WO2022256300A1 - Composés hétérocycliques bicycliques fusionnés et leurs utilisations - Google Patents

Composés hétérocycliques bicycliques fusionnés et leurs utilisations Download PDF

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WO2022256300A1
WO2022256300A1 PCT/US2022/031551 US2022031551W WO2022256300A1 WO 2022256300 A1 WO2022256300 A1 WO 2022256300A1 US 2022031551 W US2022031551 W US 2022031551W WO 2022256300 A1 WO2022256300 A1 WO 2022256300A1
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compound
disease
alkyl
optionally substituted
heterocyclyl
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PCT/US2022/031551
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English (en)
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Mark D. Rosen
Weiling Liang
JR. Robert A. GALEMMO
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Verge Analytics, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Phosphoinositide kinases catalyze the phosphorylation of phosphatidylinositol, which is a component of eukaryotic cell membranes, and related phospholipids called phosphoinositides. Phosphoinositides are involved in the regulation of diverse cellular processes, including cellular proliferation, survival, cytoskeletal organization, vesicle trafficking, glucose transport, and platelet function. Fruman et al., “Phosphoinositide Kinases,” Ann. Review. Biochem.1998, 67, 481-507.
  • PIKfyve also known as phosphatidylinositol-3-phosphate 5-kinase type III or PIPKIII
  • PIPKIII phosphatidylinositol-3-phosphate 5-kinase type III
  • PI3P phosphatidylinositol-3- phosphate
  • PIKfyve regulates endomembrane homeostasis and plays a role in the biogenesis of endosome carrier vesicles from early endosomes.
  • the enlarged endosome/lysosome structure was 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 levels of PI3P, stimulating autophagy and improving motor neuron health.
  • Phosphorylated inositides produced by PIKfyve are localized in various cellular membranes and organelles, consistent with the various PIKfyve functions of endolysosomal transport, endomembrane homeostasis, and biogenesis of endosome carrier vesicles (ECV)/multivesicular bodies (MVB) from early endosomes. Further, PIKfyve is required for endocytic-vacuolar pathway and nuclear migration. Thus, PIKfyve helps maintain proper morphology of the endosome and lysosome.
  • FIG4 phosphoinositide 5-phosphatase
  • Inhibition of PIKfyve would mimic overexpression of FIG4, thereby increasing levels of PI3P, stimulating autophagy, and improving motor neuron health.
  • Numerous diseases are correlated with FIG4 deficiencies, such as deleterious FIG4 mutations or diminished FIG4 function, and are therefore suitable as target diseases for treatment with PIKfyve inhibitors, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (including type 4J (CMT4J)), and Yunis- Varon syndrome.
  • Mutations in PIKfyve are associated with corneal fleck dystrophy, an autosomal dominant disorder characterized by numerous white flecks in all layers of the corneal stroma.
  • Exemplary diseases associated with FIG4 deficiencies are amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (including type 4J (CMT4J)), Yunis-Varon syndrome, polymicrogyria (including polymicrogyria with seizures), temporo- occipital polymicrogyria, Pick’s disease, Parkinson’s disease, Parkinson’s disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, frontotemporal dementia, diseases of neuronal nuclear inclusions of polyglutamine and intranuclear inclusion bodies, disease of Marinesco and Hirano bodies, Alzheimer’s disease, neurodegeneration, spongiform neurodegeneration, autophagy, peripheral neuropathy, leukoencephalopathy, motor neuropathy, sensory neuropathy.
  • ALS amyotrophic lateral sclerosis
  • PLS primary lateral sclerosis
  • CMT4J Charcot-Marie-Tooth
  • PIKfyve inhibitors are useful in a range of neurological disorders, such as tauopathies (including but not limited to Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementias, and chronic traumatic encephalopathy), traumatic brain injury (TBI), cerebral ischemia, ALS, frontotemporal dementia (FTD), Guillain-Barré Syndrome, chronic inflammatory demyelinating polyneuropathy, multiple sclerosis, CMT, lysosomal storage diseases (including but not limited to Fabry's disorder, Gaucher's disorder, Niemann Pick C, Tay-Sachs, and Mucolipidosis type IV), as well as several types of neuropathies.
  • tauopathies including but not limited to Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementias, and chronic traumatic encephalopathy
  • TBI traumatic brain injury
  • ALS cerebral ischemia
  • FTD frontotemporal dementia
  • PIKfyve inhibitors include Huntington’s disease and psychiatric disorders (such as ADHD, schizophrenia, mood disorders including but not limited to major depressive disorder, bipolar disorder I, and bipolar disorder 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 Publ. No. WO2016/210372; US Publ. No. US2018/0161335.
  • Embodiment 1 is a compound of Formula (I): wherein Y 1 is N or C-R 1 ; Y 2 is N or C-R 2 ; X is N, or CH; provided that when Y 1 is N, Y 2 is C-R 2 and when Y 2 is N, Y 1 is C-R 1 ; R 1 is H, or C3-8 aryl, C3-8 heteroaryl, C3-8 cycloalkyl, or C3-8 heterocyclyl, each optionally substituted with from 1 to 3 R s ; 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 with from 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 with from 1 to 3 R s , or -C(O)
  • Embodiment 2 is the compound of embodiment 1, wherein Y 1 is N, Y 2 is C-R 2 .
