-yl]propan-1-ol 15

3-[4-[2-[3-(3-methoxyphenyl)pyrazol-1-yl]-4-N-𠰌linyl-pyrazolo[1,5-a][1,3 ,5] Tris-7-yl] pyrazol-1-yl] propan-1-ol 16

4-[2-[3-(3-methoxyphenyl)pyrazol-1-yl]-7-(2-pyridyl)pyrazolo[1,5-a][1,3,5] Tris𠯤-4-yl]𠰌line 17

4-[2-[3-(m-Tolyl)pyrazol-1-yl]-7-(2-pyridyl)pyrazolo[1,5-a][1,3,5]tri-pyrazole-4 -yl]𠰌line 18

N-isopropyl-4-N-𠰌linyl-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5 ] Tris-7-formamide 19

N-isopropyl-4-N-𠰌linyl-2-(3-phenyl-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-𠯤 -7-formamide and pharmaceutically acceptable salts thereof. Methods of treatment, administration and pharmaceutical compositions

In general, compounds of the invention will be administered in therapeutically effective amounts by any acceptable mode of administration for agents that afford similar utility. A therapeutically effective amount of a compound of formula (I) may range from about 0.01 to about 500 mg per kilogram of patient body weight per day, which may be administered in single or multiple doses. In one embodiment, the dosage concentration will be from about 0.1 to about 250 mg/kg/day. In another embodiment, the dosage concentration will be from about 0.5 to about 100 mg/kg/day. Suitable dosage concentrations may be from about 0.01 to about 250 mg/kg/day, from about 0.05 to about 100 mg/kg/day, or from about 0.1 to about 50 mg/kg/day. Within this range, the dosage may be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg/kg/day. For oral administration, the composition may contain from about 1.0 to about 1000 mg of active ingredient, especially about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400 , 500, 600, 750, 800, 900 and 1000 mg active ingredient in tablet form. The actual amount of the compound of the invention (i.e., the active ingredient) will depend on many factors, such as the severity of the disease being treated, the age and relative health of the individual, the potency of the compound utilized, the route and form of administration, and other factors. .

In general, the compounds of the invention will be administered in the form of pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermally, intranasally, or via suppositories), or parenterally (e.g., intramuscularly). , intravenous or subcutaneous) administration. The preferred mode of administration is oral administration using an appropriate daily dosage regimen which can be adjusted according to the degree of affliction. The compositions may take the form of tablets, pills, capsules, semi-solids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

Pharmaceutical compositions can be formulated using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries. The formulation can be modified depending on the chosen route of administration. Pharmaceutical compositions can also include compounds described herein in free base form or in pharmaceutically acceptable salt or prodrug form.

Methods for formulating pharmaceutical compositions can include formulating any of the compounds described herein with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid combination thing. Solid compositions may include, for example, powders, lozenges, dispersible granules, and capsules, and in some aspects, solid compositions further contain nontoxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically useful substances. Additives are acceptable. Alternatively, the compositions described herein can be lyophilized or presented in powder form for reconstitution with a suitable vehicle, eg sterile pyrogen-free water, before use. The active ingredient can be encapsulated in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules, respectively), colloidal Drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions.

Pharmaceutical compositions and formulations can be sterilized. Sterilization can be achieved by filtration through sterile filtration.

The pharmaceutical compositions described herein can be formulated for administration as injections. Non-limiting examples of formulations for injection may include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension. The suspension may also contain suitable stabilizers. Injectable solutions can be formulated for bolus injection or continuous infusion.

For parenteral administration, the compounds may be formulated in unit dosage injectable forms (eg, solutions, suspensions, emulsions) in combination with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be non-toxic and non-therapeutic in nature. The vehicle can be water, normal saline, Ringer's solution, dextrose solution and 5% human serum albumin. Nonaqueous vehicles, such as fixed oils and ethyl oleate, can also be used. Liposomes can be used as carriers. The vehicle may contain minor amounts of additives such as substances which enhance isotonicity and chemical stability (eg buffers and preservatives).

Sustained release formulations may also be prepared. Examples of sustained release matrices may include polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol), polylactide, L-glutamic acid, and gamma ethyl - Copolymers of L-glutamate, non-degradable ethylene-vinyl acetate, such as LUPRON DEPO ^™ (ie, injectable microspheres composed of lactic-co-glycolic acid and leuprolide acetate ), and poly-D-(-)-3-hydroxybutyric acid.

Pharmaceutical formulations of the compositions described herein can be prepared for storage by mixing the compound with a pharmaceutically acceptable carrier, excipient and/or stabilizer. This formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients and/or stabilizers can be nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers, excipients, and/or stabilizers may include buffers, such as phosphoric acid, citric acid, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum white Protein or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or Sorbitol; a salt-forming counterion such as sodium; a metal complex; and/or a nonionic surfactant or polyethylene glycol.

The compounds of the present invention may be used in methods of combination therapy with one or more other combination agents (e.g., one, two or three other drugs) for preventing, treating, controlling, ameliorating or reducing the Risk of disease or condition. In some embodiments, the combination of drugs is safer or more effective than either drug alone. In some embodiments, a compound disclosed herein and one or more combination agents have complementary activities that do not deleteriously affect each other. Such molecules can be present in combination in amounts effective for the intended purpose. Such other drugs may be administered simultaneously or sequentially with the compounds of the invention by such usual routes and in such usual amounts. When a compound of the invention is used concomitantly with one or more other drugs, in some embodiments, the agents are administered together in unit dosage form in a single pharmaceutical composition. Accordingly, the pharmaceutical compositions of the present invention also include those pharmaceutical compositions which also contain one or more other active ingredients in addition to the compounds of the present invention. The weight ratio of the compound of the invention to the second active agent may vary and will depend on the effective dosage of each ingredient. In general, an effective dose of each will be used. In some embodiments, combination therapy includes therapy in which a compound of the invention and one or more other drugs are administered separately, and in some cases two or more agents are administered on different, overlapping time courses. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the invention and the other active ingredients may be used in lower dosages than when each is used alone. For example, the combination agents are anticancer agents such as alkylating agents, corticosteroids, platinums, purine analogs, antimetabolites or specific agents such as cyclophosphamide, chlorambucil, bendamustine, prednisone, dexamethasone, carboplatin, cisplatin, cladribine, fludarabine, Capecitabine, gemcitabine, methotrexate, pralatrexate, bleomycin, doxorubicin, vincristine ) or rituximab. In some embodiments, the combination agent is a drug for reducing symptoms of ALS. In some embodiments, the combination agent is selected from NAD supplements (such as nicotinamide riboside, available under the trade names Basis® or Tru Niagen®), vitamin _B12 (oral or injectable), glycopyrrolate ), atropine, scopolamine, baclofen, tizanidine, mexiletine, SSRIs, benzodiazepines, Neudexta , riluzole and edaravone, and combinations thereof.

The compounds, pharmaceutical compositions and methods of the invention may be suitable for use in the treatment of subjects such as, but not limited to, mammals, humans, non-human mammals, domesticated animals (e.g. laboratory animals, domestic pets or livestock), non-domesticated animals (e.g. wild animals), dogs, cats, rodents, mice, hamsters, cows, birds, chickens, fish, pigs, horses, goats, sheep or rabbits. In preferred embodiments, the compounds, pharmaceutical compositions and methods of the invention are used to treat humans.

The compounds, pharmaceutical compositions and methods described herein are useful as therapeutic agents, such as treatments that can be administered to a subject in need thereof. A therapeutic effect may be obtained in an individual by reducing, inhibiting, alleviating or eradicating a disease condition, including but not limited to its symptoms. A therapeutic effect in an individual suffering from a disease or condition or prone to developing or developing a disease or condition may be obtained by reducing, inhibiting, preventing, alleviating or eradicating the condition or disease or pre-condition or pre-disease condition.

In practicing the methods described herein, a therapeutically effective amount of a compound or pharmaceutical composition described herein can be administered to a subject in need thereof, generally for the treatment and/or prevention of the condition or progression thereof. Pharmaceutical compositions can affect the physiology of an individual, such as the immune system, inflammatory response, or other physiological effects. A therapeutically effective amount will vary depending on the severity of the disease, the age and relative health of the individual, the potency of the compound used and other factors.

Treat and/or treating may refer to any marker of success in treating or ameliorating a disease or condition. Treatment may include, for example, reducing, delaying, or lessening the severity of one or more symptoms of a disease or condition, or it may include reducing the frequency with which a patient experiences symptoms of a disease, defect, disorder, or adverse condition, and the like. Treatment may be used herein to refer to methods that result in some degree of treatment or alleviation of a disease or condition and may contemplate a range of outcomes leading to that end, including but not limited to complete prevention of the condition.

Prevent/preventing and the like can refer to preventing a disease or condition in a patient. For example, if an individual at risk of contracting a disease is treated with the methods of the invention and subsequently does not contract the disease, the disease is prevented in that individual, at least for a period of time.

A therapeutically effective amount may be that amount of the compound or pharmaceutical composition, or active ingredient thereof, sufficient to provide a beneficial effect to the individual to whom the composition is administered or otherwise reduce deleterious non-beneficial events. A therapeutically effective dose may be that dose which produces the desired or desired (eg, beneficial) effect of one or more doses administered, such administrations occurring one or more times within a given period of time. The exact dosage will depend on the purpose of the treatment and can be determined by one skilled in the art using known techniques.

