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WO2025136898A1 - Agonistes de l'activité trem2 - Google Patents

Agonistes de l'activité trem2 Download PDF

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Publication number
WO2025136898A1
WO2025136898A1 PCT/US2024/060448 US2024060448W WO2025136898A1 WO 2025136898 A1 WO2025136898 A1 WO 2025136898A1 US 2024060448 W US2024060448 W US 2024060448W WO 2025136898 A1 WO2025136898 A1 WO 2025136898A1
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compound
mmol
pharmaceutically acceptable
chloro
pyrimido
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Inventor
Manasi ANANTPUR
Yaroslav BOYKO
Joanna L. CHEN
Erin F. Dimauro
Timothy J. Henderson
Ping Liu
Vladimir SIMOV
Brandon A. VARA
Xiao Mei Zheng
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Merck Sharp and Dohme LLC
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Merck Sharp and Dohme LLC
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    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure provides certain compounds that are TREM2 agonists.
  • the compounds are useful for treatment and prevention of a neurodegenerative disorder associated with a loss of function of human TREM2.
  • the disclosed TREM2 agonists may be useful for the treatment of Alzheimer’s Disease and associated neurological conditions.
  • AD Alzheimer’s disease
  • acetylcholinesterase inhibitors e.g..
  • N-methyl-D-aspartate receptor antagonists e.g., memantine
  • TREM2 Triggering Receptor Expressed on Myeloid cells-2 (TREM2).
  • TREM2 Myeloid cells-2
  • Heterozygous mutations in the TREM2 gene have been found to increase the risk of AD by up to 3-fold (Guerreiro et al. (2013), NEngl J Med, 368: 117-127; Jonsson et al. (2013) NEngl J Med, 368: 107-116), and increase the rate at which brain volume shrinks (Rajagopalan et al. (2013) N Engl J Med, 369: 1565-1567).
  • TREM2 expression impacts amyloid pathology 7 , modulates neuritic dystrophy, tau hyperphosphorylation and aggregation, and affects synaptic and neuronal loss (Jay et al. (2017) Mol Neurodegener, 12(1 ): 56).
  • TREM2 plays a key role in limiting the development of peri-plaque tau pathologies (Leyns et al. (2019) Nat Neurosci).
  • TREM2 is expressed primarily on myeloid lineage cells, including microglia (Colonna & Wang (2016) Nat Rev Neurosci, 17:201-207).
  • Microglia are resident macrophages of the central nervous system (CNS) that, when activated appropriately, are thought to sen e an important protective role in Alzheimer’s disease through their housekeeping functions such as facilitating clearance of cellular debris through phagocytosis, as well as secretion of growth factors.
  • CNS central nervous system
  • TREM2 is exclusively expressed on microglia. It has been shown that TREM2 expression regulates microglial chemotaxis and phagocytosis, and enhances microglial cell survival, proliferation, and differentiation.
  • TREM2 may ameliorate AD symptoms and result in improvements in cognitive function through activation of the innate immune system, and as such agonists of TREM2 may be useful in the treatment of Alzheimer’s disease and other dementias and related neurodegenerative disorders.
  • agonists of TREM2 may be useful in the treatment of Alzheimer’s disease and other dementias and related neurodegenerative disorders.
  • the present invention is directed to certain carbonyl -substituted fused heteroaryl derivative compounds. These compounds are shown to exhibit agonism of the TREM2 receptor, surprisingly and advantageously.
  • the present invention is further directed to the use of these compounds in the treatment or prevention of a neurodegenerative disorder, in a subject in need thereof.
  • the present invention provides compounds that may be adapted for pharmaceutical compositions that may be administered to a subject suffering from a neurodegenerative disorder.
  • the compounds of the disclosure contain a core having two fused nitrogen-containing aryl groups, and exhibit excellent potency in activating the TREM2 receptor, such as the human TREM2 receptor.
  • the compounds of the invention exhibit superior potency as agonists of TREM2, as evidenced by the data reported herein.
  • the compounds of the invention may be useful in the treatment or prevention of neurodegenerative disorders (or one or more symptoms associated with such disorders) in which TREM2 is involved, including Alzheimer's disease and other indications, diseases and disorders as described herein.
  • the invention is also directed to pharmaceutical compositions comprising a compound of the invention and to methods for the use of such compounds and compositions for the treatments described herein.
  • X 1 and X 2 are independently N, C(F) or C(H);
  • X4 is N or C(R 8 ); wherein when Xl is N then X4 is C(R ), and when X4 is N then Xl is C(F) or C(H);
  • 5- to 6-membered heterocycloalkyl wherein said 5- to 6-membered heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S; wherein ring is unsubstituted or substituted by 1 to 3 RZ substituents independently selected from the group consisting of fluoro, Ci-3 alkyl, Ci-3 fluoroalkyl or C 1-3 alkoxy;
  • R 3 is selected from the group consisting of: wherein R 7 and R 11 are independently selected from hydrogen, a halo, -Ci-4 alkyl, cyclopropyl, and -CF?; and R 10 , R 12 and R 13 are independently selected from hydrogen and a halo;
  • R 3 is selected from:
  • Y 1 is C(H). C(F). N or O;
  • Y 3 is C(H) or N
  • R 4 is selected from hydrogen, a -C4-6 cycloalkyl, a heterocyclyl, and a heteroaryl; wherein the C4-6 cycloalkyl, heterocyclyl and heteroaryl of R 4 is unsubstituted or substituted with 1 to 3 R4a substituents independently selected from the group consisting of fluoro, C1-3 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy. C1-3 fluoroalkoxy, and C3-6 cycloalkyl, heterocyclyl and heteroaryl;
  • R9a and R9b are independently H. fluoro, or C]-3 alkyl; or, alternatively, R9a and R9b. together with the carbon atom to which they are attached, form a C3-6 cycloalkyl; and
  • the invention also encompasses pharmaceutical compositions comprising an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present disclosure is directed to compounds of Formula (I), which exhibit activity as agonists of TREM2 receptor.
  • pharmaceutical preparations comprising any of these compounds and a pharmaceutically acceptable carrier.
  • methods of treatment and prevention of a neurodegenerative disorder comprising the administration of any of these compounds to a subject.
  • methods of treatment and prevention of a condition associated with a loss of function of human TREM2 in a subject COMPOUNDS OF THE DISCLOSURE
  • the compound of Formula (I) has the Formula (II) wherein:
  • R 1 is a -Ci-3 alkyl or -OC1-3 alkyl
  • R 2 is a -C1-3 alkyl; or, alternatively, R 1 and R 2 are optionally taken together with their intervening atoms to form a C5-8 cycloalkyl or 5- to 8-membered heterocyclyl group, and wherein the C5-8 cycloalkyl or 5- to 8-membered heterocyclyl group is unsubstituted or independently substituted with one or two fluoro or methyl;
  • R 4 is selected from hydrogen and a heteroaryl that is comprised of:
  • the compounds of Formula (I) and Formula (II) are bicyclic.
  • compounds such as the below exemplary compound pharmaceutically acceptable salt thereof are compounds such as the below exemplary compound pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) and Formula (II) are tricyclic.
  • a sub-embodiment of these embodiments are compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are taken together to form a C5-6 cycloalkyl or or a 5- to 6-membered heterocyclyl that is unsubstituted or substituted with one or two fluoro.
  • R 1 and R 2 are taken together to form a C5-6 cycloalkyl that is unsubstituted.
  • R 1 and R 2 are taken together to form a 5- to 6-membered heterocyclyl containing a single O atom.
  • compounds such as the below exemplary compounds: pharmaceutically acceptable salt thereof are compounds such as the below exemplary compounds: pharmaceutically acceptable salt thereof.
  • R 12 and R 11 are each hydrogen, such that R 3 is
  • R 5 is a 4- to 8-membered cycloalkyl or heterocyclyl.
  • R 5 is a 4- to 8-membered spiro, caged or bridged 4- to 8-membered cycloalkyd or heterocyclyl.
  • R 4 is heteroary l, such as a 5- to 6-membered heteroaryl.