  • Embodiment 3 is the compound of embodiment 1, wherein Y 2 is N, Y 1 is C-R 1 .
  • Embodiment 4 is the compound of embodiment 1, wherein Y 1 is C-R 1 and Y 2 is C-R 2 .
  • Embodiment 5 is the compound of embodiment 1, wherein Y 1 is C-R 1 and Y 2 is C-R 2 , and wherein one of R 1 and R 2 is not 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 Y 1 and Y 2 is N.
  • Embodiment 8 is the compound of embodiment 1, wherein X is N, Y 1 is C-R 1 , and Y 2 is C-R 2 .
  • Embodiment 9 is the compound of embodiment 1, wherein X is N, Y 1 is C-R 1 , and Y 2 is C-R 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 Y 1 and Y 2 is N.
  • Embodiment 12 is the compound of embodiment 1, wherein X is CH, and Y 1 and Y 2 are N.
  • Embodiment 13 is the compound of any one of embodiments 1 - 12, wherein Y 1 is C-R 1 and R 1 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s .
  • Embodiment 14 is the compound of any one of embodiments 1 - 13, wherein R 1 is phenyl or pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with 1 or 2 R s .
  • Embodiment 15 is the compound of any one of embodiments 1 - 13, wherein R 1 is phenyl or pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • Embodiment 16 is the compound of any one of embodiments 1 - 15, wherein Y 2 is C-R 2 and R 2 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s .
  • Embodiment 17 is the compound of any one of embodiments 1 - 16, wherein R 2 is phenyl or pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with 1 or 2 R s .
  • Embodiment 18 is the compound of any one of embodiments 1 - 16, wherein R 2 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • Embodiment 19 is the compound of any one of embodiments 1 - 18, wherein R 4 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with from 1 to 2 R s .
  • Embodiment 20 is the compound of any one of embodiments 1 - 18, wherein R 4 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • Embodiment 21 is the compound of any one of embodiments 1 - 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 alkyl.
  • Embodiment 22 is the compound of any one of embodiments 1 - 20, wherein R s is H, Cl, OH, methyl, ethyl, propyl, methylene-OH, ethylene-OH, propylene-OH, methylene- N(CH 3 ) 2 , ethylene-N(CH 3 ) 2 , propylene-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 - 23, wherein R 4 is -C(O)NR x R y .
  • Embodiment 25 is the compound of any one of embodiments 1 - 24, wherein R x is H, or methyl or ethyl, optionally substituted with one R o .
  • Embodiment 26 is the compound of any one of embodiments 1 - 24, wherein R x is H or methyl.
  • Embodiment 27 is the compound of any one of embodiments 1 - 24, wherein R y is C 1-4 alkyl, -O-C 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.
  • Embodiment 28 is the compound of any one of embodiments 1 - 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 - 24, wherein R y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R o substituents.
  • Embodiment 30 is the compound of any one of embodiments 1 - 24, wherein R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl.
  • Embodiment 31 is the compound of any one of embodiments 1 - 24, wherein R y is methoxy.
  • Embodiment 32 is the compound of any one of embodiments 1 - 24, wherein R y is -SO 2 -methyl.
  • Embodiment 33 is the compound of any one of embodiments 1 - 24, wherein R y is cycloalkyl or -C 1-2 alkyl(cycloalkyl), each optionally substituted with one, two, or three R o substituents.
  • Embodiment 34 is the compound of any one of embodiments 1 - 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 - 24, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one, two, or three R o substituents.
  • Embodiment 36 is the compound of any one of embodiments 1 - 24, wherein R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2- cyclopropylethyl, cyclobutylmethyl, or cyclopentylmethyl.
  • Embodiment 37 is the compound of any one of embodiments 1 - 24, wherein R y 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 - 24, wherein R y is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or oxetanyloxy, each optionally substituted with one, two, or three R o substituents.
  • Embodiment 39 is the compound of any one of embodiments 1 - 24, wherein R x is H and R y is methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopentyl.
  • Embodiment 40 is the compound of any one of embodiments 1 - 24, wherein R x is H and R y is isopropyl.
  • Embodiment 41 is the compound of any one of embodiments 1 - 24, wherein R x and R y taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C 1-4 alkyl.
  • Embodiment 42 is the compound of any one of embodiments 1 - 24, wherein R x and R y taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C 1-4 alkyl.
  • Embodiment 43 is the compound of any one of embodiments 1 - 24, wherein R x and R y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with methyl.
  • Embodiment 44 is the compound of any one of embodiments 1 - 24, wherein R x and R y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa- 6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.
  • Embodiment 45 is the compound of any one of embodiments 1 - 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 - 44, wherein each R o substituent is C 1-4 alkyl.
  • Embodiment 47 is the compound of any one of embodiments 1 - 44, wherein each R o substituent is -OH.
  • Embodiment 48 is the compound of any one of embodiments 1 - 44, wherein each R o substituent is -NR p R q .
  • Embodiment 49 is the compound of any one of embodiments 1 - 48, wherein R p and R q are each independently H or methyl.