The compounds or pharmaceutical compositions described herein that are useful in therapy may be consistent with good medical practice taking into account the condition to be treated, the condition of the individual patient, the site of delivery of the compound or pharmaceutical composition, the method of administration, and other factors known to practitioners. Doses are formulated and determined in a manner consistent with practice. A compound or pharmaceutical composition can be prepared according to the preparative descriptions described herein.

Those of ordinary skill in the art will appreciate that the amount, duration, and frequency of administering a pharmaceutical composition or compound described herein to an individual in need thereof will depend on a number of factors, including, for example, but not limited to, the individual's health status, the patient's particular disease or condition, the grade or extent of the patient's particular disease or condition, additional therapeutic agents that the individual is or has been administered, and the like.

The methods, compounds and pharmaceutical compositions described herein are useful for administration to individuals in need thereof. In general, administration of a compound or pharmaceutical composition may include a route of administration, non-limiting examples of which include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or peritoneal Inside. Additionally, a pharmaceutical composition or compound may be administered to a subject by additional routes of administration, for example, by inhalation, oral, transdermal, intranasal or intrathecal administration.

A pharmaceutical composition or compound of the invention can be administered to an individual in need thereof in a first administration and one or more additional administrations. One or more additional administrations can be administered to individuals in need minutes, hours, days, weeks or months after the first administration. Any of the additional administrations may be given to those in need less than 21 days, or less than 14 days, less than 10 days, less than 7 days, less than 4 days, or less than 1 day after the first administration. individual investment. The one or more administrations can occur more than once a day, more than once a week, or more than once a month. The compound or pharmaceutical composition can be administered daily to an individual in need thereof in cycles of 21 days, 14 days, 10 days, 7 days, 4 days or over a period of one to seven days.

The compounds, pharmaceutical compositions, and methods provided herein may be useful for treating a plurality of diseases or conditions or preventing a disease or condition in an individual, or for other therapeutic applications in an individual in need thereof. In one aspect, the invention relates to a method of inhibiting PIKfyve kinase in a subject in need thereof, comprising administering to the subject an effective amount of the compound. In one aspect, the invention relates to a method for treating a neurological disease mediated by PIKfyve activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutical composition as described herein. In some aspects, the disease is a neurological disease. In some embodiments, the disease is associated with FIG4 deficiency. In some embodiments is a method for treating an individual suffering from a neurological disease or disorder associated with PIKfyve kinase activity comprising administering to the individual an effective amount of a compound or pharmaceutical composition as described herein.

In some embodiments, the neurological disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charmadoux disease (CMT; including type 4J (CMT4J)), and especially Ries-Valen syndrome, autophagy, polymicrogyria (including polymicrogyria with seizures), temporal-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy syndrome, Dementia with Lewy bodies, Lewy body disease, frontotemporal lobe dementia, neuronal endosome disease of polyglutamine and intranuclear inclusion bodies, Marris and Hirano body disease, tauopathies, Az Haimer's disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain injury (TBI), Cerebral ischemia, Guillain-Barr syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, lysodermase, Fabry disease, Gaucher disease, Niemann-Pick C disease , Tay-Sachs disease and mucolipidosis type IV, neuropathy, Huntington's disease, psychosis, ADHD, schizophrenia, mood disorders, major depressive disorder, depression, bipolar disorder type I or bipolar disorder type II .

In some embodiments, the neurological disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease, or CMT. In some embodiments, the neurological disease is ALS.

In some embodiments, the neurological disease is a tauopathy, such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.

In some embodiments, the neurological disease is a lytic storage disease, such as Fabry's disease, Gaucher's disease, Niemann-Pick type C disease, Tay-Sachs disease, or mucolipidosis type IV.

In some embodiments, the neurological disorder is a psychiatric disorder, such as ADHD, schizophrenia, or a mood disorder, such as major depressive disorder, depression, bipolar I or bipolar II.

The invention further provides any of the compounds disclosed herein for use in a method of treatment of the human or animal body by therapy. Therapy can be by any of the mechanisms disclosed herein, such as inhibiting, reducing or reducing the progression of the diseases disclosed herein. The invention further provides any of the compounds disclosed herein for use in the prevention or treatment of any of the conditions disclosed herein. The invention also provides any compound disclosed herein, or a pharmaceutical composition thereof, for use in obtaining any of the clinical outcomes disclosed herein for any of the conditions disclosed herein. The invention also provides a use of any compound disclosed herein in the manufacture of a medicament for the prevention or treatment of any disease or condition disclosed herein. example

The following preparations of compounds of formula (I) and intermediates are provided to enable those skilled in the art to understand and practice the present invention more clearly. They should not be considered as limiting the scope of the invention, but only as illustrative and representative of the invention.

Starting materials and reagents used in the preparation of these compounds can be purchased from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis, Mo.); or Prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes illustrate only some of the ways in which the compounds of the invention can be synthesized, and various modifications to these schemes can be made and will be suggested by those skilled in the art in light of the disclosure. Starting materials and intermediates and final products of the reaction can be isolated and purified using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography and the like, as desired. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein are at atmospheric pressure in the temperature range of about -78°C to about 150°C or about 0°C to about 125°C or at about room (or ambient) temperature, for example about 20°C conduct.

Compounds of formula (I) and subformulas and species described herein, including those wherein substituents are as defined herein, can be prepared as illustrated and described hereinafter.

All reagents were used without further purification unless otherwise noted. ¹ H NMR spectra were acquired at room temperature on a Bruker 300 MHz instrument in CDCl ₃ , DMSO-d ₆ or CD ₃ OD. When more than one conformer was detected, the chemical shift of the most numerous conformer was reported. Chemical shifts for ¹ H NMR spectra are reported in parts per million (ppm) based on the delta scale from the internal standard of residual solvent. Splitting patterns were designed as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. LC-MS conditions are as described below:

LCMS column: Agilent Zorbax XDB C18 4.6×50 mm, 3.5 µm a. Mobile phase: Solvent A: water (containing 0.1% formic acid); solvent B: MeOH b. Flow rate: 1.0 mL/min, c. Run time: 2 min gradient (20%-90% B), followed by 3 min at 90% B, d. Temperature: 30℃

HPLC column: Agilent SB-C18 4.6×150 mm, 3.5 µm a. Mobile phase: Solvent A: Water (containing 0.02% TFA); Solvent B: MeOH b. Flow rate: 1.0 mL/min, c. Run time: 0.5 min at 10% B, 9.5 min gradient (10%-90% B), followed by 10 min at 90% B, d. Temperature: 30°C

Preparative LC column: Phenomenex Luna 5 μ 100A, 21.2×250 mm, 5 μm a. Mobile phase: Solvent A: Water; Solvent B: MeOH b. Flow rate: 10 mL/min, c. Run time: 1 min at 20% B, 30 min gradient (20%-80% B), followed by 10 min at 90% B, d. Temperature: ambient temperature

Use the following abbreviations in the text: abbreviation words DCM Dichloromethane DIBAL-H Diisobutylaluminum hydride DMF N, N-Dimethylformamide DMSO Dimethyridine dppf 1,1'-bis(diphenylphosphino)-ferrocene Et ₂ O diethyl ether EtOH ethanol EtOAc ethyl acetate h and hr Hour m-CPBA m-chloroperoxybenzoic acid MeOH Methanol min minute PE petroleum ether rt room temperature TFA Trifluoroacetate TLC TLC

general program 1

Compound 2 : 4-[7-(1- methylpyrazol -3- yl )-2-(3- phenylpyrazol -1- yl ) pyrazolo [1,5-a][1,3, 5] Tri- 𠯤 -4- yl ] 𠰌 line

Synthesis of 1-(3- bromo -1H- pyrazol -5- yl ) thiourea -3- ethyl formate

To a solution of 3-bromo-1H-pyrazol-5-amine (10 g, 62.12 mmol) in EtOAc (70 mL) and toluene (360 mL) was added isosulfuryl dropwise at 0 °C under _N2 O-ethyl carbonisothiocyanatidate (8.2 g, 62.12 mmol). After the addition, the mixture was stirred overnight at rt. A large amount of white solid precipitated out. After filtration, the filter cake was washed with _Et2O and dried to give 1-(3-bromo-1H-pyrazol-5-yl)thiourea-3-ethyl formate (13.3 g, 45.7 mmol) as a white solid . LC-MS (ESI+): m/z 292/294 (MH ⁺ ).

Synthesis of 7- Bromo -2- thione - 2,3- dihydropyrazolo [1,5-a][1,3,5] trimethan -4(1H) -one

To a solution of NaOH (8.2 g, 205 mmol) in water (100 mL) was added 1-(3-bromo-1H-pyrazol-5-yl)thiourea-3-ethyl formate (13.3 g, 45.7 mmol ). The mixture was stirred at rt for 1 h. The completion of the reaction was monitored by TLC. The reaction was quenched with water and the pH was adjusted to 4 using 2 _{NH2SO4 solution} . A large amount of white solid precipitated out. After filtration, the filter cake was washed with water and dried to give 7-bromo-2-thioxonyl-2,3-dihydropyrazolo[1,5-a][1,3,5]tris as a white solid 𠯤-4(1H)-one (12.6 g, 51.4 mmol). LC-MS (ESI+): m/z 247/249 (MH ⁺ ). ¹ HNMR (300 MHz, CD ₃ OD) δ 5.91 (s, 1H).