  • R 4 is a pyrazole that is unsubstituted or substituted at the 1 -position with a -Ci-io alkyl.
  • Xl is N or C(F);
  • X4 is N or C(H); wherein when Xl is N then X4 is C(H), and when X4 is N then Xl is C(F);
  • R 1 and R 2 are independently H or Ci-4 alkyl, or alternatively, R 1 and R 2 , together with the carbon atoms to which they are attached, form a ring CZ; wherein ring CZ is:
  • 5- to 6-membered heterocycloalkyl wherein said 5- to 6-membered heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S; wherein ring CZ is unsubstituted or substituted by 1 to 3 RZ substituents independently selected from the group consisting of fluoro, Ci-3 alkyl, Ci-3 fluoroalkyl or C 1-3 alkoxy;
  • Y 2 is C(H), C(F), or N;
  • R 4 is:
  • R 4 is unsubstituted or substituted by 1 to 3 R4a substituents independently- selected from the group consisting of fluoro, C1-3 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy. C1-3 fluoroalkoxy, and C3-6 cycloalkyl;
  • R9a and R9b are independently H, fluoro, or Ci-3 alkyl; or, alternatively, R9a and 9b. together with the carbon atom to which they are attached, form a C3-6 cycloalkyl; and s is 0 or 1.
  • Xl is N and X4 is C(H).
  • R 4 is selected from hydrogen, a -C4-6 cycloalkyl, a heterocyclyl, and a heteroaryl.
  • Formula (I) having structural Formula (II), wherein:
  • X 3 is CH2 or O
  • R 1 is a -C1-3 alkyl or -OC1-3 alkyl
  • R 2 is a -C1-3 alkyl
  • R 7 is a halo
  • the compounds of Formulas (I)-(III) are bicyclic. In some embodiments, the compounds of Formulas (I)-(III) are tricyclic.
  • X 1 and X 2 are each N.
  • the compound is selected from the group of Example Nos. 1- 1 - 1-11, 2-1 - 2-17, 3-1 - 3-50, 4-1 - 4-40, 5-1 - 5-34, 6-1, 7-1, 8-1. and 9-1.
  • the compound is selected from group of Example Nos. the compound is selected from the group of Example Nos. 1-1 - 1-1 1, 2-1 - 2-17, 4-1 - 4-40, 5-1 - 5-34, 6-1, 7-1, 8-1, and 9-1.
  • the disclosed compounds and pharmaceutical compositions are useful for treatment and/or prevention of one or more neurodegenerative disorders. For instance, they may be useful for treatment or prevention of one or more of Alzheimer’s disease, Parkinson’s disease. frontotemporal dementia, demyelination disorder, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis (ALS). tauopathy disease, Nasu-Hakola disease, or adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
  • the disclosed compounds and compositions are useful for treatment of Alzheimer’s Disease.
  • the disclosed compounds and compositions are useful for treatment of dementia, such as frontotemporal dementia.
  • Modulation of biomarkers of Alzheimer’s disease pathology or progression in the subject may be observed by measuring any of the following biomarkers in a sample of the subject's blood, plasma and/or cerebrospinal fluid: Ab42/40 ratio, pTau and/or total Tau, NfL, GFAP, soluble Trem2 (sTrem2) and YKL-40.
  • any of the disclosed compounds improve (i.e., reduce) the subject’s Ab42/40 ratio, pTau and/or total Tau, NfL, GFAP, sTrem2 and/or YKL-40 in plasma or cerebrospinal fluid (CSF).
  • administration of any of the disclosed compounds improve the subject's Ab42/40 ratio.
  • administration of any of the disclosed compounds reduce the sTREM2 in the subject’s CSF.
  • a compound of Formula (II), or pharmaceutically acceptable salt thereof is used in the preparation of a medicament for: (a) therapy (e.g. of the human body), (b) medicine, (c) activation of TREM2 receptor, (d) treatment or prevention of Alzheimer’s Disease and/or neurological symptoms thereof, (e) treatment or prevention of dementia, or (f) treatment, prevention of, or delay in the onset or progression of Alzheimer’s Disease, dementia, and/or neurological symptoms thereof.
  • the condition associated with a loss of function of human TREM2 is dementia or cognitive impairment associated with Alzheimer’s Disease. In some embodiments, this condition is cognitive impairment associated with Parkinson’s Disease. In some embodiments, this condition is cognitive impairment associated with frontotemporal dementia, demyelination disorder, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis (ALS). tauopathy disease, Nasu-Hakola disease, or adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).
  • ALS amyotrophic lateral sclerosis
  • the disclosure further provides methods of administering any of the disclosed compounds or compositions to a subject.
  • the disclosed methods may bring about in the subject (i) a reduction in amyloid plaques, (ii) an elevation in disease-associated microglia (DAM) mRNA expression, (iii) an elevation in lipid metabolism, (iv) an elevation in DAM chemotaxis, DAM proliferation, DAM pro-inflammatory cytokine secretion, or DAM phagocytic activity, and/or (v) a reduction in dystrophic neurites.
  • the disclosed methods bring about a reduction in amyloid plaques.
  • the presently disclosed methods bring about an elevation in disease-associated microglia (DAM) mRNA expression. In some embodiments, the presently disclosed methods bring about an elevation in lipid metabolism in the subject. In some embodiments, the disclosed methods bring about an elevation in DAM chemotaxis. DAM proliferation, DAM pro-inflammatory cytokine secretion, or DAM phagocytic activity, and/or a reduction in dystrophic neurites. [0045] In some aspects, provided herein are methods for the treatment or prophylaxis of abnormal motor symptoms associated with Parkinson's disease (including but not limited to bradykinesia, rigidity and resting tremor).
  • Parkinson's disease including but not limited to bradykinesia, rigidity and resting tremor.
  • Another embodiment provides a method for the treatment or prophylaxis of abnormal non-motor symptoms associated with Parkinson’s disease (including but not limited to cognitive dysfunction, autonomic dysfunction, emotional changes and sleep disruption), Lewy body dementia, and L-Dopa induced dyskinesias.
  • abnormal non-motor symptoms associated with Parkinson’s disease including but not limited to cognitive dysfunction, autonomic dysfunction, emotional changes and sleep disruption
  • Lewy body dementia including but not limited to Lewy body dementia, and L-Dopa induced dyskinesias.
  • any of the presently described compounds, compositions and methods provide a reduction in the likelihood or severity of symptoms of Alzheimer’s Disease in one or more subjects. In some embodiments, any of these compounds, compositions, and methods may provide a partial or complete reduction/inhibition of one or more symptoms. Any of the disclosed compounds, compositions, and methods may provide a partial or complete activation of the TREM2 receptor. Any of the disclosed compounds, compositions, and methods may provide a partial or complete reversal of a loss of function of human TREM2 in a subject. Any of the disclosed methods may provide an improvement in cognitive function following administration of any of the disclosed compounds.
  • a “subject” is a human or non-human mammal.
  • a subject is a human.
  • a subject is a primate.
  • a subject is anon- human primate, e.g.. a monkey.
  • a subject is a rhesus monkey.
  • a subject is a rodent, such as a rat.
  • the subject is a companion animal.
  • the subject is a laboratory 7 animal.
  • an effective amount refers to an amount of compound and/or an additional therapeutic agent, or a composition thereof that is effective in agonizing the human TREM2 receptor and in producing the desired therapeutic, ameliorative, or preventative effect when administered to a subject suffering from a neurodegenerative disorder.
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.
  • treating includes inhibiting the severity of a neurodegenerative disorder, e.g., arresting or reducing the development of the neurodegenerative disorder or its clinical symptoms; or ameliorating or relieving symptoms of the neurodegenerative disorder, e.g, causing regression of the severity of the neurodegenerative disorder or its clinical symptoms.
  • the disclosed compounds, pharmaceutical compositions, and methods may be useful for arresting or reducing the development of, or relieving symptoms of. Alzheimer’s Disease or neurological conditions associated with Alzheimer’s Disease.