  • Embodiment 50 is the compound of any one of embodiments 1 - 48, wherein R p and R q taken together with the nitrogen to which they are attached form a heterocyclyl.
  • Embodiment 51 is the compound of any one of embodiments 1 - 48, wherein R p and R q taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa- 6-azaspiro[3.3]heptanyl.
  • Embodiment 52 is the compound of any one of embodiments 1 - 51, wherein R 5 is H, methyl, ethyl, propyl, Cl, Br, or -OH.
  • Embodiment 53 is the compound of any one of embodiments 1 - 51, wherein R 5 is H or methyl.
  • Embodiment 54 is the compound of any one of embodiments 1 - 51, wherein R 5 is H.
  • Embodiment 55 is a compound selected from Table 1, and/or pharmaceutically acceptable salts thereof.
  • Embodiment 56 is the compound of any one of embodiments 1 - 55, wherein one or more hydrogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.
  • Embodiment 57 is a pharmaceutical composition comprising a compound and/or a pharmaceutically acceptable salt or prodrug of any one of embodiments 1-56 and a pharmaceutically acceptable excipient.
  • Embodiment 58 is a method of inhibiting PIKfyve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 56, or a pharmaceutical composition of embodiment 57.
  • Embodiment 59 is a method of treating a neurological disease associated with PIKfyve activity in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of embodiments 1 to 56, or a pharmaceutical composition of embodiment 57.
  • 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), Charcot-Marie-Tooth (CMT; including type 4J (CMT4J)), and Yunis-Varon syndrome, autophagy, polymicrogyria (including polymicrogyria with seizures), temporo-occipital polymicrogyria, Pick’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, tauopathy, Alzheimer’s disease, neurodegeneration, spongiform neurodegeneration, peripheral neuropathy, leukoencephalopathy, inclusion body disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, traumatic brain injury (ALS), primary
  • 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’s disorder, Gaucher's disorder, Niemann Pick C disease, Tay- Sachs disease, or Mucolipidosis type IV.
  • Embodiment 66 is the method of embodiment 59, wherein the disease is a psychiatric disorder such as ADHD, schizophrenia, or mood disorders 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 treating a neurological disease treatable by inhibition of PIKfyve kinase.
  • Embodiment 69 is the use of a compound of any one of embodiments 1 to 56 in the manufacture of a medicament for treating a disease in a subject in which PIKfyve contributes to the pathology and/or symptoms of the disease.
  • PIKfyve contributes to the pathology and/or symptoms of the disease.
  • -C(O)NH 2 is attached through the carbon atom.
  • a dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning.
  • a wavy line or a dashed line drawn through a line in a Formula indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.
  • the prefix “Cu-v” indicates that the following group has from u to v carbon atoms.
  • C 1-6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X”.
  • the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., 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 with from 1 to x carbon atoms.
  • Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Aryl refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems.
  • aryl has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 18 carbon ring atoms (i.e., C6-18 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl) or 6 to 10 carbon ring atoms (i.e., C 6-10 aryl).
  • aryl groups include phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl.
  • “Amino” means a -NH 2 .
  • “Alkoxy” means a -OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Cycloalkyl means a cyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms wherein one or two carbon atoms may be replaced by an oxo group, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • Cx-ycycloalkyl refers to a cycloalkyl group with from x to y carbon atoms in the ring, where x and y are integers.
  • Carboxy means –COOH.
  • Halo means fluoro, chloro, bromo, or iodo; in one embodiment fluoro or chloro.
  • Haloalkyl means alkyl radical as defined above, which is substituted with one or one to five halogen atoms (in one embodiment fluorine or chlorine,) including those substituted with different halogens, e.g., -CH 2 Cl, -CF 3 , -CHF 2 , -CH 2 CF 3 , -CF 2 CF 3 , -CF(CH 3 ) 2 , and the like.
  • C x-y -haloalkyl “C x-y ” means the number of carbon atoms in the alkyl group ranges from x to y. When the alkyl is substituted with only fluoro, it can be referred to in this disclosure as fluoroalkyl.
  • “Heterocyclyl” means a saturated or unsaturated monovalent monocyclic or bi-cyclic group (fused bi-cyclic or bridged bi-cyclic) of 4 to 10 ring atoms in which one or two ring atoms are heteroatom selected from N, O, and S(O)n, where n is an integer from 0 to 2, the remaining ring atoms being C.
  • heterocyclyl includes, but is not limited to, oxetanyl, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one-yl, tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one- yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-yl, 3-oxa-8-azabicyclo[3.2.1]octane-yl, and the like.
  • heterocyclylalkyl and “heterocycloalkyl” mean an –(alkylene)-R radical where R is heterocyclyl ring as defined above e.g., tetraydrofuranylmethyl, piperazinylmethyl, morpholinylethyl, and the like.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms where one or more, (in one embodiment one, two, or three), ring atoms are heteroatom selected from N, O, and S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolopyridinyl, indazolyl, furopyrimidinyl, and the like.
  • Cx-yheteroaryl refers to a heteroaryl group with from 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, mammal is a human.