Synthesis of 7- bromo -2-( methylsulfanyl ) pyrazolo [1,5-a][1,3,5] tris - 4(3H) -one

To 7-bromo-2-thione-2,3-dihydropyrazolo[1,5-a][1,3,5]tri-4(1H)-one (11.5 g, 46.7 mmol) , NaOH (3.74 g, 93.5 mmol) in EtOH (250 mL) and H ₂ O (5 mL) was added CH ₃ I (8.23 g, 58.0 mmol) dropwise. The mixture was stirred at rt for 1 h. The completion of the reaction was monitored by TLC. To the mixture was added 40 mL of 1 N aqueous HCl and a large amount of white solid precipitated out. After filtration, the filter cake was washed with PE and dried to give 7-bromo-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]trimethan-4 as a white solid (3H)-Kone (10.5 g, 40.2 mmol). LC-MS (ESI+): m/z 261/263 (MH ⁺ ). ¹ HNMR (300 MHz, D ₂ O) δ 6.17 (s, 1H), 2.36 (s, 3H).

Synthesis of 7- bromo - 4- chloro -2-( methylsulfanyl ) pyrazolo [1,5-a][1,3,5] trimethanone

7-Bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]tris-4(3H)-one (9.4 g, 53.8 mmol) was dissolved in POCl ₃ ( 50 mL) of the solution was heated to 120°C overnight. The completion of the reaction was monitored by TLC. The reaction mixture was directly concentrated under reduced pressure to afford crude 7-bromo-4-chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]trimethanone, which was not subjected to further Purification was used directly in the next step.

Synthesis of 4-(7- bromo - 2-( methylsulfanyl ) pyrazolo [1,5-a][1,3,5] tri - 4- yl ) pyrazole

To the crude material 7-bromo-4-chloro-2-(methylsulfanyl)pyrazolo[1,5-a][1,3,5]trisulfone (6.0 g, 21.58 mmol) in 1,4- To a solution in dioxane (60 mL) was added phylloline (2.0 g, 23.1 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was directly concentrated and purified by silica gel column chromatography with gradient elution from 20% EtOAc/PE to 50% EtOAc/PE to give 4-(7-bromo-2-(methylsulfide) as a yellow solid yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)pyrazoline (4.6 g, 13.94 mmol). LC-MS (ESI+): m/z 330/332 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 6.23 (s, 1H), 4.43-4.24 (m, 4H), 3.88-3.82 (m, 4H), 2.52 (s, 3H).

Synthesis of 4-(7-(1- methyl - 1H- pyrazol -3- yl )-2-( methylthio ) pyrazolo [1,5-a][1,3,5 ] tri- 4- yl ) 𠰌 line

To 4-(7-bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]tri-(4-yl)-(460 mg, 1.39 mmol) in Add 1-methyl-3-( _4,4,5,5 -tetramethyl-1,3,2- Dioxaborolan-2-yl)-1H-pyrazole (350 mg, 1.67 mmol), K ₂ CO ₃ (575 mg, 4.17 mmol) and PdCl ₂ (PPh ₃ ) ₂ (102 mg, 0.14 mmol) . The reaction was stirred at 80 °C for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with DCM (2 x 20 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient elution from 10% EtOAc/PE to 30% EtOAc/PE to afford 4-(7-(1-methyl-1H-pyrazole-3 as a white solid -yl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]tri-(4-yl)-(174 mg, 0.53 mmol). LC-MS (ESI+): m/z 332 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.41 (d, J = 1.8 Hz, 1H), 6.69 (d, J = 1.8 Hz, 1H), 6.56 (s, 1H), 4.55-4.32 (m, 4H), 3.99 (s, 3H), 3.91-3.86 (m, 4H), 2.56 (s, 3H).

Synthesis of 4-(7-(1- methyl -1H- pyrazol -3- yl ) -2-( methylsulfonyl ) pyrazolo [1,5-a][1,3,5] trimethanone -4- yl ) 𠰌 line

To 4-(7-(1-methyl-1H-pyrazol-3-yl)-2-(methylthio)pyrazolo[1,5-a][1,3,5]three- To a solution of 4-yl) 𠰌line (200 mg, 0.60 mmol) in DCM (10 mL) was added m-CPBA (410 mg, 2.4 mmol). The mixture was stirred overnight at rt. The completion of the reaction was monitored by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 1% MeOH/DCM to 2% MeOH/DCM to give 4-(7-(1-methyl-1H-pyridine as a yellow solid Azol-3-yl)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)-(181 mg, 0.50 mmol). LC-MS (ESI+): m/z 365 (MH ⁺ ). ¹ HNMR (300 MHz, CD ₃ OD) δ 7.68 (d, J = 2.4 Hz, 1H), 6.92 (s, 1H), 6.81 (d, J = 2.4 Hz, 1H), 4.55-4.32 (m, 4H) , 3.98 (s, 3H), 3.89-3.84 (m, 4H), 3.31 (s, 3H).

Synthesis of 4-[7-(1- methylpyrazol -3- yl )-2-(3- phenylpyrazol -1- yl ) pyrazolo [1,5-a][1,3,5] Tris 𠯤 -4- yl ] 𠰌 line

To 4-(7-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]tri-pyrazole -4 _- yl ₎ ? 0.55 mmol) and Cu ₂ O (6 mg, 0.03 mmol). The reaction was stirred overnight at 110°C. The reaction mixture was quenched with water (10 mL). The aqueous solution was extracted with DCM (3 x 10 mL). The combined organic phases were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a gradient elution from 1% MeOH/DCM to 3% MeOH/DCM to afford 4-(7-(1-methyl-1H-pyrazole-3) as a white solid -yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-𠯤-4-yl)𠰌line (30 mg, 0.07 mmol). LC-MS (ESI+): m/z 428 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.55 (d, J = 2.1 Hz, 1H), 8.02-7.99 (m, 2H), 7.47-7.34 (m, 4H), 6.81 (d, J = 2.1 Hz, 2H), 6.73 (d, J = 2.1 Hz, 1H), 4.77-4.60 (m, 4H), 4.07 (s, 3H), 3.97-3.92 (m, 4H).

general program 2

Compound 3 : 4-(7-( pyridin -3- yl )-2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [1,5-a][1,3 ,5] Tri- 𠯤 -4- yl ) 𠰌 line

Synthesis of 4-(7- bromo - 2-( methylsulfonyl ) pyrazolo [1,5-a][1,3,5] tri - 4- yl ) pyrazoline

To 4-(7-bromo-2-(methylthio)pyrazolo[1,5-a][1,3,5]tri-(4-yl)-(1.61 g, 5.39 mmol) in To a solution in DCM (130 mL) was added m-CPBA (3.67 g, 21.5 mmol). The reaction mixture was stirred overnight at rt. The completion of the reaction was monitored by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with gradient elution from 20% EtOAc/PE to 50% EtOAc/PE to give 4-(7-bromo-2-(methylsulfonate) as a yellow solid Acyl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)pyrazoline (970 mg, 2.69 mmol). LC-MS (ESI+): m/z 362/364 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 6.67 (s, 1H), 4.86-4.68 (m, 2H), 4.20-4.05 (m, 2H), 3.92-3.86 (m, 4H), 3.31 (s, 3H) .

Synthesis of 4-(7- bromo -2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [ 1,5-a][1,3,5] trimethanone -4- base ) 𠰌 line

To 4-(7-bromo-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]tri-4-yl)pyrazole (800 mg, 2.20 mmol) To a solution in _CH3CN ( ₁₃₀ mL) was added _Cs2CO3 (3.67 g, 21.5 mmol) and 3-(m-tolyl)-1H-pyrazole (420 mg, 2.65 mmol). The reaction mixture was stirred overnight at 100 °C in a sealed tube. The completion of the reaction was monitored by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 20% EtOAc/PE to 50% EtOAc/PE to give 4-(7-bromo-2-(3-( m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)-pyrazole (150 mg, 0.34 mmol). LC-MS (ESI+): m/z 440/442 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 3.0 Hz, 1H), 7.86 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.35-7.30 (m, 1H) , 7.20-7.18 (m, 1H), 6.81 (d, J = 3.0 Hz, 1H), 6.45 (s, 1H), 4.65-4.49 (m, 4H), 3.99-3.90 (m, 4H), 2.42 (s , 3H).

Synthesis of 4-(7-( pyridin -3- yl )-2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [1,5-a][1,3,5 ] Tri- 𠯤 -4- yl ) 𠰌 line

To 4-(7-bromo-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]trimethanone-4- Base) 𠰌line (75 mg, 0.17 mmol) in 1,4-dioxane/H ₂ O (4/1, 10 mL) was added pyridin-3-ylboronic acid (boronic acid) (40 mg, 0.21 mmol), CsF (85 mg, 0.55 mmol) and PdCl ₂ (PPh ₃ ) ₂ (21 mg, 0.030 mmol). The reaction was stirred at 80 °C under microwave for 30 min. The completion of the reaction was monitored by TLC. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 5% MeOH/DCM to 20% MeOH/DCM to give 4-(7-(pyridin-3-yl)- 2-(3-(m-Tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tris-4-yl)pyrazole (20 mg, 0.046 mmol). LC-MS (ESI+): m/z 439 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.18 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.18 (d, J = 8.1 Hz , 1H), 7.89 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.82-6.79 (m, 2H), 4.65-4.49 (m, 4H), 3.99-3.95 (m, 4H), 2.43 (s, 3H).

compound 5 : 4-(2-(3-(3- Methoxyphenyl )-1H- pyrazole -1- base )-7-(3- methyl -1H- pyrazole -5- base ) Pyrazolo [1,5-a][1,3,5] three 𠯤 -4- base ) 𠰌 phylloline

General procedure 3 :

Synthesis of 5-(3- methoxyphenyl )-1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazole

To a solution of 1-bromo-3-methoxybenzene (2.0 g, 10.7 mmol) in 1,4-dioxane/H ₂ O (4/1, 80 mL) was added CsF (4.88 g, 32.1 mmol ), PdCl ₂ (PPh ₃ ) ₂ (1.5 g, 2.1 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)-1H-pyrazole (5.0 g, 11.7 mmol). The reaction was stirred at 100 °C for 3 h under _N2 . The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with EtOAc (2 x 50 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient elution from 5% EtOAc/PE to 15% EtOAc/PE to give 5-(3-methoxyphenyl)-1- as a yellow oil. (Tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.2 g, 8.53 mmol). LC-MS (ESI+): m/z 259 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.60 (s, 1H), 7.37 (t, J = 8.4 Hz, 1H), 7.11-7.09 (m, 2H), 6.99-6.96 (m, 1H), 6.33 (s , 1H), 5.26-5.22 (m, 1H), 4.13-4.11 (m, 1H), 3.85 (s, 3H), 3.62-3.51 (m, 1H), 2.70-2.50 (m, 1H), 2.10-2.05 (m, 1H), 1.88-1.54 (m, 4H).