  • preventing or “prophylaxis,” as used herein with respect to a neurodegenerative disorder, encompasses impeding the development or progression of clinical symptoms of the disease, disorder, or condition in a mammal that may be exposed to or predisposed to the disease, disorder or condition but does not yet experience or display symptoms of the disease, and the like.
  • Alky l as well as other groups having the prefix “alk”, such as alkoxy, and the like, means carbon chains which may be linear or branched, or combinations thereof, containing the indicated number of carbon atoms.
  • a Ci-6 alkyl means an alkyl group having one (i. e. , methyl) up to 6 carbon atoms (i.e., hexyl).
  • linear alkyl groups have 1-6 carbon atoms and branched alkyl groups have 3-7 carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.
  • Alkoxy and “alkyl-O-” are used interchangeably and refer to an alkyd group linked to oxygen. “Haloalkoxy” means an alkoxy that is mono-or multiple-halo-substituted. The bond to the parent group is through the oxygen atom of the group.
  • Cycloalkyl means a cyclic hydrocarbon radical. Unless otherwise specified, “cycloalkyl” refers to a saturated cycloalkyl. In particular embodiments, the cycloalkyl group has 3-12 carbon atoms, forming 1-3 carbocyclic rings, wherein cyclic systems having 2-3 rings can be fused. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. In certain embodiments, e.g., the cycloalkyl is fused to a hetereraryl ring, the cycloalkyl may be a non-aromatic, partially unsaturated ring.
  • Fluoroalkyl includes mono-substituted as well as multiple fluoro-substituted alky 1 groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1 -difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included. The bond to the parent group is through one of the carbon atoms of the alkyl component.
  • Bicyclic ring system refers to two joined rings.
  • Tricyclic ring system refers to three joined rings.
  • Tetracyclic ring system refers to four joined rings.
  • Heterocyclic and cycloalkyl rings may be fused, i.e., share two adjacent atoms, or “spirocyclic”. i.e., share only a single atom, or “bridged”, i.e., share three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom.
  • Heteroaryl rings may be fused.
  • halo means -F, -Cl, -Br or -I.
  • haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with halo (i.e., -F, -Cl, -Br and/or -I).
  • “Fluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted alkyd groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1 -difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included.
  • “Fluoroalkoxy” includes monosubstituted as well as multiple fluoro-substituted “alkoxy” groups as previously defined.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of urity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as. for example, T. W. Greene et al.. Protective Groups in Organic Synthesis (1991), Wiley, New York.
  • any variable e.g., Rl, R x , R Y
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substitution by a named substituent is permitted on any atom in a ring (e.g. , cycloalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound.
  • heteroaryl or “heteroaromatic ring” refers to aromatic monocyclic, bicyclic, tricyclic, or tetracyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O. S, or N atoms.
  • heteroaryl groups include pyrazolyl, oxadiazolonyl, pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.
  • a “heteroaromatic” ring is a carbon-containing ar l ring may contain 1, 2, 3 or 4 heteroatoms.
  • a “heteroaromatic” ring may contain one or more nitrogen atoms (e.g., 1 to 3 nitrogen atoms), one or more oxygen atoms, or one or more sulfur atoms.
  • Heteroaromatic rings may be herein expressed using subscripts that denote the total number of atoms making up the ring.
  • a heteroaromatic ring may have 5-12 ring atoms wherein each atom is selected from carbon, nitrogen, oxygen and sulfur.
  • a 6- membered heteroaryl substituent may contain 4 carbon atoms and two oxygen atoms.
  • Heterocycloalkyl or “heterocyclic ring” or “heterocycle” or “heterocyclyl” (when the ring is bonded to a parent moiety) means a non-aromatic monocyclic, bicyclic, tricyclic or tetracyclic ring system comprising about 3 to about 17 ring atoms, preferably about 3 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphorus or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. In some embodiments, heterocycloalkyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa, phospha or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, phosphorus or sulfur atom respectively is present as a ring atom.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.
  • “Spiroheterocycloalkyl” refers to a fused ring system in which the rings share only a single atom and at least one of the rings is a heterocycloalkyl.
  • the compounds disclosed herein contain a heteroaryl substituent containing one nitrogen atom. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range.
  • a “heterocyclic” ring is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms. 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom. 2 heteroatoms. 3 heteroatoms, or 4 heteroatoms.
  • the ring may contain one or more nitrogen atoms (e.g, 1 to 3 nitrogen atoms), one or more oxygen atoms, or one or more sulfur atoms.
  • any of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups described herein may be optionally substituted with one or more groups.
  • “optionally substituted with one to five groups” is intended to include as aspects thereof, the cycloalkyl, heterocyclyl. aryl or heteroaryl substituted with 1 to 5 substituents, 2 to 5 substituents, 3 to 5 substituents, 4 to 5 substituents, 5 substituents, 1 to 4 substituents, 2 to 4 substituents, 3 to 4 substituents, 4 substituents, 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent.
  • ‘'optionally substituted with one to three groups” is intended to include as aspects thereof, the cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.
  • salt(s) denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term “salt(s)” as used herein.
  • Compounds can be administered in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to a salt which is not biologically or otherwise undesirable (e.g.. is neither toxic nor otherwise deleterious to the recipient thereof).
  • the compounds of Formulas (I)-(III), and pharmaceutically acceptable salts thereof, which contain one or more basic groups, i.e., groups which can be protonated, can be used according to the invention in the form of their acid addition salts with inorganic or organic acids as, for example but not limited to, salts with hydrogen chloride, hydrogen fluoride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid, /7-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid
  • one or more N atoms e.g., an N atom in a heteroaryl or heterocyclyl ring, or an N atom in an NH2 group
  • an N atom that is a ring member of a heteroaryl or heterocyclyl ring of any of the compounds of Formulas (I)-(III) is protonated in a salt form.
  • this N atom is protonated in a salt form with trifluoroacetate.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formulas I and/or II by customary methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts.
  • the present disclosure also includes all salts of the compounds of Formulas (I)-(III) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • compositions comprised of a compound of Formulas I and/or II or a compound that is a salt thereof, including for example but not limited to, a composition comprised of said compound associated together with one or more additional molecular and/or ionic component(s) which may be referred to as a “co-crystal.”
  • co- crystaf refers to a solid phase (which may or may not be cry stalline) wherein two or more different molecular and/or ionic components (generally in a stoichiometric ratio) are held together by non-ionic interactions including but not limited to hydrogen-bonding, dipole-dipole interactions, dipole-quadrupole interactions or dispersion forces (van der Waals).
  • Compounds of the present invention may exist in amorphous form and/or one or more cry stalline forms, and as such all amorphous and cry stalline forms and mixtures thereof of the compounds of Formulas (I)-(III) are intended to be included within the scope of the present invention.
  • some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents.
  • Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhy drous forms.
  • the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof.
  • Solvates of the disclosed compounds of Formulas (I)-(III) are contemplated herein.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves vary ing degrees of ionic and covalent bonding, including hydrogen bonding. In certain situations, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • “Solvate” encompasses both solution-phase and isolatable solvates.
  • Non-limiting examples of solvates include ethanolates, methanolates, and the like.
  • a "hydrate” is a solvate wherein the solvent molecule is water.
  • a typical, non-limiting, process involves dissolving the compound in desired amounts of the desired solvent (organic or water or mixtures thereol) at a higher than room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the compounds of Formulas (I)-(III) can form salts which are also within the scope of this invention.
  • the salt is a pharmaceutically acceptable salt.
  • the salt is other than a pharmaceutically acceptable salt. Salts of the compounds of Formulas (I)-(III) may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogencontaining groups may be quartemized with agents such as lower alkyl halides (e.g.
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides
  • arylalkyl halides e.g., benzyl and phenethyl bromides
  • This disclosure includes individual diastereomers, particularly epimers, i.e., compounds having the same chemical formula but which differ in the spatial arrangement around a single atom.
  • This disclosure also includes mixtures of diastereomers, particularly mixtures of epimers, in all ratios.
  • This disclosure encompasses compounds of Formulas (I)-(III) having either the R or S stereo-configuration at an asymmetric center and at any additional asymmetric centers that may be present in a compound of Formula (I), as w ell as stereo-isomeric mixtures thereof.