  • the term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • 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, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • heterocyclyl group optionally substituted with an alkyl group means that the alkyl may but need not be present, and the description includes situations where the heterocyclyl group is substituted with an alkyl group and situations where the heterocyclyl group is not substituted with alkyl.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • 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.
  • materials which 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 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, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • Treating” or “treatment” of a disease includes: (1) preventing the disease, e.g., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or (3) relieving the disease, e.g., causing regression of the disease or its clinical symptoms.
  • a “therapeutically effective amount” means the amount of a compound of Formula (I) (or any of the embodiments thereof described herein), that, when administered to a mammal for treating a disease, is sufficient to treat the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • the compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. All chiral, diastereomeric, racemic forms, as individual forms and mixtures thereof, are within the scope of this disclosure, unless the specific stereochemistry or isomeric form is specifically indicated.
  • Compounds of the present disclosure containing an asymmetrically substituted atom 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 materials.
  • Stereoisomers may be performed by chromatography or by forming diastereomers and separating 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, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. [0103] Certain compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof can exist as tautomers and/or geometric isomers.
  • the compounds described herein include hydrates and solvates of the compounds or pharmaceutically acceptable salts thereof.
  • the present disclosure also includes the prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof.
  • the term prodrug is intended to represent covalently bonded carriers, which are capable of releasing the active ingredient of Formula (I) (or any of the embodiments thereof described herein) when the prodrug is administered to a mammalian subject. Release of the active ingredient occurs in vivo.
  • Prodrugs can be prepared by techniques known to one skilled in the art. These techniques generally modify appropriate functional groups in a given compound. These modified functional groups however regenerate original functional groups in vivo or by routine manipulation.
  • Prodrugs of compounds of Formula (I) include compounds wherein a hydroxy, amino, carboxylic, or a similar group is modified.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • amides e.g., trifluoroacet
  • Prodrugs of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof are also within the scope of this disclosure.
  • the present disclosure also includes polymorphic forms (amorphous as well as crystalline) and deuterated forms of compounds of Formula (I) (or any of the embodiments thereof described herein) and/or a pharmaceutically acceptable salt or prodrug thereof.
  • the compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C. In one particular embodiment, the compound is deuterated in at least one position.
  • deuterated forms can be made by the procedure described in U.S. Patent Nos.5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
  • structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.
  • the compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds.
  • the compounds may be labeled with isotopes, such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • isotopes such as for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Isotopic substitution with 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 are all contemplated.
  • the compounds disclosed herein have some or all of the 1 H atoms replaced with 2 H atoms.
  • the methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
  • Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S.
  • Y 1 is N, Y 2 is C-R 2 . In some embodiments, Y 2 is N, Y 1 is C-R 1 . In some embodiments, Y 1 is C-R 1 and Y 2 is C-R 2 . In some embodiments, Y 1 is C-R 1 and Y 2 is C-R 2 , and one of R 1 and R 2 is not H.
  • X is N. In some embodiments, X is N, and one of Y 1 and Y 2 is N. In some embodiments, X is N, Y 1 is C-R 1 , and Y 2 is C-R 2 .
  • X is N, Y 1 is C-R 1 , and Y 2 is C-R 2 , and one of R 1 and R 2 is not H.
  • X is CH.
  • X is CH, and one of Y 1 and Y 2 is N.
  • X is CH, and Y 1 and Y 2 are N.
  • Y 1 is C-R 1 and R 1 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s .
  • R 1 is phenyl or pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with 1 or 2 R s . In some embodiments, R 1 is phenyl or pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • Y 2 is C-R 2 and R 2 is H, or phenyl or C 3-8 heteroaryl each optionally substituted with from 1 to 3 R s . In some embodiments, R 2 is phenyl or pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with 1 or 2 R s .
  • R 2 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • 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 alkylP(O))(OR x ) 2 , C 1-4 alkylene-C3-8 aryl, C 1-4 alkylene-C3-8 heteroaryl, C 1-4 alkylene-C 3-8 cycloalkyl, or C 1-4 alkylene-C 3-8 heterocyclyl, each optionally substituted with from 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-
  • R 4 is phenyl, pyridinyl, pyrimidinyl, or pyrazolyl each optionally substituted with from 1 to 2 R s . In some embodiments, R 4 is phenyl, pyridinyl, or pyrazolyl each optionally substituted with 1 R s .
  • R 4 is pyrazolylmethyl, imidazolylmethyl, morpholinomethyl, piperidinylmethyl, dioxanylmethy, dioxanylethyl, dioxanylethylenyl, dioxanylpropyl, dioxanylpropylenyl, cyclohexenyl, cyclopentenyl, dihydropyridinyl, each optionally substituted with from 1 to 2 R s .
  • 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 alkylNR x C(O)R y .
  • R 4 is -C(O)NR x R y .
  • R s is H, F, Cl, Br, NH 2 , OH, OC 1-6 alkyl, or C 1-6 alkyl.
  • R s is OC 1-4 alkyl, or C 1-4 alkyl.
  • R s is H, Cl, OH, methyl, ethyl, propyl, methylene-OH, ethylene-OH, propylene-OH, methylene-N(CH 3 ) 2 , ethylene- N(CH 3 ) 2 , propylene-N(CH 3 ) 2 .