Synthesis of 3-(3- methoxyphenyl )-1H- pyrazole

To a solution of 5-(3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.2 g, 8.53 mmol) in DCM (40 mL) Add TFA (10 mL). The solution was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NaHCO ₃ to adjust the pH to 9. The resulting mixture was extracted with DCM (3 x 40 mL). The combined organic phases were concentrated under reduced pressure to give crude 3-(3-methoxyphenyl)-1H-pyrazole (2.87 g, 10.75 mmol) as a brown oil. LC-MS (ESI+): m/z 175 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 7.62 (s, 1H), 7.34-7.29 (m, 3H), 6.91-6.87 (m, 1H), 6.61 (d, J = 2.1 Hz, 1H), 3.87 (s , 3H).

Synthesis of 4-(7- bromo -2-(3-(3- methoxyphenyl )-1H- pyrazol -1- yl ) pyrazolo [1,5-a][1,3,5] tri 𠯤 -4- yl ) 𠰌 line

To 4-(7-bromo-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]tri-4-yl)pyrazole (1.4 g, 3.87 mmol) To a solution in _CH3CN (12 mL) _was added 3-(3-methoxyphenyl)-1H-pyrazole (1.01 g, 5.80 mmol) and _K2CO3 (1.07 g, 7.73 mmol). The reaction mixture was stirred overnight at 60 °C. The completion of the reaction was monitored by TLC. The reaction mixture was directly concentrated. The resulting residue was purified by silica gel column chromatography using a gradient elution from 1% MeOH/DCM to 3% MeOH/DCM to give 4-(7-bromo-2-(3-(3-methanol) as a white solid Oxyphenyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)(1.44 g, 3.16 mmol). LC-MS (ESI+): m/z 456/458 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 8.51 (d, J = 2.7 Hz, 1H), 7.61-7.52 (m, 2H), 7.35 (t, J = 8.1 Hz, 1H), 6.94-6.92 (m, 1H ), 6.79 (d, J = 2.7 Hz, 1H), 6.48 (s, 1H), 4.60-4.40 (m, 4H), 3.95- 3.92 (m, 4H), 3.90 (s, 3H).

Synthesis of 4-(2-(3-(3- methoxyphenyl )-1H- pyrazol -1- yl )-7-(5- methyl -1-( tetrahydro -2H- pyran -2- Base )-1 H- pyrazol -3- yl ) pyrazolo [1,5-a][1,3,5] tri- 𠯤 -4- yl ) 𠰌 line

To 4-(7-bromo-2-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri To a solution of 𠯤-4-yl)𠰌line (100 mg, 0.22 mmol) in 1,4-dioxane/H ₂ O (4/1, 10 mL) was added 5-methyl-1-(tetrahydro -2H-pyran-2-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.33 mmol), K ₂ CO ₃ (90 mg, 0.66 mmol) and Pd(PPh ₃ ) ₄ (23 mg, 0.02 mmol). The reaction was stirred at 90 °C for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with DCM (3 x 25 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The _resulting residue was purified by preparative TLC eluting with EtOAc/PE/ _NH3.H2O (1:1:0.1) to afford 95 mg of crude product as an oil. The crude product was further slurried in MeOH (2 mL) to give pure 4-(2-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-7- (5-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a][1,3,5]tripyrazole -4-yl)𠰌line (65 mg, 0.12 mmol). LC-MS (ESI+): m/z 542 (MH ⁺ ).

Compound 5 : Synthesis of 4-(2-(3-(3- methoxyphenyl )-1H- pyrazol -1- yl )-7-(3- methyl -1H- pyrazol -5- yl ) pyridine Azolo [1,5-a][1,3,5] tri- 𠯤 -4- yl ) 𠰌 line

To 4-(2-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-7-(5-methyl-1-(tetrahydro-2H-pyran-2- yl)-1H-pyrazol-3-yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)pyrazole (65 mg, 0.12 mmol) in DCM (5 mL ) was added TFA (1 mL). The solution was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NaHCO ₃ to adjust the pH to 8. The resulting mixture was extracted with DCM/MeOH (15:1, 3 x 20 mL). The combined organic phases were concentrated under reduced pressure. The resulting residue was slurried in MeOH (3 mL) to give 4-(2-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)-7-( 3-Methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)pyrazoline (24 mg, 0.053 mmol). LC-MS (ESI+): m/z 458 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 8.51 (d, J = 2.7 Hz, 1H), 7.57-7.53 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 6.94 (dd, J = 4.8 Hz, 2.1 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.72 (s, 1H), 6.53 (s, 1H), 4.76-4.56 (m, 4H), 3.95- 3.92 (m, 4H ), 3.90 (s, 3H), 2.39 (s, 3H).

compound 10 :synthesis 4-(2-(3-(3- Methoxyphenyl )-1H- pyrazole -1- base )-7-( pyridine -4- base ) Pyrazolo [1,5-a][1,3,5] three 𠯤 -4- base ) 𠰌 phylloline

General procedure 4 :

Compound 12 : Synthesis of 4-(2-(3-(3- methoxyphenyl )-1H- pyrazol -1- yl )-7-( pyridin -4- yl ) pyrazolo [1,5-a ][1,3,5] tri- 𠯤 -4- yl ) 𠰌 line

To 4-(7-bromo-2-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri To a solution of 𠯤-4-yl)𠰌line (90 mg, 0.20 mmol) in 1,4-dioxane/H ₂ O (4/1, 10 mL) was added pyridin-4-ylboronic acid (30 mg, 0.24 mmol), NaHCO ₃ (33 mg, 0.40 mmol), PPh ₃ (54 mg, 0.20 mmol) and Pd(OAc) ₂ (15 mg, 0.02 mmol). The reaction was stirred at 70 °C for 1 h. TLC showed major new spots with some starting material remaining. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with EtOAc (3 x 20 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The resulting residue was purified by preparative TLC eluting with 6% MeOH/DCM to afford 4-(2-(3-(3-methoxyphenyl)-1H-pyrazol-1-yl as a white solid )-7-(pyridin-4-yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)pyrazole) (14.3 mg, 0.031 mmol). LC-MS (ESI+): m/z 455 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 8.73 (d, J = 6.0 Hz, 2H), 8.56 (d, J = 2.7 Hz, 1H), 7.90 (d, J = 6.0 Hz, 2H), 7.57-7.54 ( m, 2H), 7.36 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.83-6.80 (m, 2H), 4.66-4.57 (m, 4H), 4.00-3.97 (m, 4H), 3.91 (s, 3H).

compound 12 :synthesis N,N- Dimethyl -3-(4-(4-N- 𠰌 Linyl -2-(3-( m-tolyl )-1H- pyrazole -1- base ) Pyrazolo [1,5-a][1,3,5] three 𠯤 -7- base )-1H- pyrazole -1- base ) C -1- amine

General procedure 5 :

Synthesis of 4-(7- bromo -2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [ 1,5-a][1,3,5] trimethanone -4- base ) 𠰌 line

To 4-(7-bromo-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]tri-4-yl)pyrazole (1.0 g, 2.75 mmol) To a solution in _CH3CN (12 mL) was added 3-(m-tolyl)-1H-pyrazole (520 mg, 3.3 mmol) and _K2CO3 ( ₇₅₈ mg, 5.49 mmol). The reaction mixture was stirred overnight at 60 °C. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with DCM/MeOH (15:1, 3 x 40 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The reaction mixture was directly concentrated and purified by silica gel column chromatography with a gradient elution from 1% MeOH/DCM to 3% MeOH/DCM to afford 4-(7-bromo-2-(3-( m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)pyrazole (976 mg, 2.22 mmol). LC-MS (ESI+): m/z 440/442 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 2.4 Hz, 1H), 7.85 (s, 1H), 7.73 (d, J = 6.9 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 6.48 (s, 1H), 4.58-4.41 (m, 4H), 3.95-3.91 (m, 4H ), 2.42 (s, 3H).

