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WO2025017059A1 - Modulateurs de trem2 - Google Patents

Modulateurs de trem2 Download PDF

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Publication number
WO2025017059A1
WO2025017059A1 PCT/EP2024/070237 EP2024070237W WO2025017059A1 WO 2025017059 A1 WO2025017059 A1 WO 2025017059A1 EP 2024070237 W EP2024070237 W EP 2024070237W WO 2025017059 A1 WO2025017059 A1 WO 2025017059A1
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Prior art keywords
methyl
alkyl
pyrimidin
chloro
pharmaceutically acceptable
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English (en)
Inventor
Jakob Busch-Petersen
Gavin Whitlock
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Muna Therapeutics Aps
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Muna Therapeutics Aps
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Priority to AU2024294814A priority Critical patent/AU2024294814A1/en
Publication of WO2025017059A1 publication Critical patent/WO2025017059A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 (“TREM2”).
  • TREM2 Triggering Receptor Expressed on Myeloid Cells-2
  • the invention also relates to the compounds for use in treatment of conditions related to loss of function of TREM2, such as neurodegenerative diseases, and to pharmaceutical compositions comprising the compounds.
  • Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor belonging to the immunoglobulin superfamily and is encoded by the TREM2 gene, which maps to human chromosome 6p21.
  • TREM2 consists of an extracellular part that includes a single immunoglobulin domain and a short ectodomain, a single transmembrane helix and a short cytosolic tail (Colonna, M. et al. (2016))).
  • TREM2 Insight to the role of TREM2 is provided by its restricted expression pattern. It is expressed exclusively on myeloid lineage cells, such as macrophages, microglia, dendritic cells and osteoclasts. It plays a role in tissue maintenance, as a sensor of pathology and inducer of innate immune signalling in specific tissues. In the brain TREM2 is exclusively expressed in microglia and is functionally required e.g. in phagocytosis of cellular debris, but has also been assigned roles in restricting inflammation as well as promoting cell survival (Deczkowska, A. et al. (2020)).
  • TREM2 has a wide range of ligands such as bacterial anionic molecules/endotoxins, phospholipids incl phosphatidylserine, lipoproteins and apolipoproteins incl ApoE, as well as oligomeric Ap (Hammond, T. R. (2019)).
  • ligands such as bacterial anionic molecules/endotoxins, phospholipids incl phosphatidylserine, lipoproteins and apolipoproteins incl ApoE, as well as oligomeric Ap (Hammond, T. R. (2019)).
  • the adaptor molecule DAP 12 is expressed as a homodimer at the surface of a variety of cells participating in the innate immune response, including microglia, macrophages, granulocytes, NK cells, and dendritic cells.
  • ITAM immunoglobulin-associated activation motif
  • tyrosine phosphorylation of DAP12 by SRC-family kinases drive the recruitment and activation of the Syk kinase and/or ZAP70 kinase.
  • Downstream of TREM2/DAP12/Syk several signaling pathways have been described involved in cell survival, cell activation and differentiation, and in the control of the actin cytoskeleton.
  • sTREM2 soluble TREM2
  • CSF human cerebrospinal fluid
  • TREM2-deficiency leads to a blunted microglial response to pathological agents.
  • TREM2-deficiency in vitro has been shown in the context of stimulation with typical TLR ligands, such as LPS.
  • Loss-of-function genetic variants of TREM2 are associated with neurodegenerative diseases and supports a central role of microglial function in disease pathogenesis. Homozygous loss-of- function TREM2 variants cause Nasu-Hakola disease (Yamazaki, K. et al. (2015); Paloneva BM, J. et al. (2001); Ulrich J.D. et al.
  • heterozygous loss-of- function TREM2 variants are associated with an increased risk for several neurological and neurodegenerative disorders such as Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), Parkinson's disease, FTLD-like syndrome, and Amyotrophic lateral sclerosis (ALS).
  • AD Alzheimer's disease
  • FTLD Frontotemporal lobar degeneration
  • Parkinson's disease FTLD-like syndrome
  • ALS Amyotrophic lateral sclerosis
  • the most prevalent mutation associated with AD is the loss-of-function mutation R47H, which has been shown to abrogate ligand binding and phagocytosis (Atagi, Y. et al. (2015); Kleinberger, G. et al (2014)).
  • Neurodegenerative disorders that may be treated by modulation of TREM2 activity and/or signaling include, but is not limited to, Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), FTLD-like syndrome, Parkinson's disease, Huntington disease, Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), Multiple sclerosis (MS), Guillain- Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie- Tooth disease andAmyotrophic lateral sclerosis (ALS).