  • R s is H or methyl.
  • R x is H, or methyl or ethyl, optionally substituted with one R o . In some embodiments, R x is H or methyl.
  • R y is C 1-4 alkyl, -O-C 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.
  • R y is C 1-4 alkyl, optionally substituted with one, two, or three R o substituents.
  • R y is methyl, ethyl, propyl, or isopropyl, each optionally substituted with one, two, or three R o substituents.
  • R y is methyl, ethyl, isopropyl, methoxyethyl, dimethoxypropanyl, (dimethylamino)ethyl, or (dimethylamino)butyl.
  • R y is methoxy.
  • R y is -SO 2 -methyl.
  • R y is C 1-4 alkyl-R r , C 1-4 alkyl, -O-C 1- 4 alkyl, -SO 2 -C 1-4 alkyl, C 1-4 alkyl-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 optionally substituted with 1 to 3 R o substituents.
  • R y is cycloalkyl, or (C 1-4 alkyl)monocyclic cycloalkyl, or -C 1- 2alkyl(cycloalkyl), each optionally substituted with one, two, or three R o substituents.
  • R y is monocyclic cycloalkyl, optionally substituted with one, two, or three R o substituents.
  • R y is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, cyclohexenyl, or cyclopentenyl, each optionally substituted with one, two, or three R o substituents.
  • R y is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, cyclohexenylpropyl, or cyclopentenylpropyl.
  • R y is heterocyclyl or -O- heterocyclyl, optionally substituted with one, two, or three R o substituents.
  • R y is tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, dioxanyl, pyrazolyl, dihydropyridinyl, or oxetanyloxy, each optionally substituted with one, two, or three R o substituents.
  • R y is tetrahydrofuranylmethyl, tetrahydropyranylmethyl, oxetanylmethyl, azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, dioxanylmethyl, pyrazolylmethyl, dihydropyridinylmethyl, or oxetanyloxymethyl, tetrahydrofuranylpropyl, tetrahydropyranylpropyl, oxetanylpropyl, azetidinylpropyl, pyrrolidinylpropyl, piperidinylpropyl, morpholinylpropyl, piperazinylpropyl, dioxanylpropyl, pyrazolylpropyl, dihydropyridinylpropyl, or oxetanyloxypropyl, each optionally substituted with
  • R x is H and R y is methyl, ethyl, isopropyl, cyclopropyl, methoxy, or cyclopentyl. In some embodiments, R x is H and R y is isopropyl. [0129] In some embodiments, R x and R y taken together with the nitrogen to which they are attached form a heterocyclyl, optionally substituted with C 1-4 alkyl. In some embodiments, R x and R y taken together with the nitrogen to which they are attached form a heterocycloalkyl, optionally substituted with C 1-4 alkyl.
  • R x and R y taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl, optionally substituted with methyl.
  • R x and R y are taken together with the nitrogen to which they are attached to form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl, each optionally substituted with methyl.
  • each R r is C 1-4 alkyl or -NR p R q .
  • R r is methyl, ethyl, propyl, or isopropyl or -NR p R q .
  • each R o substituent is independently C 1-4 alkyl, -OH, -OC 1-4 alkyl, or -NR p R q .
  • each R o substituent is C 1-4 alkyl.
  • each R o substituent is -OH.
  • each R o substituent is -NR p R q .
  • R p and R q are each independently H or methyl.
  • R p and R q taken together with the nitrogen to which they are attached form a heterocyclyl. In some embodiments, R p and R q taken together with the nitrogen to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl 6-oxa-1-azaspiro[3.3]heptanyl, or 2-oxa-6-azaspiro[3.3]heptanyl. [0134] In some embodiments, R 5 is H, methyl, ethyl, propyl, Cl, Br, or -OH. In some embodiments, R 5 is H or methyl.
  • the compound of Formula (I) or the pharmaceutically acceptable salt thereof is a compound of Formula (I): as defined herein, wherein one or mo re y rogen atoms attached to carbon atoms of the compound are replaced by deuterium atoms.
  • one or more hydrogen atoms attached to carbon atoms of R 1 , R 2 , R 4 , and/or R 5 are replaced by deuterium atoms.
  • 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 by deuterium atoms.
  • one or more C 1-4 alkyl group has one or more hydrogen atoms attached to carbon atoms replaced by deuterium atoms.
  • one or more methyl groups have one or more hydrogen atoms attached to the carbon atom replaced by deuterium atoms.
  • the compound of Formula (I) comprises a -D in place of at least one -H, or a -CD 3 substituent in place of at least one CH 3 . Table 1
  • the compounds of this disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
  • Therapeutically effective amounts of compounds of Formula (I) may range from about 0.01 to about 500 mg per kg patient body weight per day, which can be administered in single or multiple doses.
  • the dosage level will be about 0.1 to about 250 mg/kg per day.
  • the dosage level will be about 0.5 to about 100 mg/kg per day.
  • a suitable dosage level may be about 0.01 to about 250 mg/kg per day, about 0.05 to about 100 mg/kg per day, or about 0.1 to about 50 mg/kg per day.