Synthesis of 4-(7-(1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -4- yl )-2-(3-( m-tolyl )-1H- pyrazole -1 -yl ) pyrazolo [1,5-a][1,3,5] tri- 𠯤 -4 - yl ) 𠰌 line

To 4-(7-bromo-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]trimethanone-4- 1-(tetrahydro-2H-pyran-2 _- yl )-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (475 mg, 1.7 mmol), K ₃ PO ₄ (666 mg, 3.41 mmol) and PdCl ₂ (PPh ₃ ) ₂ (160 mg, 0.23 mmol). The reaction was stirred at 90 °C for 2 h under _N2 . The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with DCM/MeOH (15:1, 3 x 20 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient elution from 20% EtOAc/PE to 50% EtOAc/PE to afford 4-(7-(1-(tetrahydro-2H-pyran) as a yellow solid -2-yl)-1H-pyrazol-4-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3 ,5] Tris-(4-yl)-(550 mg, 0.97 mmol). LC-MS (ESI+): m/z 512 (MH ⁺ ).

Synthesis of 4-(7-(1H- pyrazol -4- yl )-2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [1,5-a][1, 3,5] tri -(( 4- yl )) 𠰌 -line

To 4-(7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(3-(m-tolyl)-1H-pyrazole-1 To a solution of -yl)pyrazolo[1,5-a][1,3,5]tri-(4-yl)pyridine (550 mg, 0.97 mmol) in DCM (10 mL) was added TFA (2 mL). The solution was stirred at rt for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with aqueous NaHCO ₃ to adjust the pH to 8. The resulting mixture was extracted with DCM/MeOH (15:1, 3 x 20 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The resulting residue was slurried in EtOAc/PE (2:1, 10 mL) to afford 4-(7-(1H-pyrazol-4-yl)-2-(3-(m-tolyl) as a white solid )-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-(220 mg, 0.51 mmol). LC-MS (ESI+): m/z 428 (MH ⁺ ). ¹ HNMR (300 MHz, DMSO- d ₆ ) δ 13.20 (s, 1H), 8.74 (d, J = 2.4 Hz, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H ), 7.76 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.70 (s, 1H), 4.50-4.40 (m, 4H), 3.85-3.77 (m, 4H), 2.40 (s, 3H).

Compound 12 : Synthesis of N,N- dimethyl -3-(4-(4-N- 𠰌 linyl -2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [ 1,5-a][1,3,5] tri- ( 7- yl )-1H- pyrazol -1- yl ) propan -1- amine

To 4-(7-(1H-pyrazol-4-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1, 3,5] To a solution of tris-(4-yl)-(50 mg, 0.12 mmol) in DMF (5 mL) was added 3-bromo-N,N-dimethylpropan-1-amine (44 mg , 0.18 mmol) and Cs ₂ CO ₃ (75 mg, 0.23 mmol). The reaction mixture was stirred at 70 °C for 2 h. The completion of the reaction was monitored by TLC. The reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with DCM/MeOH (10:1, 3 x 20 mL). The combined org. phases were dried over _{anhydrous Na2SO4} , filtered and concentrated. The resulting residue was purified by silica gel column chromatography using a gradient elution from 5% MeOH/DCM to 10% MeOH/DCM to afford N,N-dimethyl-3-(4-(4- N-𠰌linyl-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-𠯤-7-yl) -1H-pyrazol-1-yl)propan-1-amine (16.8 mg, 0.033 mmol). LC-MS (ESI+): m/z 513 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 2.7 Hz, 1H), 7.92-7.87 (m, 3H), 7.75 (d, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 6.50 (s, 1H), 4.70- 4.45 (m, 4H), 4.29 (t, J = 6.6 Hz, 2H), 3.97-3.94 (m, 4H), 2.50-2.48 (m, 2H), 2.43 (s, 3H), 2.39 (s, 6H), 2.23-2.18 (m, 2H).

Compound 14 : Synthesis of 3-(4-(4-N-? olinyl -2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [1,5-a][ 1 ,3,5] Tris- ( 7- yl )-1H- pyrazol -1- yl ) propan -1- ol General procedure 6 :

Compound 14 : Synthesis of 3-(4-(4-N-? olinyl -2-(3-( m-tolyl )-1H- pyrazol -1- yl ) pyrazolo [1,5-a][ 1 ,3,5] tri- ( 7- yl )-1H- pyrazol -1- yl ) propan -1- ol

To 4-(7-(1H-pyrazol-4-yl)-2-(3-(m-tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1, 3,5] To a solution of tris-(4-yl)-(100 mg, 0.24 mmol) in DMF (4 mL) was added 3-bromopropan-1-ol (40 mg, 0.28 mmol) and K ₂ CO ₃ (200 mg, 0.58 mmol). The reaction mixture was stirred overnight at 45°C. The completion of the reaction was monitored by TLC. The reaction was filtered and the filtrate was directly concentrated. The resulting residue was purified by preparative TLC eluting with 6% MeOH/DCM to give 3-(4-(4-N-Πolinyl-2-(3-(m-tolyl)-1H) as a gray solid -pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]tri-(7-yl)-1H-pyrazol-1-yl)propan-1-ol (19 mg , 0.039 mmol). LC-MS (ESI+): m/z 486 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.87 (s, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.35 -7.30 (m, 1H), 7.20-7.18 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.50 (s, 1H), 4.65- 4.50 (m, 4H), 4.37 (t, J = 6.3 Hz, 2H), 3.97-3.94 (m, 4H), 3.68 (t, J = 5.4 Hz, 2H), 2.42 (s, 3H), 2.13 (t, J = 6.0 Hz, 2H).

1 LC-MS (ESI+): m/z 442 (MH ⁺)。 ¹H NMR (300 MHz, CDCl ₃) δ8.54 (d, J= 1.8 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J= 7.8 Hz, 1H), 7.69 (d, J= 7.2 Hz, 1H), 7.35-7.20 (m, 1H), 7.20-7.18 (m, 1H), 6.81 (s, 2H), 6.73 (d, J= 1.8 Hz, 1H), 4.70- 4.58 (m, 4H), 4.04 (s, 3H), 4.01-3.94 (m, 4H), 2.42 (s, 3H)。 2

1 LC-MS (ESI+): m/z 428 (MH ⁺)。 ¹H NMR (300 MHz, CDCl ₃) δ8.55 (d, J= 2.1 Hz, 1H), 8.02-7.99 (m, 2H), 7.47-7.34 (m, 4H), 6.81 (d, J= 2.1 Hz, 2H), 6.73 (d, J= 2.1 Hz, 1H), 4.77-4.60 (m, 4H), 4.07 (s, 3H), 3.97-3.92 (m, 4H)。 3

2 LC-MS (ESI+): m/z 439 (MH ⁺)。 ¹H NMR (300 MHz, CDCl ₃) δ9.18 (s, 1H), 8.67 (d, J= 4.8 Hz, 1H), 8.55 (d, J= 2.7 Hz, 1H), 8.18 (d, J= 8.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J= 7.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.33 (t, J= 7.5 Hz, 1H), 7.20 (d, J= 8.1 Hz, 1H), 6.82-6.79 (m, 2H), 4.65-4.49 (m, 4H), 3.99-3.95 (m, 4H), 2.43 (s, 3H)。 4

2 LC-MS (ESI+): m/z 425 (MH ⁺)。 ¹H NMR (300 MHz, CDCl ₃) δ9.21 (s, 1H), 8.68 (d, J= 3.9 Hz, 1H), 8.56 (d, J= 2.7 Hz, 1H), 8.10 (d, J= 7.2 Hz, 1H), 8.03 (d, J= 8.1 Hz, 2H), 7.47- 7.36 (m, 4H), 6.83 (d, J= 2.7 Hz, 1H), 6.79 (s, 1H), 4.67- 4.43 (m, 4H), 4.00-3.94 (m, 4H)。 5

3 LC-MS (ESI+): m/z 458 (MH ⁺)。 ¹HNMR (300 MHz, CDCl3) δ8.51 (d, J= 2.7 Hz, 1H), 7.57-7.53 (m, 2H), 7.35 (t, J= 7.8 Hz, 1H), 6.94 (dd, J= 4.8 Hz, 2.1 Hz, 1H), 6.79 (d, J= 2.7 Hz, 1H), 6.72 (s, 1H), 6.53 (s, 1H), 4.76-4.56 (m, 4H), 3.95- 3.92 (m, 4H), 3.90 (s, 3H), 2.39 (s, 3H)。 6

4 LC-MS (ESI+): m/z 455 (MH ⁺)。 ¹H NMR (300 MHz, CD ₃OD) δ9.50 (s, 1H), 9.23 (d, J= 8.1 Hz, 1H), 8.90 (d, J= 6.0 Hz, 1H), 8.70 (d, J= 2.7 Hz, 1H), 8.24-8.19 (m, 1H), 7.63 (s, 1H), 7.52 (d, J= 7.5 Hz, 1H), 7.37 (t, J= 7.8 Hz, 1H), 7.09 (s, 1H), 6.97-6.94 (m, 2H), 4.79- 4.56 (m, 4H), 3.97-3.94 (m, 4H), 3.89 (s, 3H)。 7

2 LC-MS (ESI+): m/z 439 (MH ⁺)。1H NMR (300 MHz, DMSO- d ₆ ) δ8.92 (d, J= 5.7 Hz, 2H), 8.80 (d, J= 2.1 Hz, 1H), 8.40-8.38 (m, 2H), 7.82-7.76 (m, 2H), 7.40-7.35 (m, 2H), 7.23 (d, J= 7.2 Hz, 1H), 7.12 (s, 1H), 4.76-4.41 (m, 4H), 3.91-3.88 (m, 4H), 2.41 (s, 3H)。 8