  • Embodiments of this disclosure also include a mixture of enantiomers enriched with 51% or more of one of the enantiomers, including for example 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer.
  • a single epimer is preferred.
  • An individual or single enantiomer refers to an enantiomer obtained by chiral synthesis and/or using generally known separation and purification techniques, and which may be 100% of one enantiomer or may contain small amounts (e.g., 10% or less) of the opposite enantiomer.
  • individual enantiomers are a subject of this disclosure in pure form, both as levorotatory 7 and as dextrorotatory 7 antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
  • this disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios.
  • the preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary' methods, for example by chromatography or cry stallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
  • a derivatization can be carried out before a separation of stereoisomers.
  • the separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formulas (I)-(III), or it can be done on a final racemic product.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration.
  • absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis.
  • VCD Vibrational Circular Dichroism
  • the present disclosure includes all such isomers, as well as salts, solvates (which includes hydrates), and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound ( ⁇ ?.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g, hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound ⁇ ?.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques.
  • some of the compounds of Formulas (I)-(III) may be atropisomers (e.g.. substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be directly separated using chiral chromatographic techniques.
  • the compounds of Formulas (I)-(III) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • each of the keto/enol and imine/enamine tautomeric forms of the disclosed compounds are encompassed w ithin embodiments of the disclosed compounds that depict either form individually.
  • both the hydroxypyridine and pyridinone forms of oxosubstituted pyridine substituents are encompassed within embodiments of the disclosed compounds that depict either form individually.
  • Absolute stereochemistry of separate stereoisomers in the examples and intermediates may not have been determined unless stated otherwise in an example or explicitly in the nomenclature. Otherwise, for compounds in the Examples that contain a chiral center, isomer mixtures may have been separated, yielding the particular stereoisomer(s) depicted.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate” and the like, is intended to apply equally to the salt and solvate of enantiomers, stereoisomers, rotamers, tautomers or racemates of the disclosed compounds.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formulas (I)-(III).
  • different isotopic forms of hydrogen (H) include protium 6 1 H ) and deuterium ( 2 H).
  • Protium is the predominant hydrogen isotope found in nature.
  • Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds of Formulas (I)-(III) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • a compound of Formulas (I)-(III) has one or more of its hydrogen atoms replaced with deuterium.
  • the articles “a’' and “an” refer to one or to more than one (i. e.. to at least one) of the grammatical object of the article.
  • an element means one element or more than one element.
  • use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.
  • the term “about” when modifying a quantitative term refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules).
  • the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.”
  • the terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients/steps and permit the presence of other ingredients/steps.
  • such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.
  • Impairment in TREM2 receptor function has been linked to several human diseases. For instance, mutations in both TREM2 and DAP 12 have been linked to the autosomal recessive disorder Nasu-Hakola Disease, which is characterized by bone cysts, muscle wasting and demyelination phenotypes. Guerreiro et al. 2013. Variants in the TREM2 gene have been linked to increased risk for Alzheimer’s disease (AD) and other forms of dementia including frontotemporal dementia. (Jonsson et al. 2013, Guerreiro & Lohmann et al. 2013, and Jay & Miller et al.
  • a pharmaceutically acceptable salt thereof for treatment or prevention of PLOSL.
  • methods of administering any of the disclosed compounds for treatment or prevention of NHD Further provided herein are methods of administering any of the disclosed compounds for treatment or prevention of adult-onset leukoencephalopathy, with or without axonal spheroids and pigmented glia. Further provided herein are methods of administering any of the disclosed compounds for treatment or prevention of ALSP.
  • TREM2 is expressed in myeloid lineage cells of the liver.
  • these compounds, or a pharmaceutically acceptable salt thereof may be useful to treat or prevent a liver disease associated with impaired TREM2 function.
  • these compounds are useful to treat or prevent alcoholic liver disease (ALD) or non-alcoholic steatohepatitis (NASH).
  • ALD alcoholic liver disease
  • NASH non-alcoholic steatohepatitis
  • the subject is a non-human mammal.
  • the subject is a companion animal.
  • the subject is a laboratory animal.
  • the subject is a rodent.
  • the subject is a non-human primate.
  • any of the disclosed compounds may be combined with any pharmaceutically acceptable inert carrier.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, sachets and suppositories. Tablets, powders, sachets and capsules may be suitable for oral administration. Powders and tablets may be comprised of between about 0.5 and about 95 percent of any of the disclosed pharmaceutical compositions. [OHl] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as gly ceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • compositions of the present invention may be formulated in extended dosing, or sustained release, forms to provide a rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e.. TREM2 activation.
  • Suitable dosage forms for sustained release include long-acting injectable and implant dosage forms.
  • Other suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Solid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. These preparations may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Liquid preparations suitable for oral administration e.g., suspensions, syrups, elixirs and the like
  • any of the disclosed pharmaceutical compositions comprise pharmaceutically acceptable carriers that are suitable or adapted for administration to the subject by injection. In some embodiments, these carriers are adapted for long-action injection. In some embodiments, these carriers are liquid form preparations that include solutions, suspensions, emulsions, or nano-emulsions for intramuscular or subcutaneous administration. In some embodiments, any of the disclosed pharmaceutical compositions are adapted for long-acting injectable formulations.
  • compositions may comprise pharmaceutically acceptable carriers that are suitable or adapted for administration parenterally, including subcutaneous, intravenous, intramuscular, intraperitoneal or intrastemal injection, or other infusion techniques (one or more injections or infusions may be administered at each dosing interval as needed to deliver the appropriate amount of active agent), in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional pharmaceutically acceptable carriers, adjuvants and vehicles for the treatment of a subject suffering from a neurodegenerative disorder.
  • the compositions may also be administered parenterally via an implantable drug delivery composition or device adapted to provide an effective amount of the compound over an extended period of time. In some embodiments, the composition is administered parenterally once per month, once per every three months, once per every six months, or once per every twelve months.
  • the disclosed compositions are adapted for intramuscular administration. In some embodiments, the disclosed compositions are adapted for subcutaneous administration. In some embodiments, the disclosed compositions are adapted for intravenous administration. In some embodiments, the disclosed compositions are adapted for intraperitoneal administration. In some embodiments, the disclosed compositions are adapted for intracerebroventricular (ICV), intrathecal, or intracistemal administration. In some embodiments, the disclosed compositions may be adapted for inhalation spray, intranasal, vaginal, rectal, sublingual, buccal or topical routes of administration.
  • ICV intracerebroventricular
  • the disclosed compositions may be adapted for inhalation spray, intranasal, vaginal, rectal, sublingual, buccal or topical routes of administration.
  • Parenteral compositions can be prepared according to techniques known in the art. These compositions may employ sterile water as a carrier and optionally other ingredients. A continuous dosing regimen may be used for subjects suffering from a neurodegenerative disease, such as Alzheimer’s Disease. Any of the disclosed pharmaceutical preparations for parenteral inj ection may comprise solutions, suspensions or emulsions that may include water, a suspending agent, a viscosity modifier, a tonicity modifier, and/or a pH modifier.
  • Formulations of compounds of Formula (I) that result in drug supersaturation and/or rapid dissolution may be utilized to facilitate oral drug absorption.
  • Formulation approaches to cause drug supersaturation and/or rapid dissolution include, but are not limited to, nanoparticulate systems, amorphous systems, solid solutions, solid dispersions, and lipid systems.
  • Such formulation approaches and techniques for preparing them are known in the art.
  • solid dispersions can be prepared using excipients and processes as described in reviews (e.g., A.T.M. Serajuddin, J Pharm Sci, 88: 10. pp. 1058-1066 (1999)).
  • Nanoparticulate systems based on both attrition and direct synthesis have also been described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).
  • the compounds of Formula (I) may be administered in a dosage range of, e.g., 1 to 20 mg/kg, or 1 to 10 mg/kg. or about 5 mg/kg of mammal (e.g., human) body weight per day, or at other time intervals as appropriate, in a single dose or in divided doses.