  • the dosage can be about 0.05 to about 0.5, about 0.5 to about 5 or about 5 to about 50 mg/kg per day.
  • the compositions may be provided in the form of tablets containing about 1.0 to about 1000 milligrams of the active ingredient, particularly about 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient.
  • the actual amount of the compound of this disclosure, i.e., the active ingredient will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound being utilized, the route and form of administration, and other factors.
  • compositions will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration.
  • routes oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration.
  • parenteral e.g., intramuscular, intravenous, or subcutaneous
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
  • Pharmaceutical compositions can be formulated using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries.
  • the formulation can be modified depending upon the route of administration chosen.
  • the pharmaceutical compositions can also include the compounds described herein in a free base form or a pharmaceutically acceptable salt or prodrug form.
  • Methods for formulation of the 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 composition.
  • Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid compositions further contain nontoxic, auxiliary substances, for example wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives.
  • compositions described herein can be lyophilized or in powder form for re- constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the active ingredients can be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacylate) microcapsules, respectively), in colloidal drug- delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • the pharmaceutical compositions and formulations can be sterilized.
  • Sterilization can be accomplished by filtration through sterile filtration.
  • the pharmaceutical compositions described herein can be formulated for administration as an injection.
  • Non-limiting examples of formulations for injection can include a sterile suspension, solution, or emulsion in oily or aqueous vehicles.
  • Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils, synthetic fatty acid esters, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension.
  • the suspension can also contain suitable stabilizers.
  • Injections can be formulated for bolus injection or continuous infusion.
  • the compounds can be formulated in a unit dosage injectable form (e.g., solution, suspension, emulsion) in association with a pharmaceutically acceptable parenteral vehicle.
  • a pharmaceutically acceptable parenteral vehicle e.g., water, 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 can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).
  • Sustained-release preparations can also be prepared.
  • sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ⁇ ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPO TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(–)-3-hydroxybutyric acid.
  • polyesters e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)
  • polylactides e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)
  • polylactides e.g., poly(2-
  • compositions described herein can be prepared for storage by mixing a compound with a pharmaceutically acceptable carrier, excipient, and/or a 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 used.
  • Acceptable carriers, excipients, and/or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes; and/or non- ionic surfactants or polyethylene glycol.
  • buffers such as phosphate, citrate, and other organic acids
  • antioxidants including ascorbic acid and methionine
  • preservatives polypeptides
  • proteins such as serum albumin or gelatin
  • hydrophilic polymers amino acids
  • Compounds of the present disclosure may be used in methods of treating in combination with one or more other combination agents (e.g., one, two, or three other drugs) that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present disclosure are useful.
  • the combination of the drugs together are safer or more effective than either drug alone.
  • the compound disclosed herein and the one or more combination agents have complementary activities that do not adversely affect each other.
  • Such molecules can be present in combination in amounts that are effective for the purpose intended.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of the present disclosure.
  • the agents are administered together in a single pharmaceutical composition in unit dosage form.
  • the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients, in addition to a compound of the present disclosure.
  • the weight ratio of the compound of the present disclosure to the second active agent may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • combination therapy includes therapies in which the compound of the present disclosure and one or more other drugs are administered separately, and in some cases, the two or more agents are administered on different, overlapping schedules.
  • the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly.
  • the combination agent is an anticancer agent, such as an alkylating agent, a corticosteroid, a platinum drug, a purine analog, an anti-metabolite, or particular agents such as cyclophosphamide, chlorambucil, bendamustine, prednisone, dexamethasone, carboplatin, cisplatin, cladribine, fludarabine, capecitabine, gemcitabine, methotrexate, pralatrexate, bleomycin, doxorubicin, vincristine, or rituximab.
  • an anticancer agent such as an alkylating agent, a corticosteroid, a platinum drug, a purine analog, an anti-metabolite, or particular agents such as cyclophosphamide, chlorambucil, bendamustine, prednisone,
  • the combination agent is a drug for reduction of symptoms of ALS.
  • the combination agent is selected from an NAD supplement (such as nicotinamide riboside, offered under the trade names Basis® or Tru Niagen®), vitamin B12 (oral or injection), glycopyrrolate, atropine, scopolamine, baclofen, tizanidine, mexiletine, an SSRI, a benzodiazepine, Neudexta, riluzole, and edaravone, and combinations thereof.
  • the compounds, pharmaceutical compositions, and methods of the present disclosure can be useful for treating a subject such as, but not limited to, a mammal, a human, a non-human mammal, a domesticated animal (e.g., laboratory animals, household pets, or livestock), a non- domesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig, a horse, a goat, a sheep, or a rabbit.
  • a mammal e.g., a human
  • a non-human mammal e.g., a domesticated animal (e.g., laboratory animals, household pets, or livestock), a non- domesticated animal (e.g., wildlife), a dog, a cat, a rodent, a mouse, a hamster, a cow, a bird, a chicken, a fish, a pig
  • the compounds, pharmaceutical compositions, and methods described herein can be useful as a therapeutic, for example a treatment that can be administered to a subject in need thereof.