1 LC-MS (ESI+): m/z 442 (MH ⁺)。 ¹H NMR (300 MHz, CDCl ₃) δ8.50 (s, 1H), 7.88 (s, 1H), 7.75 (d, J= 7.5 Hz, 1H), 7.33 (t, J= 7.5 Hz, 1H), 7.18 (d, J= 7.8 Hz, 1H), 6.79 (d, J= 2.7 Hz, 1H), 6.73 (s, 1H), 6.54 (s, 1H), 4.72-4.57 (m, 4H), 3.96-3.93 (m, 4H), 2.42 (s, 3H), 2.39 (s, 3H)。 9

3 LC-MS (ESI+): m/z 444 (MH ⁺)。1HNMR (300 MHz, CD ₃OD) δ8.66 (d, J= 2.7Hz, 1H), 8.42 (s, 2H), 7.60 (s, 1H), 7.54 (d, J= 7.8 Hz, 1H), 7.36 (t, J= 7.8Hz, 1H), 7.0 (d, J= 2.7 Hz, 1H), 6.99-6.95 (dd, J= 8.1 Hz, 2.1 Hz, 1H), 6.71 (s, 1H), 4.80- 4.49 (m, 4H), 3.96-3.93 (m, 4H), 3.87 (s, 3H)。 10

4 LC-MS (ESI+): m/z 455 (MH ⁺)。 ¹HNMR (300 MHz, CDCl3) δ8.73 (d, J= 6.0 Hz, 2H), 8.56 (d, J= 2.7 Hz, 1H), 7.90 (d, J= 6.0 Hz, 2H), 7.57-7.54 (m, 2H), 7.36 (t, J= 7.8 Hz, 1H), 6.94 (d, J= 8.1 Hz, 1H), 6.83-6.80 (m, 2H), 4.66-4.57 (m, 4H), 4.00-3.97 (m, 4H), 3.91 (s, 3H)。 11

1 LC-MS (ESI+): m/z 428 (MH ⁺)。1H NMR (300 MHz, DMSO- d ₆ ) δ8.75 (d, J= 2.1 Hz, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.76 (d, J= 7.5 Hz, 1H), 7.37 (t, J= 7.5 Hz, 1H), 7.22 (d, J= 7.2 Hz, 1H), 7.08 (d, J= 2.7 Hz, 1H), 6.70 (s, 1H), 4.51-4.38 (m, 4H), 3.85-3.77 (m, 4H), 2.40 (s, 3H)。 12

5 LC-MS (ESI+): m/z 513 (MH ⁺)。 ¹H NMR (300 MHz, CDCl ₃) δ8.53 (d, J= 2.7 Hz, 1H), 7.92-7.87 (m, 3H), 7.75 (d, J= 7.2 Hz, 1H), 7.32 (t, J= 7.2 Hz, 1H), 7.18 (d, J= 7.8 Hz, 1H), 6.80 (d, J= 2.7 Hz, 1H), 6.50 (s, 1H), 4.70- 4.45 (m, 4H), 4.29 (t, J= 6.6 Hz, 2H), 3.97-3.94 (m, 4H), 2.50-2.48 (m, 2H), 2.43 (s, 3H), 2.39 (s, 6H), 2.23-2.18 (m, 2H)。 13

3 & 5 LC-MS (ESI+): m/z 529 (MH ⁺)。1HNMR (300 MHz, CDCl ₃) δ8.53 (d, J= 2.7 Hz, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.57-7.53 (m, 2H), 7.35 (t, J= 7.8 Hz, 1H), 6.94 (dd, J= 7.5, 2.7 Hz, 1H), 6.79 (d, J= 2.7 Hz, 1H), 6.49 (s, 1H), 4.70-4.57 (m, 4H), 4.26 (t, J= 6.6 Hz, 2H), 3.97-3.91 (m, 4H), 3.90 (s, 3H), 2.31-2.24 (m, 6H), 2.12- 2.03 (m, 2H)。 14

1 & 6 LC-MS (ESI+): m/z 486 (MH ⁺)。 ¹H NMR (300 MHz, CDCl ₃) δ8.53 (d, J= 2.4 Hz, 1H), 7.94 (s, 1H), 7.87 (s, 2H), 7.75 (d, J= 7.2 Hz, 1H), 7.35-7.30 (m, 1H), 7.20-7.18 (m, 1H), 6.80 (d, J= 2.4 Hz, 1H), 6.50 (s, 1H), 4.65- 4.50 (m, 4H), 4.37 (t, J= 6.3 Hz, 2H), 3.97-3.94 (m, 4H), 3.68 (t, J= 5.4 Hz, 2H), 2.42 (s, 3H), 2.13 (t, J= 6.0 Hz, 2H)。 15

3 & 6 LC-MS (ESI+): m/z 502 (MH ⁺)。1HNMR (300 MHz, CDCl ₃) δ8.54 (d, J= 2.7 Hz, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.58-7.53 (m, 2H), 7.35 (t, J= 7.8 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H), 6.79 (d, J= 2.7 Hz, 1H), 6.49 (s, 1H), 4.57-4.47 (m, 4H), 4.37 (t, J= 6.3 Hz, 2H), 3.97-3.94 (m, 4H), 3.91 (s, 3H), 3.70-3.66 (m, 2H), 2.14-2.08 (m, 2H)。 16

4 LC-MS (ESI+): m/z 455 (MH ⁺)。1HNMR (300 MHz, DMSO- d ₆ ) δ8.73-8.64 (m, 2H), 8.19-8.17 (m, 1H), 8.11-7.90 (m, 1H), 7.61-7.30 (m, 4H), 7.14 (s, 1H), 6.98 (s, 2H), 4.74-4.41 (m, 4H), 3.95-3.63 (m, 7H)。 17

2 LC-MS (ESI+): m/z 439 (MH ⁺)。1HNMR (300 MHz, DMSO- d ₆ ) δ8.78-8.73 (m, 2H), 8.19 (d, J= 7.8 Hz 1H), 7.96 (t, J= 7.2 Hz 1H), 7.82-7.75 (m, 2H), 7.52-7.45 (m, 1H), 7.40-7.35 (m, 1H), 7.24-7.21 (m, 1H), 7.09 (d, J= 2.7 Hz, 1H), 6.98 (s, 1H), 4.70-4.41 (m, 4H), 3.95-3.80 (m, 4H), 2.40 (s, 3H)。 The compounds in Table 2 were prepared using the methods described herein above. table 2 Compound number structure General process material 1

1 LC-MS (ESI+): m/z 442 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.54 (d, J = 1.8 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 7.2 Hz , 1H), 7.35-7.20 (m, 1H), 7.20-7.18 (m, 1H), 6.81 (s, 2H), 6.73 (d, J = 1.8 Hz, 1H), 4.70- 4.58 (m, 4H), 4.04 (s, 3H), 4.01-3.94 (m, 4H), 2.42 (s, 3H). 2

1 LC-MS (ESI+): m/z 428 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.55 (d, J = 2.1 Hz, 1H), 8.02-7.99 (m, 2H), 7.47-7.34 (m, 4H), 6.81 (d, J = 2.1 Hz, 2H), 6.73 (d, J = 2.1 Hz, 1H), 4.77-4.60 (m, 4H), 4.07 (s, 3H), 3.97-3.92 (m, 4H). 3

2 LC-MS (ESI+): m/z 439 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.18 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 8.18 (d, J = 8.1 Hz , 1H), 7.89 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.82-6.79 (m, 2H), 4.65-4.49 (m, 4H), 3.99-3.95 (m, 4H), 2.43 (s, 3H). 4

2 LC-MS (ESI+): m/z 425 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 9.21 (s, 1H), 8.68 (d, J = 3.9 Hz, 1H), 8.56 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 7.2 Hz , 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.47- 7.36 (m, 4H), 6.83 (d, J = 2.7 Hz, 1H), 6.79 (s, 1H), 4.67- 4.43 (m, 4H), 4.00-3.94 (m, 4H). 5

3 LC-MS (ESI+): m/z 458 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl3) δ 8.51 (d, J = 2.7 Hz, 1H), 7.57-7.53 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 6.94 (dd, J = 4.8 Hz , 2.1 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.72 (s, 1H), 6.53 (s, 1H), 4.76-4.56 (m, 4H), 3.95- 3.92 (m, 4H) , 3.90 (s, 3H), 2.39 (s, 3H). 6

4 LC-MS (ESI+): m/z 455 (MH ⁺ ). ¹ H NMR (300 MHz, CD ₃ OD) δ 9.50 (s, 1H), 9.23 (d, J = 8.1 Hz, 1H), 8.90 (d, J = 6.0 Hz, 1H), 8.70 (d, J = 2.7 Hz, 1H), 8.24-8.19 (m, 1H), 7.63 (s, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.09 (s, 1H ), 6.97-6.94 (m, 2H), 4.79- 4.56 (m, 4H), 3.97-3.94 (m, 4H), 3.89 (s, 3H). 7

2 LC-MS (ESI+): m/z 439 (MH ⁺ ). 1H NMR (300 MHz, DMSO- d ₆ ) δ 8.92 (d, J = 5.7 Hz, 2H), 8.80 (d, J = 2.1 Hz, 1H), 8.40-8.38 (m, 2H), 7.82-7.76 (m , 2H), 7.40-7.35 (m, 2H), 7.23 (d, J = 7.2 Hz, 1H), 7.12 (s, 1H), 4.76-4.41 (m, 4H), 3.91-3.88 (m, 4H), 2.41 (s, 3H). 8