  • AD Alzheimer's disease
  • FTLD Frontotemporal lobar degeneration
  • FTLD-like syndrome Parkinson's disease
  • Parkinson's disease Huntington disease
  • Nasu-Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy
  • MS Multiple sclerosis
  • the present invention relates to compounds that modulates TREM2.
  • P6647PC00 in one aspect, relates to a compound of Formula IA or Formula IB: Formula IA wherein XA is N or C(R 5 ); R5 is H; R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl,and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R 6 ; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, halogen and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with1 to 3 individually selected substituents R 9 ; R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8
  • the present invention relates a compound of Formula IA or Ib as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with loss-of-function of TREM2, such as a neurodegenerative disease.
  • a disease associated with loss-of-function of TREM2 such as a neurodegenerative disease.
  • the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise.
  • the terms “approximately” and “about” as referred herein are synonymous. In some embodiments, “about” refer to the recited amount, value, or duration ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, or ⁇ 0.5%.
  • C1-3 alkyl refers to a straight or branched hydrocarbon chains containing from 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively.
  • C1-3 alkyl, C1-5 alkyl and C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, pentyl and hexyl.
  • C2-4 alkenyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight and branched moieties.
  • C2-4 alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl -2 -propenyl, and butenyl.
  • C3-6 cycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbon atoms.
  • Representative examples of C3- 6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • diC 1-3 alkylamino refer to -NR*R**, wherein R* and R** independently represent a C 1-3 alkyl as defined herein.
  • diC 1-3 alkylamino include, but are not limited to, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 2 CH 3 ) 2 and -N(CH(CH 3 ) 2 ) 2 .
  • C 1-3 alkoxy and “C 1-6 alkoxy” as used herein refer to -OR # , wherein R # represents a C 1-3 alkyl and C 1-6 alkyl group, respectively, as defined herein.
  • C 1-3 alkoxy and C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.
  • halogen refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.
  • halo as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein. The halogen is independently selected at each occurrence.
  • C1-6 haloalkyl refers to a C1-6 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • Representative examples of C1-6 haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and - CH(CH2F)(CF3).
  • C1-6 haloalkoxy for example refers to a C1-6 alkoxy as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • C1-6 haloalkoxy include, but are not limited to, - OCH2F, -OCHF2, -OCF3, -OCHFCl, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, - OCF(CHF2)2, and -OCH(CH2F)(CF3).
  • CN is used herein to indicate a cyano group ( ).
  • 5-membered heteroaryl or “6-membered heteroaryl” as used herein refers to a 5 or 6-membered carbon ring with two or three double bonds containing one ring heteroatom selected from N, S, and O and optionally one or two further ring N atoms instead of the one or more ring carbon atom(s).
  • Representative examples of a 5- membered heteroaryl include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl.
  • C 3-6 heterocycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbons and wherein one or more carbon atoms are substituted with heteroatom(s) selected from N, O, and S.
  • a “C 3-6 heterocycloalkyl” refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbons and wherein one carbon atom is substituted with a heteroatom selected from N, O, and S.
  • C 3-6 heterocycloalkyl group is a C 6 heterocycloalkyl
  • one or two carbon atoms are substituted with a heteroatom independently selected from N, O, and S.
  • Representative examples of C 3-6 heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.
  • spiro compound refers to a compound having one atom (usually a quaternary carbon) as the only common member of two rings
  • C5-8 spiroalkyl refers to a bicyclic ring system comprising 5 to 8 carbon atoms, wherein the two rings are connected through a single common carbon atom.
  • Representative examples of C5-8 spiroalkyl include, but are not limited to, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, and spiro[2.5]octanyl.
  • C5-8 tricycloalkyl refers a tricyclic ring system, wherein all three cycloalkyl rings share the same two ring atoms.
  • Representative examples of C5-8 tricycloalkyl include, but are not limited to, tricyclo[1.1.1.0 1,3 ]pentanyl, tricyclo[2.1.1.0 1,4 ]hexanyl, tricyclo [3.1.1.0 1,5 ]hexanyl and tricyclo[3.2.1.0 1,5 ]octanyl.
  • C5-8 bicycloalkyl refers a bicyclic ring system, wherein both cycloalkyl rings share the same two ring atoms.
  • C5-8 bicycloalkyl includes bridged bicyclic compounds, i.e. wherein the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • C5-8 bicycloalkyl includes bicyclo[1.1.1]pentyl.
  • C5-8 bicycloalkyl includes .
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl” or “heteroaralkoxy” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom in the context of “heteroaryl” particularly includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin- 3(4H)-one.
  • a heteroaryl group may be monocyclic or bicyclic.
  • the term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • the term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. As described herein, compounds of the present invention may contain “substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position, i.e. the substituent may be individually/independently selected from a group of substituents. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • a chemical group is “a bond”, which may also be referred to as said chemical group is absent.