  • the compounds of Formula (I) may be administered in a dosage range of 0.001 to 2000 mg per day in a single dose or in divided doses. Examples of dosage ranges are 0.01 to 1500 mg per day, or 0.1 to 1000 mg per day, administered orally or via other routes of administration in a single dose or in divided doses.
  • the dosage units may contain 100 mg to 1500 mg of the active ingredient, for example but not limited to 0. 1 mg to about 1500 mg of the active ingredient, for example but not limited to 0.1, 0.25, 0.5, 1, 2, 2.5, 5, 10, 15, 20, 25, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 1000, 1250, or 1500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compound may be formulated in oral formulations for immediate or modified release such as extended or controlled release.
  • reference to an amount of the compound in milligrams or grams is based on the free form (i.e., the non-salt form) of the compound.
  • Daily administration can be via any suitable route of administration but is preferably via oral administration and can be a single dose or more than one dose at staggered times (divided daily doses) within each 24-hour period. Each dose may be administered using one or multiple dosage units as appropriate.
  • the disclosed compounds and compositions are administered once daily. In some embodiments, the disclosed compounds and compositions are administered twice daily.
  • the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability 7 and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the effect of other drugs the subject is taking, the severity of the particular condition, and the host undergoing therapy. In some cases, depending on the potency of the compound or the individual response, it may be necessary to deviate upwards or downwards from the given dose. The amount and frequency of administration will be regulated according to the judgment of the attending clinician considering such factors.
  • the compounds of this invention are also useful in the preparation and execution of screening assays for agonists of TREM2. Furthermore, the compounds of this invention may be useful in establishing or determining the binding site of other TREM2 agonists.
  • a pharmaceutical composition which comprises the product prepared by combining (e.g, mixing) an effective amount of a compound of Formulas (I)-(III) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Additional embodiments of the present disclosure include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound of Formula (I) or its salt employed therein in substantially pure.
  • a pharmaceutical composition comprising a compound of Formulas (I)-(III) or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term “substantially pure” is in reference to a compound of Formulas (I)-(III) or its salt per se.
  • the present methods for treating or preventing a neurodegenerative disorder can further comprise the administration of one or more additional therapeutic agents that are not any of the disclosed compounds.
  • Examples of additional therapeutic agents that the compounds of this disclosure may also be combined with include, without limitation, treatments for Alzheimer’s disease, Parkinson's disease, rheumatoid arthritis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, demyelination disorder, Huntington’s disease, amyotrophic lateral sclerosis (ALS). tauopathy disease, adult-onset leukoencephalopathy, argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, HIV -induced dementia, or neuroinflammation.
  • the present invention provides methods for treating a neurodegenerative disorder in a subject, the method comprising administering to the subject: (i) at least one compound of Formulas (I)-(III) (which may include two or more different compounds), or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than any of the disclosed compounds, wherein the amounts administered are together effective to treat or prevent a neurodegenerative disorder.
  • the additional therapeutic agent is a tau targeting therapy.
  • the additional therapeutic agent is an amyloid-0-targeting therapy.
  • Administration of a tau targeting therapy or an amyloid-P targeting therapy has been shown to improve cognitive function, reverse (partially) the neurodegenerative effects of Alzheimer’s Disease, and/or treat or prevent Alzheimer’s Disease.
  • provided herein are methods of administering any of the disclosed compounds wherein the methods further comprise a step of administering a tau targeting therapy or an amyloid-P targeting therapy to the subject. Such methods may be used to promote the treatment or prevention of a neurodegenerative disorder in a subject. Such methods may be used to promote the treatment or prevention of AD in a subject.
  • therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • a compound and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).
  • any of the disclosed compounds or a pharmaceutically acceptable salt thereof is administered orally, and the additional therapeutic agent is further administered orally.
  • the compound and the other agent(s) may be administered simultaneously (i.e.. in separate compositions one right after the other) or sequentially.
  • a disclosed compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours. 10 hours, 11 hours, 12 hours, 13 hours. 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent.
  • a disclosed compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
  • At least one compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • at least one compound and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy.
  • at least one compound and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy.
  • the additional therapeutic agent(s) is present in a pharmaceutical composition.
  • this composition is suitable for subcutaneous administration.
  • this composition is suitable for intramuscular administration.
  • this composition is suitable for oral administration.
  • this composition is suitable for intravenous administration.
  • the at least one compound and the additional therapeutic agent(s) can act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a neurodegenerative disorder may be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age. sex and general health of the subject; and the type and severity of the neurodegenerative disease or neurological symptoms thereof.
  • the compound and the other agent(s) may be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially.
  • kits comprising the separate dosage forms is therefore advantageous.
  • the compounds of the present disclosure can be prepared according to the procedures of the following Examples, using appropriate materials.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the Examples further illustrate details for the preparation of the compounds of the present disclosure.
  • Those skilled in the art will readily understand that known variations of protecting groups, as well as of the conditions and processes of the following preparative procedures, can be used to prepare these compounds. It is also understood that whenever a particular chemical reagent is not commercially available, such a chemical reagent can be readily prepared following one of numerous methods described in the literature.
  • Scheme 1-2 describes a general synthetic method to a chemical matter to install R 3 group via Liebeskind Srogl cross coupling first then palladium-catalyzed C-N coupling or Sx Ar reaction.
  • Scheme 1-4 describes the Liebeskind Srogl cross coupling on the monocyclic core, followed by SxAr with an amine and condensation reaction as the last step.
  • Scheme 1-5 describes the Liebeskind Srogl cross coupling on the monocyclic core, followed by SxAr with an amine and condensation reaction as the last step.
  • Scheme 1-6 demonstrates an alternative way of C-C bond formation through Suzuki sp2-sp2 coupling, followed by reduction of the alkene double bond to afford the substituted linker compound.
  • Scheme 1-7 describes the synthesis of the dihydrofuran tricyclic core through hetero aryl amine condensation with a corresponding keto-ester, followed by ester hydrolysis and cyclization to afford the tricyclic core. Next, sequential C-C coupling reactions are used to install R3 and the R3S/R4S linker substituent.
  • Step 2 Preparation of (S)-2-(4-chloro-2-fluorophenyl)-6-(2-(l -methyl- 17/-pyrazol-4- yl)morpholino)pyrimidin-4-amine
  • Step 1 Preparation of methyl 4-((6-chloro-2-(methylthio)pyrimidin-4-yl)amino)-2.5- dihvdrofuran-3-carboxylate
  • Step 2 Preparation of 4-((6-chloro-2-(methylthio)pyrimidin-4-yl)amino)-2,5-dihydrofuran-3- carboxylic acid
  • Peak 3 mixture sample from above was separated via a second SFC run to yield one of the isomers as Peak 3-1 at 2.7 min and Intermediate 1-8 (Peak 3-2) at 3.3 min.
  • Step 1 Preparation of 2-(tetrahvdrofuran-3-yl)tetrahvdro-2E7-pyran-4-ol
  • Step 2 Preparation of 4-iodo-2-(tetrahydrofuran-3-yl )tetrahydro-277-pyran [0165] To a mixture of 2-(tetrahydrofuran-3-yl)tetrahydro-2//-pyran-4-ol (1 g, 5.81 mmol) and Imidazole (0.514 g, 7.55 mmol). PPhs (1.828 g, 6.97 mmol) in DCM (25 mL) was added h (1.768 g, 6.97 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h.
  • a microwave vial containing 8-chloro-2,3-dimethyl-6-(methylthio)-4E7-pyrimido[l,6- a]pyrimidin-4-one (320 mg, 1.25 mmol), (4-chloro-2-fluorophenyl)boronic acid (273 mg, 1.56 mmol), Tris(dibezylideneacetone)dipalladium (115 mg, 125 pmol) and Phosphine, tri-2-furanyl- (58. 1 mg, 250 pmol) was purged with Ar three times, then THF (6.3 mL) was added. The reaction mixture was purged with Ar three times again. It was sealed and heated in a microwave reactor at 100 °C for 7 min.