1 LC-MS (ESI+): m/z 442 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 7.88 (s, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.73 (s, 1H), 6.54 (s, 1H), 4.72-4.57 (m, 4H), 3.96-3.93 ( m, 4H), 2.42 (s, 3H), 2.39 (s, 3H). 9

3 LC-MS (ESI+): m/z 444 (MH ⁺ ). 1HNMR (300 MHz, CD ₃ OD) δ 8.66 (d, J = 2.7Hz, 1H), 8.42 (s, 2H), 7.60 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.36 ( t, J = 7.8Hz, 1H), 7.0 (d, J = 2.7 Hz, 1H), 6.99-6.95 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 6.71 (s, 1H), 4.80- 4.49 ( m, 4H), 3.96-3.93 (m, 4H), 3.87 (s, 3H). 10

4 LC-MS (ESI+): m/z 455 (MH ⁺ ). ¹ HNMR (300 MHz, CDCl3) δ 8.73 (d, J = 6.0 Hz, 2H), 8.56 (d, J = 2.7 Hz, 1H), 7.90 (d, J = 6.0 Hz, 2H), 7.57-7.54 (m , 2H), 7.36 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.83-6.80 (m, 2H), 4.66-4.57 (m, 4H), 4.00-3.97 ( m, 4H), 3.91 (s, 3H). 11

1 LC-MS (ESI+): m/z 428 (MH ⁺ ). 1H NMR (300 MHz, DMSO- d ₆ ) δ 8.75 (d, J = 2.1 Hz, 1H), 8.36 (s, 1H), 8.03 (s, 1H), 7.81 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 2.7 Hz, 1H), 6.70 (s, 1H), 4.51-4.38 (m, 4H), 3.85-3.77 (m, 4H), 2.40 (s, 3H). 12

5 LC-MS (ESI+): m/z 513 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 2.7 Hz, 1H), 7.92-7.87 (m, 3H), 7.75 (d, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 2.7 Hz, 1H), 6.50 (s, 1H), 4.70- 4.45 (m, 4H), 4.29 (t, J = 6.6 Hz, 2H), 3.97-3.94 (m, 4H), 2.50-2.48 (m, 2H), 2.43 (s, 3H), 2.39 (s, 6H), 2.23-2.18 (m, 2H). 13

3 & 5 LC-MS (ESI+): m/z 529 (MH ⁺ ). 1HNMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 2.7 Hz, 1H), 7.92 (s, 1H), 7.87 (s, 1H), 7.57-7.53 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 6.94 (dd, J = 7.5, 2.7 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.49 (s, 1H), 4.70-4.57 (m, 4H), 4.26 ( t, J = 6.6 Hz, 2H), 3.97-3.91 (m, 4H), 3.90 (s, 3H), 2.31-2.24 (m, 6H), 2.12- 2.03 (m, 2H). 14

1 & 6 LC-MS (ESI+): m/z 486 (MH ⁺ ). ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.53 (d, J = 2.4 Hz, 1H), 7.94 (s, 1H), 7.87 (s, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.35 -7.30 (m, 1H), 7.20-7.18 (m, 1H), 6.80 (d, J = 2.4 Hz, 1H), 6.50 (s, 1H), 4.65- 4.50 (m, 4H), 4.37 (t, J = 6.3 Hz, 2H), 3.97-3.94 (m, 4H), 3.68 (t, J = 5.4 Hz, 2H), 2.42 (s, 3H), 2.13 (t, J = 6.0 Hz, 2H). 15

3 & 6 LC-MS (ESI+): m/z 502 (MH ⁺ ). 1HNMR (300 MHz, CDCl ₃ ) δ 8.54 (d, J = 2.7 Hz, 1H), 7.94 (s, 1H), 7.87 (s, 1H), 7.58-7.53 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 2.7 Hz, 1H), 6.49 (s, 1H), 4.57-4.47 (m, 4H), 4.37 (t, J = 6.3 Hz, 2H), 3.97-3.94 (m, 4H), 3.91 (s, 3H), 3.70-3.66 (m, 2H), 2.14-2.08 (m, 2H). 16

4 LC-MS (ESI+): m/z 455 (MH ⁺ ). 1HNMR (300 MHz, DMSO- d ₆ ) δ 8.73-8.64 (m, 2H), 8.19-8.17 (m, 1H), 8.11-7.90 (m, 1H), 7.61-7.30 (m, 4H), 7.14 (s , 1H), 6.98 (s, 2H), 4.74-4.41 (m, 4H), 3.95-3.63 (m, 7H). 17

2 LC-MS (ESI+): m/z 439 (MH ⁺ ). 1HNMR (300 MHz, DMSO- d ₆ ) δ 8.78-8.73 (m, 2H), 8.19 (d, J = 7.8 Hz 1H), 7.96 (t, J = 7.2 Hz 1H), 7.82-7.75 (m, 2H) , 7.52-7.45 (m, 1H), 7.40-7.35 (m, 1H), 7.24-7.21 (m, 1H), 7.09 (d, J = 2.7 Hz, 1H), 6.98 (s, 1H), 4.70-4.41 (m, 4H), 3.95-3.80 (m, 4H), 2.40 (s, 3H).

biological instance 1 : PIKfyve inhibition

Full-length human recombinant PIKFYVE expressed as an N-terminal GST-fusion protein (265 kDa) in a baculovirus expression system was obtained from Carna Biosciences (Kobe, Japan). Kinase receptors were prepared by mixing and sonicating fluorescently labeled phosphatidylinositol 3-phosphate (PI3P) and phospho-L-serine (PS) in a 1:10 ratio in 50 mM HEPES buffer pH 7.5. quality.

Kinase reactions were assembled in 384-well plates (Greiner) in a total volume of 20 mL as follows. Kinase proteins were pre-diluted in assay buffer containing 25 mM HEPES (pH 7.5), 1 mM DTT, 2.5 mM MgCl ₂ and 2.5 mM MnCl ₂ and 0.005% Triton X-100, and dispensed into 384-well plates (10 microliters liter/hole). Test compounds were sequentially pre-diluted in DMSO and added to protein samples by acoustic dispensing (Labcyte Echo). The concentration of DMSO was made equal to 1% in all samples. All test compounds were tested at 12 concentrations. Apilimod was used as a reference compound and tested in the same manner in each assay plate. Control samples (0% inhibition in the absence of inhibitor, DMSO only) and 100% inhibition (in absence of enzyme) were assembled in four replicates and used to calculate inhibition in the presence of compound %. Reactions were initiated by adding 10 µL of 2x PI3P/PS substrate supplemented with ATP. The final concentration of enzyme was 2 nM, the final concentration of ATP was 10 mM, and the final concentration of PI3P/PS substrate was 1 µM (PI3P). The kinase reaction was allowed to proceed for 3 h at room temperature. After incubation, the reaction was quenched by adding 50 mL of stop buffer (100 mM HEPES (pH 7.5), 0.01% Triton X-100, 20 mM EDTA). Terminated discs were analyzed on a microfluidic electrophoresis instrument (Caliper LabChip® 3000, Caliper Life Sciences/Perkin Elmer). Changes in the relative fluorescence intensity of the PI(3)P substrate and PI(3,5)P product peaks were measured. The activity in each test sample was determined as the product-to-sum ratio (PSR): P/(S+P), where P is the peak height of the product and S is the peak height of the substrate. The % inhibition (P _inh ) was determined using the following equation: P _inh = (PSR _0%inh - PSR _compound )/(PSR _0%inh - PSR _100%inh )*100 where PSR _compound is the product/sum in the presence of the compound Ratio, PSR _0%inh is the ratio of product/sum in the absence of compound and PSR _100%inh is the ratio of product/sum in the absence of enzyme. To determine the _IC50 (50% inhibition) of test compounds, the % inhibition data ( _Pinh vs. compound concentration) was fitted by a four-parameter sigmoidal dose-response model using XLfit software (IDBS).

_IC50 values for certain compounds of the invention are provided in Table 3 below.

surface 3 compound PIKfyve _IC50 [nM] 1 3.8 2 98.1 3 4.2 4 58 5 75 6 62 7 6.4 8 1.3 9 twenty three 10 121 11 0.8 12 2.7 13 148 14 3.3 15 12.6 16 43.4 17 7.2

Claims (54)

A compound of formula (I):