  • a therapeutic effect can be obtained in a subject by reduction, suppression, remission, or eradication of a disease state, including, but not limited to, a symptom thereof.
  • a therapeutic effect in a subject having a disease or condition, or pre-disposed to have or is beginning to have the disease or condition can be obtained by a reduction, a suppression, a prevention, a remission, or an eradication of the condition or disease, or pre-condition or pre-disease state.
  • therapeutically effective amounts of the compounds or pharmaceutical compositions described herein can be administered to a subject in need thereof, often for treating and/or preventing a condition or progression thereof.
  • a pharmaceutical composition can affect the physiology of the subject, such as the immune system, inflammatory response, or other physiologic affect.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • Treat and/or treating can refer to any indicia of success in the treatment or amelioration of the disease or condition.
  • Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treat can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely. [0154] Prevent, preventing, and the like can refer to the prevention of the disease or condition in the patient.
  • a therapeutically effective amount can be the amount of a compound or pharmaceutical composition or an active component thereof sufficient to provide a beneficial effect or to otherwise reduce a detrimental non-beneficial event to the individual to whom the composition is administered.
  • a therapeutically effective dose can be a dose that produces one or more desired or desirable (e.g., beneficial) effects for which it is administered, such administration occurring one or more times over a given period of time. An exact dose can depend on the purpose of the treatment and can be ascertainable by one skilled in the art using known techniques.
  • the compounds or pharmaceutical compositions described herein that can be used in therapy can be formulated and dosages established in a fashion consistent with good medical practice taking into account the disorder 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.
  • the compounds or pharmaceutical compositions can be prepared according to the description of preparation described herein.
  • a pharmaceutical composition or compound described herein can be for administration to a subject in need thereof.
  • administration of the compounds or pharmaceutical compositions can include routes of administration, non-limiting examples of administration routes include intravenous, intraarterial, subcutaneous, subdural, intramuscular, intracranial, intrasternal, intratumoral, or intraperitoneally.
  • compositions or compounds of the present disclosure can be administered to a subject in need thereof in a first administration, and in one or more additional administrations.
  • the one or more additional administrations can be administered to the subject in need thereof minutes, hours, days, weeks, or months following the first administration. Any one of the additional administrations can be administered to the subject in need thereof 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.
  • the one or more administrations can occur more than once per day, more than once per week, or more than once per month.
  • the compounds or pharmaceutical compositions can be administered to the subject in need thereof in cycles of 21 days, 14 days, 10 days, 7 days, 4 days, or daily over a period of one to seven days.
  • the compounds, pharmaceutical compositions, and methods provided herein can be useful for the treatment of a plurality of diseases or conditions or preventing a disease or a condition in a subject, or other therapeutic applications for subjects in need thereof.
  • the disclosure relates to a method of inhibiting PIKfyve kinase in a subject in need thereof comprising administering to the subject an effective amount of a compound.
  • the disclosure relates to a method for treating a neurological disease mediated by PIKfyve activity in a subject in need thereof, comprising administering an effective amount of a compound or a pharmaceutical composition as described herein to the subject.
  • the disease is a neurological disease.
  • the disease is associated with a FIG4 deficiency.
  • a method for treating a subject with a neurological disease or disorder associated with PIKfyve kinase activity comprising administering to the subject an effective amount of a compound or pharmaceutical composition as described herein.
  • the neurological disease is amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), Charcot-Marie-Tooth (CMT; including type 4J (CMT4J)), and Yunis-Varon syndrome, autophagy, polymicrogyria (including polymicrogyria with seizures), temporo-occipital polymicrogyria, Pick’s disease, Parkinson’s disease, Parkinson’s disease with Lewy bodies, dementia with Lewy bodies, Lewy body disease, frontotemporal dementia, diseases of neuronal nuclear inclusions of polyglutamine and intranuclear inclusion bodies, disease of Marinesco and Hirano bodies, tauopathy, 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, Guilla
  • ALS amyotroph
  • 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.
  • the neurological disease is a tauopathy such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, or chronic traumatic encephalopathy.
  • the neurological disease is a lysosomal storage disease such as Fabry’s disorder, Gaucher's disorder, Niemann Pick C disease, Tay-Sachs disease, or Mucolipidosis type IV.
  • the neurological disease is a psychiatric disorder such as ADHD, schizophrenia, or mood disorders such as major depressive disorder, depression, bipolar disorder I, or bipolar disorder II.
  • the disclosure further provides any compounds disclosed herein for use in a method of treatment of the human or animal body by therapy. Therapy may be by any mechanism disclosed herein, such as inhibiting, reducing, or reducing progression of the diseases disclosed herein.
  • the disclosure further provides any compound disclosed herein for prevention or treatment of any condition disclosed herein.
  • the disclosure also provides any compound or pharmaceutical composition thereof disclosed herein for obtaining any clinical outcome disclosed herein for any condition disclosed herein.
  • the disclosure also provides use of any compound disclosed herein in the manufacture of a medicament for preventing or treating any disease or condition disclosed herein.
  • the reaction was stirred at 80 o 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 organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 10% EtOAc/PE to 30% EtOAc/PE to provide 4-(7-(1-methyl-1H-pyrazol-3-yl)-2- (methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-yl)morpholine (174 mg, 0.53 mmol) as a white solid.
  • reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 1% MeOH/DCM to 2% MeOH/DCM to provide 4-(7-(1-methyl-1H-pyrazol-3-yl)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4- yl)morpholine (181 mg, 0.50 mmol) as a yellow solid.
  • the reaction was stirred at 110 o C overnight.
  • the reaction mixture was quenched with water (10 mL).
  • the aqueous solution was extracted with DCM (3 x 10 mL).
  • the combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated under reduce pressure.
  • reaction mixture was stirred at rt overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 4-(7- bromo-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)morpholine (970 mg, 2.69 mmol) as a yellow solid.
  • reaction mixture was stirred at 100 o C in a sealed tube overnight. The completion of the reaction was monitored by TLC.
  • the reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 20% EtOAc/PE to 50% EtOAc/PE to provide 4-(7-bromo-2-(3-(m- tolyl)-1H-pyrazol-1-yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)morpholine (150 mg, 0.34 mmol) as a yellow solid.
  • the reaction was stirred at 80 o C under microwave for 30 min. The completion of the reaction was monitored by TLC.
  • the reaction mixture was concentrated directly and purified by silica gel column chromatography with a gradient elution of 5% MeOH/DCM to 20% MeOH/DCM to provide 4-(7-(pyridin-3-yl)-2-(3-(m-tolyl)-1H-pyrazol-1- yl)pyrazolo[1,5-a][1,3,5]triazin-4-yl)morpholine (20 mg, 0.046 mmol) as a gray solid.
  • the reaction was stirred at 100 o C under N 2 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 EtOAc (2 x 50 mL).
  • the combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • the resulting residue was purified by silica gel column chromatography with a gradient elution of 5% EtOAc/PE to 15% EtOAc/PE to provide 5-(3-methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (2.2 g, 8.53 mmol) as a yellow oil.
  • the reaction was stirred at 90 o 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 organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • the resulting residue was purified by preparative TLC with a elution of EtOAc/PE/NH 3 .H 2 O (1:1:0.1) to provide 95 mg of crude product as oil.
  • reaction was stirred at 70 o C for 1 h. TLC showed a major new spot and some of the starting material was remained.
  • the reaction mixture was quenched with water (30 mL). The aqueous solution was extracted with EtOAc (3 x 20 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • reaction mixture was stirred at 60 o C overnight. 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 organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • the reaction was stirred at 90 o C under N 2 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 (15:1, 3 x 20 mL).
  • the combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • 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 NaHCO3 solution to adjust pH to 8.
  • the resulting mixture was extracted with DCM/MeOH (15:1, 3 X 20 mL). The combined organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • the reaction mixture was stirred at 70 o 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 organic phase was dried over anhydrous Na 2 SO 4 , filtrated and concentrated.
  • Biological Example 1 Inhibition of PIKfyve
  • Full length human recombinant PIKFYVE expressed in baculovirus expression system as N-terminal GST-fusion protein (265 kDa) was obtained from Carna Biosciences (Kobe, Japan).
  • the kinase substrate was prepared by mixing and sonicating fluorescently-labeled phosphatidylinositol 3-phosphate (PI3P) with phospho-L-serine (PS) at a 1:10 ratio in 50 mM HEPES buffer pH7.5.
  • the kinase reactions were assembled in 384-well plates (Greiner) in a total volume of 20 mL as follows.
  • Kinase protein was pre-diluted in an assay buffer comprising 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 a 384-well plate (10 ⁇ L per well).
  • Test compounds were serially pre-diluted in DMSO and added to the protein samples by acoustic dispensing (Labcyte Echo). The concentration of DMSO was equalized to 1% in all samples. All test compounds were tested at 12 concentrations. Apilimod was used as a reference compound and was tested in identical manner in each assay plate.
  • Control samples (0%-inhibition, in the absence of inhibitor, DMSO only) and 100%-inhibition (in the absence of enzyme) were assembled in replicates of four and were used to calculate %-inhibition in the presence of compounds.
  • the reactions were initiated by addition of 10 ⁇ L 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 ⁇ M (PI3P).
  • the kinase reactions were allowed to proceed for 3 h at room temperature.
  • Terminated plates were analyzed on a microfluidic electrophoresis instrument (Caliper LabChip® 3000, Caliper Life Sciences/Perkin Elmer). The change in the relative fluorescence intensity of the PI(3)P substrate and PI(3,5)P product peaks was 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.
  • PSR product to sum ratio
  • IC 50 of test compounds 50%-inhibition
  • the %-inh cdata (Pinh versus compound concentration) were fitted by a four-parameter sigmoid dose- response model using XLfit software (IDBS).
  • IDBS XLfit software

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Abstract

La présente divulgation concerne des composés de formule (I) qui sont des inhibiteurs de la kinase PlKfyve et sont par conséquent utiles pour le traitement de maladies neurologiques pouvant être traitées par l'inhibition des kinases PlKfyve. L'invention concerne également des compositions pharmaceutiques contenant de tels composés, et des méthodes de traitement de maladies neurologiques faisant appel à de tels composés.
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