  • Step 3 Synthesis of l-(2-methylpyridin-4-yl)-2-nitroethan-l-ol
  • Step 7 Preparation of 2-(2-(dibenzylamino)-l-(2-methylpyridin-4-yl)ethoxy)-2.2-difluoroacetic acid
  • Step 9 Synthesis of 2.2-difluoro-6-(2-methylpyridin-4-yl)morpholine
  • Step 1 Synthesis of 4-( 1 -ethoxy vinyl)-2-methylpyridine ,
  • the crude product was purified by flash silica gel chromatography (eluent of 0-30% Ethyl acetate/Petroleum ether) to give l-(2-methylpyridin- 4-yl) ethan-l-one as a desired product.
  • Step 4 Synthesis of 2-(benzyl(2-hvdroxypropyl)amino)-l-(2-methylpyridin-4-yl)ethan-l-one
  • Step 5 Synthesis of 4-benzyl-2-methyl-6-(2-methylpyridin-4-yl)-3.4-dihvdro-2H-l,4-oxazine
  • TMSOTf (1.25 kg, 5.63 mol) was added to 2-(benzyl (2 -hydroxypropyl) amino)-l-(2- methylpyridin-4-yl) ethan-l-one (5) (560 g, 1.88 mol) and DCE (11.2 L, 20V) at 0 °C.
  • the resulting mixture was heated to 90 °C for 16 h, then quenched with sodium bicarbonate (8%, 5.6 L, 10 V) and extracted with 10% methanol in dichloromethane. The organic layer was washed with brine (10%.
  • Step 1 Synthesis of 6-(tetrahvdrofuran-3-yl)-3,6-dihvdro-2H-pyran-4-yl trifluoromethanesulfonate
  • Step 2 Synthesis of 4,4.5.5-tetraethyl-2-(6-(tetrahydrofuran-3-yl)-3.6-dihydro-2H-pyran-4-yl)-
  • Step 1 Preparation of 2.3-dimethyl-8-(2-(l-methyl-17/-pyrazol-4-yl)morpholino)-6-(methylthio)- 4//-pyrimido
  • the reaction was then purged with Ar and heated in a hot plate at 100 °C for 1 h.
  • the reaction was cooled to room temperature, water (5 mL) was added, and the mixture was extracted with DCM (5 mL) two times.
  • the combined organic extracts were washed with brine (3 mL) and dried over anhydrous MgSCh. The filtrate was evaporated under reduced pressure.
  • Step 2 Preparation of 1-1 (5) 6-(4-chloro-2-fluorophenyl)-2,3-dimethyl- 8-(2-( 1 -methyl- 1//- pyrazol-4-yl)morpholino)-47/-pyrimido[L6-a1pyrimidin-4-one and 1-2 (R) 6-(4-chloro-2- fluorophenyl)-2.3-dimethyl- 8-(2-(l -methyl- l/7-pyrazol-4-yl)morpholino)-47f-pyrimido[ 1.6- alpyrimidin-4-one
  • the vial was then purged with Ar again and heated in a microwave reactor at 120 °C for 7 min.
  • the reaction mixture was diluted with water (2 mL) and extracted with DCM (2 mL) two times.
  • the organic extracts were then stirred with 300 mg of Silia MetS ® (Si-Thiol) at room temperature, filtered and concentrated.
  • Step 1 Preparation of 8-chloro-6-(4-chloro-2-fluorophenyl)-2.3-dimethyl-4//-pyrimido[L6- g
  • reaction mixture was cooled to RT and diluted with DCM (10 mL), then filtered through Celite. The filter cake was rinsed with DCM three times. The organic extracts were combined and diluted with water. Saturated NaHCCL aq. (3 mL) was added, then extracted with EtOAc (5 mL) three times. The organic extracts were then concentrated. The residue was purified by column chromatography on silica gel, eluting with 20-60% EtOAc in hexanes to yield desired product 8-chloro-6-(4-chloro- 2-fluorophenyl)-2,3-dimethyl-47/-pyrimido[L6-a]pyrimidin-4-one.
  • Step 2 Preparation of 1-3 (R or S')-6-(4-chloro-2-fluorophenyl)-2.3-dimethyl-8-(3-(2- methylpyrimidin-4-yl)piperidin-l-yl)-477-pyrimido[1.6-a1pyrimidin-4-one and 1-4 (S or R)-6-(4- chloro-2-fluorophenyl)-2.3-dimethyl-8-(3-(2-methylpyrimidin-4-yl)piperidin-l-yl)-47/- pyrimido[1.6-a]pyrimidin-4-one
  • Example Table 1 Examples shown in Example Table 1 below, were prepared according to procedures analogous to those outlined in Examples 1-3 and 1-4 above using appropriate starting materials. Table 2: Examples 1-5 and 1-6
  • Step 1 Synthesis of 8-(2.2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-6-(2.4- difluorophenyl)-2.3-dimethyl-4H-pyrimido[ 1.6-a
  • Step 2 Synthesis of 1-7 (R or S) 8-(2.2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-6-(2.4- difluorophenyl)-2.3-dimethyl-4H-pyrimido[1.6-a]pyrimidin-4-one & 1-8 (S or R) 8-(2.2- difluoro-6-(2-methylpyridin-4-yl)morpholino)-6-(2.4-difluorophenyl)-2.3-dimethyl-4H- pyrimido) 1 ,6-al py rimidin-4-one
  • Step 1 Preparation of 3-(2-(l-methyl-17/-pyrazol-4-yl)morpholino)-l-(methylthio)-7,8- dihvdrocvclopentak/lpyrirnidol 1 .6-fl
  • reaction mixture was purged with Ar and heated in a hot plate at 100 °C for 1 h.
  • the reaction mixture was cooled to room temperature, diluted with water (5 mL) and extracted with DCM (4 mL) two times. The organic extracts were washed with brine (4 mL), dried over anhydrous MgSCh.
  • Step 2 Preparation of 2-1 (5)-l-(4-chloro-2-fluorophenyl)-3-(2-(l-methyl-177-pyrazol-4- yl)morpholino)-7.8- [1.6-a1pyrimidin-9(677)-one and 2-2 (A)-l-(4- chloro-2-fluorophenyl)-3-(2-(l-methyl-17f-pyrazol-4-yl)morpholino)-7.8- dihydrocyclopentati71pyrimido[1.6-fi'1pyrimidin-9 -one
  • the reaction mixture was purged with Ar followed by addition of Pd(PPhs)4 (17.4 mg, 0.015 mmol).
  • the vial was then purged with Ar again and heated in a micro wave reactor at 120 °C for 7 min.
  • the reaction mixture was diluted with water (2 mL) and extracted with DCM (2.5 mL) two times. To the organic extracts were then added thiol-Si scavenger and stirred at room temperature for 10 min. The mixture was filtered and the filtrate was concentrated.
  • Step 1 Preparation of 3-(2-(l-methyl-177-pyrazol-4-yl)morpholino)-l-(methylthio)-6,7.8.9- tetrahy dro-1077-pyrimido[6, 1 -61 quinazolin- 10-one
  • the vial was then purged with Ar again and heated in a hot plate at 100 °C for 2 h.
  • the reaction mixture was cooled to rt, diluted with water (6 mL) and extracted with DCM (4 mL) two times. The organic extracts were washed with brine (4 mL), dried over anhydrous MgSO-i. and concentrated.
  • Step 2 Preparation of 2-3 (5)-l-(4-chloro-2-fluorophenyl)-3-(2-(l-methyl-177-pyrazol-4- yl)morpholino)-6.7.8.9-tetrahydro-1077-pyrimido[6.1- 61 quinazolin- 10-one and 2-4 (7?)-l-(4- chloro-2-fluorophenyl)-3-(2-(l-methyl-177-pyrazol-4-yl)morpholino)-6.7.8.9-tetrahvdro-1077- pyrimido[6.1 -61 quinazolin- 10-one
  • the vial was purged with Ar again and heated in a microwave reactor at 120 °C for 12 min. Upon cooling, the reaction mixture was diluted with water (5 mL) and extracted with DCM (4 mL x 2). To the combined organic extracts was added Silia MetS ® (Si-Thiol) (20 mg), filtered and concentrated.