Where Y ¹ is N or CR ¹ ; Y ² is N or CR ² ; X is N or CH; the restriction is that when Y ¹ is N, Y ² is CR ² , and when Y ² is N, Y ¹ is CR ¹ ; R ¹ is H or C _3-8 aryl, C _3-8 heteroaryl, C _3-8 cycloalkyl or C _3-8 heterocyclyl substituted by 1 to 3 R ^s as appropriate R ² is H or C _3-8 aryl, C 3-8 heteroaryl, C _3-8 cycloalkyl or _{C 3-8 heterocyclyl} , each optionally substituted by 1 to 3 R ^s ; R ⁴ is C _3-8 aryl, C 3-8 heteroaryl _, C _3-8 cycloalkyl or C _3-8 heterocyclyl, each optionally substituted by 1 to 3 R ^s , or -C(O )NR ^x R ^y ; R ^s is H, halogen, amino, OH, OC _1-6 alkyl, C _1-6 alkyl, C _1-6 alkylene-OH or C _1-6 alkylene -NR ^p R ^q ; R ^x is H or optionally substituted C _1-4 alkyl by R ^o ; R ^y is H, each optionally substituted by 1 to 3 R ^o substituents C _1-4 alkyl , -OC _1-4 alkyl, -SO ₂ -C _1-4 alkyl, C _1-4 alkyl-SO ₂ -R ^r , cycloalkyl, -C _1-4 alkylene-cycloalkyl, Heterocyclyl or -O-heterocyclyl; or R ^x and R ^y together with the nitrogen to which they are attached form a heterocyclic group optionally substituted by C _1-4 alkyl; each R ^r is C _1-4 alkyl or -NR ^p R ^q ; each R ^o substituent is independently C _1-4 alkyl, -OH, -OC _1-4 alkyl, halo, cyano or -NR ^p R ^q ; each of R ^p and R ^q independently H or C _1-4 alkyl; or R ^p and R ^q form a heterocyclic group together with the nitrogen to which they are attached; and R ⁵ is H, C _1-6 alkyl, halo, -OH or -OC _1-6 alkyl. The compound according to claim 1, wherein Y ¹ is N, and Y ² is CR ² . The compound according to claim 1, wherein Y ² is N, and Y ¹ is CR ¹ . The compound according to claim 1, wherein Y ¹ is CR ¹ and Y ² is CR ² . The compound of claim 1, wherein Y ¹ is CR ¹ and Y ² is CR ² , and one of R ¹ and R ² is not H. The compound as claimed in item 1, wherein X is N. The compound as claimed in claim 1, wherein X is N, and one of ^Y1 and ^Y2 is N. The compound according to claim 1, wherein X is N, Y ¹ is CR ¹ , and Y ² is CR ² . The compound of claim 1, wherein X is N, Y ¹ is CR ¹ , and Y ² is CR ² , and one of R ¹ and R ² is not H. The compound as claimed in item 1, wherein X is CH. The compound as claimed in item 1, wherein X is CH, and one of ^Y1 and ^Y2 is N. The compound as claimed in item 1, wherein X is CH, and Y ¹ and Y ² are N. The compound according to any one of claims 1 to 12, wherein Y ¹ is CR ¹ , and R ¹ is H, or phenyl or C _3-8 heteroaryl each optionally substituted by 1 to 3 R ^s . The compound according to any one of claims 1 to 13, wherein R ¹ is phenyl or pyridyl, pyrimidyl or pyrazolyl substituted by 1 or 2 R ^s each as appropriate. The compound according to any one of claims 1 to 13, wherein R ¹ is phenyl or pyridyl or pyrazolyl substituted by 1 R ^s each as appropriate. The compound according to any one of claims 1 to 15, wherein Y ² is CR ² and R ² is H, or phenyl or C _3-8 heteroaryl substituted by 1 to 3 R ^s as appropriate. The compound according to any one of claims 1 to 16, wherein R ² is phenyl or pyridyl, pyrimidyl or pyrazolyl substituted by 1 or 2 R ^s each as appropriate. The compound according to any one of claims 1 to 16, wherein R ² is phenyl, pyridyl or pyrazolyl, each optionally substituted by 1 R ^s . The compound according to any one of claims 1 to 18, wherein R ⁴ is phenyl, pyridyl, pyrimidyl or pyrazolyl substituted by 1 to 2 R ^s each as appropriate. The compound according to any one of claims 1 to 18, wherein R ⁴ is phenyl, pyridyl or pyrazolyl, each optionally substituted by 1 R ^s . The compound according to any one of claims 1 to 20, wherein R ^s is H, F, Cl, Br, NH ₂ , OH, OC _1-4 alkyl, C _1-4 alkyl, C _1-4 alkane Group -OH or C _1-4 alkylene -NR ^p R ^q , wherein R ^p and R ^q are independently H or C _1-4 alkyl. The compound as any one of claims 1 to 20, wherein R ^s is H, Cl, OH, methyl, ethyl, propyl, methylene-OH, ethylidene-OH, propylidene-OH, Methylene-N(CH ₃ ) ₂ , Ethylene-N(CH ₃ ) ₂ , Propylene-N(CH ₃ ) ₂ . The compound according to any one of claims 1 to 20, wherein R ^s is H or methyl. The compound according to any one of claims 1 to 23, wherein R ⁴ is -C(O)NR ^x R ^y . The compound according to any one of claims 1 to 24, wherein R ^x is H, or methyl or ethyl optionally substituted by one R ^o . The compound according to any one of claims 1 to 24, wherein R ^x is H or methyl. A compound as claimed in any one of claims 1 to 24, wherein ^Ry is C _1-4 alkyl, -OC _1-4 alkyl, -SO ₂ -C _1-4 alkyl, C _1-4 alkyl- SO ₂ -R ^r , cycloalkyl, -C _1-4 alkyl(cycloalkyl), heterocyclyl, -O-heterocyclyl, each optionally substituted with 1 to 3 R ^o substituents. The compound according to any one of claims 1 to 24, wherein R ^y is C _1-4 alkyl optionally substituted by one, two or three R ^o substituents. The compound according to any one of claims 1 to 24, wherein R ^y is a monocyclic cycloalkyl group optionally substituted by one, two or three R ^o substituents. The compound according to any one of claims 1 to 24, wherein R ^y is a heterocyclyl or -O-heterocyclyl optionally substituted by one, two or three R ^o substituents. The compound according to any one of claims 1 to 24, wherein R ^x is H, and R ^y is methyl, ethyl, isopropyl, cyclopropyl, methoxy or cyclopentyl. The compound according to any one of claims 1 to 24, wherein R ^x and R ^y form together with the nitrogen to which they are attached a heterocyclic group optionally substituted by C _1-4 alkyl. The compound according to any one of claims 1 to 32, wherein each R ^o substituent is independently C _1-4 alkyl, -OH, -OC _1-4 alkyl or -NR ^p R ^q . The compound according to any one of claims 1 to 33, wherein R ^p and R ^q are each independently H or methyl. The compound according to any one of claims 1 to 33, wherein R ^p and R ^q form a heterocyclic group together with the nitrogen to which they are attached. The compound as any one of claims 1 to 33, wherein R ^p and R ^q form azetidinyl, pyrrolidinyl, piperidinyl, piperyl, thiolyl, thiol together with the nitrogen to which they are attached 𠰌linyl, 6-oxa-1-azaspiro[3.3]heptyl, or 2-oxa-6-azaspiro[3.3]heptyl. The compound as claimed in any one of items 1 to 36, wherein R ^is H, methyl, ethyl, propyl, Cl, Br or -OH. The compound as claimed in any one of items 1 to 36, wherein R ⁵ is H or methyl. The compound according to any one of claims 1 to 36, wherein R ⁵ is H. A compound selected from Table 1 and/or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 40, wherein one or more hydrogen atoms attached to the carbon atoms of the compound are replaced by deuterium atoms. A pharmaceutical composition comprising the compound and/or pharmaceutically acceptable salt or prodrug according to any one of claims 1 to 41 and a pharmaceutically acceptable excipient. A method of inhibiting PIKfyve kinase in an individual in need thereof, comprising administering an effective amount of the compound according to any one of claims 1 to 41 or the pharmaceutical composition according to claim 42 to the individual. A method for treating a neurological disease associated with PIKfyve activity in an individual in need, comprising administering an effective amount of the compound according to any one of claims 1 to 41 or the pharmaceutical composition according to claim 42 to the individual. The method of claim 44, wherein the disease is associated with PIKfyve activity. The method as claimed in item 44, wherein the disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (primary lateral sclerosis; PLS), Charcot's disease (Charcot -Marie-Tooth, CMT; including type 4J (CMT4J) and Yunis-Varon syndrome, autophagy, polymicrogyria (including polymicrogyria with seizures), temporal Temporo-occipital polymicrogyria, Pick's disease, Parkinson's disease, Parkinson's disease with Lewy bodies, loss of Lewy bodies Dementia with Lewy bodies, Lewy body disease, fronto-temporal dementia, polyglutamine and neuronal endosome diseases of intranuclear inclusion bodies ( diseases of neuronal nuclear inclusions of polyglutamine and intranuclear inclusion bodies), disease of Marinesco and Hirano bodies, tauopathies, Alzheimer's disease, neurodegeneration, spongiform neurodegeneration (spongiform neurodegeneration), peripheral neuropathy, leukoencephalopathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain Injury (TBI), cerebral ischemia, Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, lytic storage disease ( lysosomal storage disease), Fabry's disorder, Gaucher's disorder, Niemann Pick C disease, Tay-Sachs disease and Mucolipidosis type IV, neuropathy, Huntington's disease, psychosis, ADHD, schizophrenia, mood disorders, major depressive disorder, depression, bipolar disorder I ) or bipolar II disorder. The method of claim 44, wherein the disease is ALS, FTD, Alzheimer's disease, Parkinson's disease, Huntington's disease or CMT. The method according to claim 44, wherein the disease is ALS. The method of claim 44, wherein the disease is a tauopathy, such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy. The method of claim 44, wherein the disease is a lysoderm storage disease, such as Fabry's disease, Gaucher's disease, Niemann-Pick type C disease, Tay-Sachs disease, or type IV mucolipid storage disease accumulated disease. The method of claim 44, wherein the disease is a mental disorder, such as ADHD, schizophrenia, or a mood disorder, such as major depressive disorder, depression, bipolar disorder I or bipolar disorder II. The compound according to any one of claims 1 to 41, which is used as a medicine. The compound according to claim 52, wherein the compound is used for the treatment of neurological diseases which can be treated by inhibiting PIKfyve kinase. A use of the compound according to any one of claims 1 to 41 for the manufacture of a medicament for treating a disease in an individual, wherein PIKfyve causes the pathological changes and/or symptoms of the disease.