  • Step 1 Preparation of ( l S)-3-(2-(l-methyl-177-pyrazol-4-yl)morpholino)-l-(methylthio)-6.7.8.9- tetrahy dro-107f-pyrimido[6, 1 -61 quinazolin- 10-one
  • the vial was purged with Ar followed by the addition of RuPhos Pd G4 (30.2 mg, 0.035 mmol).
  • the reaction mixture was then purged with Ar and heated in a hot plate at 100 °C for 3 h.
  • the reaction mixture was cooled, diluted with water (6 mL) and extracted with DCM (5 mL) two times. The organic extracts were dried over anhydrous MgSCL then concentrated.
  • Step 2 Preparation of 2-5 (S)-l-(2.4-difluorophenyl)-3-(2-(l-methyl-17/-pyrazol-4- y l)morpholino)-6,7.8,9-tetrahy dro- 10/7-pyri mi do [6,1-61 quinazolin- 10-one
  • Step 1 Synthesis of 3-chloro-l-(4-chloro-2-fluorophenyl)-6.7.8.9-tetrahvdro-107f-pyrimido[6.1- 61 quinazolin- 10-one
  • Step 2 Synthesis of 2-6 (R or S)-l-(4-chloro-2-fluorophenyl)-3-(2-(2-methylpyridin-4- yl)morpholino)-6.7.8.9-tetrahvdro-10/Z-pyrimido[6.1-6]quinazolin-10-one and 2-7 (S or R)-l-(4- chloro-2-fluorophenyl)-3-(2-(2-methylpyridin-4-yl)morpholino)-6.7.8.9-tetrahvdro-107/- pyrimido[6,l -6] quinazolin- 10-one
  • the vial was purged with Ar again and heated in a hot plate at 100 °C for 2.5 h. Upon completion, the reaction mixture was cooled to rt, diluted with water (3 mL) and extracted with DCM (3 mL x 2). The organic extracts were treated with Silia MetS ® (Si-Thiol), filtered and concentrated.
  • Step 1 Preparation of ( ⁇ S)-7-(2-(l-methyl-l/f-pyrazol-4-yl)morpholino)-9-(methylthio)-3.4- dihvdropyrano[3,2-6 ⁇ npyrimido[L6-a
  • Step 2 Preparation of 2-8 (5)-9-(4-chloro-2-fluorophenyl)-7-(2-(l-methyl-l/7-pyrazol-4- yl)morpholino)-3.4-dihydropyrano[3.2-tZ]pyrimido[1.6-a1pyrimidin-l l(2/Z)-one
  • the reaction was then heated in a microwave reactor at 100 °C for 7 min.
  • the reaction mixture was diluted with DCM and treated with 100 mg of Silia MetS® (Si-Thiol).
  • the mixture was stirred at rt for 5 min, then filtered.
  • the filtrate w as concentrated, diluted with water (2 mL) and sat. NaHCOs aq. (1 mL) and extracted with DCM (2 mL x 2).
  • Examples 2-10 through 2-12 below were prepared according to procedures analogous to those outlined in Example 2-9 above using the appropriate starting materials.
  • Step 1 Synthesis of 8-(2.4-difluorophenyl)-6-llCIS)-2-methyl-6-(2-methylpyridin-4- yl)morpholino)-1.3-dihydro-10H-furo[3.4-d]pyrimido[1.6-a1pyrimidin-10-one
  • Step 2 Preparation of 2-13 8-(2.4-difluorophenyl)-6-( 6R or 2R,6S)-2-methyi-6-(2- methylpyridin-4-yl)morpholino)-1.3-dihvdro-10H-furo[3.4-d]pyrimido[1.6-a1pyrimi din- 10-one
  • Examples 2-15 through 2-17 below were prepared according to procedures analogous to those outlined in Example 2-13 to 2-14 above using the appropriate starting materials.
  • Example 3-29 The synthesis of diastereomers of Example 3-29 are described below in Examples 4-1 and 4-2.
  • the vial was purged with Ar three times, followed by the addition of DMA (1.5 mL). It was purged with Ar three times again and stirred at rt for a few minutes, then heated in a hot plate at 60 °C for 1 h 15 min. The mixture was cooled to room temperature, then water was added, and the mixture was extracted with DCM. The combined organic extracts were concentrated.
  • pyridine-2,6- bis(carboximidamide) hydrochloride (3.0 mg, 14.8 pmol) and nickel chloride, dimethoxyethane adduct (3.3 mg, 14.8 pmol).
  • the mixture was purged with Ar several times, followed by addition of DMA (1 mL).
  • the resulting solution was purged with Ar three times and stirred at rt for a few mins before the reaction mixture was heated at 60 °C for 1 h.
  • Step 1 Preparation of 6-(4-chloro-2-fluorophenyl)-2.3-dimethyl-8-(2-(tetrahvdrofuran-3- yl )tetrahvdro-2/7-pyran-4-yl )-4H-pyrimido
  • Step 2 Preparation 6-(4-chloro-2-fluorophenyl)-2.3-dimethyl-8-((2S.4R)-2-((R)-tetrahvdrofuran- 3-yl )tetrahvdro-2//-pyran-4-yl )-4//-pyrimido
  • Step 4 Synthesis of 6-(2.4-difluorophenyl)-2.3-dimethyl-8-(6-((tetrahvdrofuran-3-yl)methyl)- 3.6-dihvdro-2H-pyran-4-yl)-4H-pyrimido[1.6-a]pyrimidin-4-one
  • Step 5 Synthesis of 6-(2.4-difluorophenyl)-2,3-dimethyl-8-(2-((tetrahvdrofuran-3- yl)methyl)tetrahvdro-2H-pyran-4-yl)-4H-pyrimidol 1.6-a
  • Step 1 Preparation of 6-(2-(2-methylpyridin-4-yl)tetrahydro-27/-pyran-4-yl)-8-(methylthio)-l,3- dihydro-10H-furo[3.4-d1pyrimido[1.6-a1pyrimi din-10-one
  • Step 2 Preparation of 8-(2.4-difluorophenyl)-6-(2-(2-methylpyridin-4-yl)tetrahydro-27/-pyran-4- yl)- 1 ,3-dihvdro- 1 OEf-furo [3,4-dl pyrimidof 1.6-a] pyrimidin- 10-one
  • Step 3 Preparation of 5-1 8-(2,4-difluorophenyl)-6-((2S,4R or 2R,4S)-2-(2-methylpyridin-4- yl)tetrahvdro-27/-pyran-4-yl)-l,3-dihydro-1077-furo[3.4-d1pyrimido[L6-a1pyrimi din- 10-one and 5-2 8-(2.4-difluorophenyl)-6-((2R,4S or 2S.4R)-2-(2-methylpyridin-4-yl)tetrahydro-277-pyran-4- yl)- 1.3-dihvdro- 1 O/7-furol 3.4-d I pyrimidol 1.6-al pyrimidin- 10-one
  • the reaction was heated to 100 °C for 15 min in a microwave.
  • the reaction mixture was quenched with aqueous ammonium chloride (15 mL) and extracted with EtOAc (15 mL*3).
  • the combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.
  • the residue was purified by flash silica gel chromatography (0-30% ethyl acetate/petroleum ether) to give 6-chloro-8-(2,4-difluorophenyl)- 1 ,3-dihy dro- 1 ()//-furo
  • Step 2 Preparation of 6-(6-(l-cyclopropyl-177-pyrazol-4-yl)-3.6-dihydro-2//-pyran-4-yl)-8-(2.4- difluorophenyl)-L3-dihvdro-10/7-furo[3.4-d1pyrimido[L6-a1pyrimidin-10-one
  • Step 3 Preparation of 6-(2-(l-cyclopropyl-177-pyrazol-4-yl)tetrahydro-27/-pyran-4-yl)-8-(2.4- difluorophenyl)-1.3-dihvdro-1077-furo[3.4-d1pyrimido[L6-a1pyrimidin-10-one
  • Step 4 Preparation of 5-3 6-((2S.4R or 2R.4S)-2-(l-cvclopropyl-l/f-pyrazol-4-yl)tetrahydro-27/- pyran-4-yl)-8-(2.4-difluorophenyl)-1.3-dihydro-107/-furo[3.4-d1pyrimido[1.6-a1pyrimidin-10- one and 5-4 6-((2R,4S or 2S.4R)-2-(l-cvclopropyl-17f-pyrazol-4-yl)tetrahvdro-27if-pyran-4-yl)-8-
  • Step 1 Synthesis of 6-chloro-8-(4-chloro-2-fluorophenyl)-l-methyl-1.3-dihydro-10H-furo[3.4- dlpyrimidol L6-a1pyrimidin-10-one
  • Step 3 Preparation of 5-18 (R or M-8-(4-chloro-2-fluorophenyl)-l-methyl-6-((27?, AS* or 2S.4RY 2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-L3-dihvdro-10H-furo[3.4-d1pyrimido[L6- a] pyrimidin- 10-one & 5-19 (S or 7?)-8-(4-chloro-2-fluorophenyl)-l-methyl-6-((2J?,-/S or 2S,4R)- )-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-L3-dihvdro-10H-furo[3.4-d1pyrimido[L6- al pyrimidin- 10-one & 5-20 (S or 7U-8-(4-chloro-2-fluoropheny
  • Step 1 Synthesis of 8-(2.4-difluorophenyl)-6-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-l,3- dihvdro-10H-furo[3.4-d1pyri mi do[L6-a1pyrimi din- 10-one
  • Step 3 Synthesis of 8-(2.4-difluorophenyl)-6-(2-(tetrahvdrofuran-3-yl)tetrahvdro-2H-pyran-4- vP- 1.3-dihy dro- 1 OH-furo [ 3 ,4-d] pyrimido [ 1.6-al pyrimidin- 10-one
  • Step 1 Synthesis of 6-chloro-8-(4-chloro-2-fluorophenyl)-1.3-dihydro-10H-furol3.4- d1pyrimido[l,6-a1pyrimidin-10-one
  • reaction was heated to 100 °C and stirred for 15 min in a micro wave reactor.
  • the reaction mixture was quenched with aqueous ammonium chloride (15 mL) and extracted with CH2CI2 (15 mL*3).
  • the combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure.
  • Step 3 Synthesis of 8-(4-chloro-2-fluorophenyl)-6-(2-(tetrahvdrofuran-3-yl)tetrahvdro-2H- pyran-4-yl)-1.3-dihvdro-10H-furo[3.4-dlpyrimido[1.6-a1pyrimidin-l 0-one
  • Step 1 Preparation of (S)-4-chloro-5-fluoro-6-(2-(l-methyl-17/-pyrazol-4- yl)morpholino)pyrimidin-2-amine
  • Step 3 Preparation of (S)-7-fluoro-2.3-dimethyl-8-(2-(l-methyl-17/-pyrazol-4-yl)morpholino)-6- (methylthio)-4//-pyrimido[ 1 .2-a]pyrimidin-4-one [0251] To a vial containing (S)-5-fluoro-4-(2-(l -methyl- l//-pyrazol-4-y l)morpholino)-6- (methylthio)pyrimidin-2-amine (160 mg, 493 pmol) and ethyl 2-methylacetoacetate (356 mg, 2.47 mmol) was added PPA (990 pL).
  • Step 4 Preparation of 6-1 (S)-6-(4-chloro-2-fluorophenyl)-7-fluoro-2.3-dimethyl-8-(2-(l-methyl- l//-pyrazol-4-yl)morpholino)-477-pyrimido[ 1.2-a1pyrimidin-4-one
  • Step 1 Synthesis of 4-chloro-6-(methylthio)pyrimidin-2-amine
  • Step 4 Synthesis of 2.3-dimethyl-8-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-6-
  • Step 5 Synthesis of 7-1 6-(4-chloro-2-riuoroDhenyl )-2.3-dimethyl-8-( -2-methyl-6-(2- methylpyridin-4-yl)morpholino)-4H-pyrimido[1.2-a1pyrimidin-4-one
  • Step 1 Synthesis of 6-chloro-5-fluoro-2-(methylthio)pyrimidin-4-amine
  • Step 2 Synthesis of (S)-5-fluoro-6-(2-(l -methyl- lH-pyrazol-4-yl)morpholino)-2- (methylthio)pyrimidin-4-amine
  • Step 3 Synthesis of ( )-4-fluoro-3-(2-(l -methyl- lH-pyrazol-4-yl)morpholino)-l-(methylthio)-
  • Step 4 Synthesis of 8-1 -l-(4-chloro-2-fluorophenyl)-4-fluoro-3-(2-(l-methyl-lH-pyrazol-4- yl)morpholino)-6.7.8.9-tetrahydro-10H-pyrimido[6.1-b1quinazolin-l 0-one
  • the vial was purged with Ar for three times, then THF (0.4 mL) was added.
  • the reaction mixture was purged with Ar for three times again, then heated in a microwave reactor at 100 °C for 7 min. Upon completion, the reaction mixture was diluted with water and extracted with 2 mL of EtOAc.
  • Step 1 Synthesis of -2-((R and S)tetrahydrofuran-3-yl)-2.3-dihydro-47f-pyran-4-one
  • a 30-mL oven-dried dram vial equipped with a magnetic stir bar was charged with molecular sieves 4A (15 g) and (7?,7?)-Jacobsen catalyst, Tetrafluoroborate (1.046 g. 1.530 mmol). The vial was sealed and purged with N2 for 5 min. The catalyst was dissolved in EtOAc (10.20 mL).
  • Step 2 Synthesis of (2/?)-2-((R and S)tetrahydrofuran-3-yl)tetrahydro-47f-pyran-4-one
  • Step 3 Synthesis of (AS)-6-((R and S)tetrahvdrofuran-3-yl)-3.6-dihvdro-277-pyran-4-yl trifluoromethanesulfonate and (27?)-2-((R and S)tetrahydrofuran-3-yl)-3.6-dihvdro-277-pyran-4-yl trifluoromethanesulfonate
  • Step 5 Synthesis of 9-1 6-(2.4-difluorophenyl)-8-((2A!.4R or 2R,4A)-4-fluoro-2-((S and
  • the compounds of the disclosure surprisingly and advantageously, exhibit good potency as agonists of TREM2.
  • the potency of the compounds were measured as follows. In vitro measurement of TREM2 activity' using cell-based pSyk (phosphorylation of Spleen Tyrosine Kinase) assay
  • TREM2 agonist potency was done using a HEK cell line expressing human TREM2 and DAP12 (HEK293T-hTREM2 cells). Binding of small molecules to, and activation of, TREM2 increases the phosphorylation of Syk. The resultant levels of Syk phosphorylation are measured using a commercial AlphaLisa reagent kit. To perform the assay, HEK-hTREM2 cells were plated at 14,000 cells per well in a 384 well plate, in 25 pL of complete grow th media and incubated at 37 °C, 5% CO2 for 20-24 hours.
  • AlphaLISA reagents were added to the lysate using the manufacturer's recommended bead ratios and incubation times, and fluorescence intensity was measured using a BMG LabTech PHERAstar FSX plate reader. Intensities were used to generate Max and Min controls, and % activation w as calculated. Curve fitting was performed using IDBS ABASE software with XE runner, which generates a four parameter fit with variable slope using the log(agonist) vs response, and EC50s were calculated from the curve fit.
  • This assay may be used to test any of the compounds described herein to assess and characterize a compound’s ability to act as an agonist of TREM2.
  • Potency (ECso) results from the pSYK assays of the disclosed compounds are provided in Table 6, below: Table 6

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Abstract

La présente divulgation concerne des composés de formule (I) et leur utilisation en tant qu'agonistes de TREM2 pour le traitement et la prévention d'un trouble neurodégénératif associé à une perte de fonction du TREM2 humain. Les agonistes de TREM2 divulgués peuvent être utiles pour le traitement de la maladie d'Alzheimer et d'états neurologiques associés.
PCT/US2024/060448 2023-12-18 2024-12-17 Agonistes de l'activité trem2 Pending WO2025136898A1 (fr)

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US12459952B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators

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