  • R a in CH 3 -R a -OH is “a bond”, it refers to CH 3 OH.
  • two R groups are linked together to form a ring, i.e. a ring is formed by the two R groups and the intervening atom(s).
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • the present invention relates to a compound of Formula IA or Formula IB: Formula IA wherein XA is N or C(R 5 ); R5 is H; R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R 6 ; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, halogen and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with1 to 3 individually selected substituents R 9 ; R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, C5-8 bicycloalkyl
  • the present invention relates to a compound of Formula IA or Formula IB: Formula IA wherein XA is N or C(R 5 ); R5 is H; R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl,and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R 6 ; R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, halogen and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with1 to 3 individually selected substituents R 9 ; R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, C5-8 bicycloalkyl cyclopent-1-en-1-yl,
  • the present invention relates to a compound of Formula IA or Formula IB: Formula IA wherein XA is N or C(R 5 ); R5 is H; R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl,and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R 6 ; R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with1 to 3 individually selected substituents R 9 ; R3 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-8 spiroalkyl, C 5-8 tricycloalkyl, C 5-8 bicycloalkyl cyclopent-1-en-1-
  • the compound is of Formula IA. In some embodiments, the compound is of Formula IB. In one aspect, the present inventon relates to a compound of Formula IA: Formula IA wherein R 1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R 2 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl and H; R 3 is phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, and C 1-3 haloalkyl; X A is N or C(H); R 4 is of Formula XXVI: Formula XXVI wherein X B is N or C(H); R 15 is 5-membered heteroaryl or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl,
  • X A is N. In some embodiments, X A is C(R 5 ) and R 5 is H. In some embodiments, the compound is of Formula IA and X A is N. In some embodiments, the compound is of Formula IA and X A is C(R 5 ) and R 5 is H. In some embodiments, the compound is of Formula IB and X A is C(R 5 ) and R 5 is H. In some embodiments, R 1 is C1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R 6 . In some embodiments, R 1 is C1-3 alkyl. In some embodiments, R 1 is -CH3.
  • R 1 is C1-6 alkyl substituted with 1 to 3 individually selected substituents R 6 . In some embodiments, R 1 is C1-3 alkyl substituted with 1 to 3 individually selected substituents R 6 . In some embodiments, R 6 is halogen. In some embodiments, R 6 is F. In some embodiments, R 1 is C1-6 haloalkyl. In some embodiments, R 1 is C1-3 haloalkyl. In some embodiments, R 1 is -CF3. In some embodiments, R 2 is C1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R 9 . In some embodiments, R 2 is C1-3 alkyl optionally substituted with 1 to 3 individually selected substituents R 9 .
  • R 2 is -CH3. In some embodiments, R 2 is halogen. In some embodiments, R 2 is Cl. In some embodiments, R 2 is F. In some embodiments, R 3 is phenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy and CN. In some embodiments, R 3 is phenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, and CN.
  • R 3 is 6-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 haloalkyl and CN.
  • R 3 is of Formula III: Formula III wherein X H is C(R 31 ) or N; X I is C(R 32 ) or N; R 28 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 29 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 30 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 31 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; and R 32 is H, halogen, C
  • R 3 is of Formula III, wherein X H is C(R 31 ) or N; X I is C(R 32 ) or N; R 28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R 29 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN; R 30 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN; R 31 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN; and R 32 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN.
  • X H is C(R 31 ). In some embodiments, X H is N. In some embodiments, X I is C(R 32 ), or a pharmaceutically acceptable salt thereof. In some embodiments, X I is N. In some embodiments, X H is C(R 31 ), and X I is C(R 32 ), or a pharmaceutically acceptable salt thereof. In some embodiments, X H is N, and X I is C(R 32 ). In some embodiments, X H is C(R 31 ), and X I is N. In some embodiments, R 31 is H.
  • R 3 is of Formula IV: Formula IV wherein R 28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R 29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R 30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; and R 31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN.
  • R 3 is of Formula IV wherein R 28 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN; R 29 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN; R 30 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN; and R 31 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN.
  • R 28 is H.
  • R 28 is halogen.
  • R 28 is F or Cl.
  • R 28 is C 1-3 alkyl, such as –CH 3 .
  • R 28 is CN.
  • R 29 is H.
  • R 29 is halogen.
  • R 29 is F.
  • R 30 is halogen.
  • R 30 is F or Cl.
  • R 30 is C 1-3 alkyl, such as – CH 3 .
  • R 30 is C 1-3 haloalkyl, such as –CF 3 .
  • R 30 is C 1-3 haloalkyl, such as –CHF 2 .
  • R 30 is CN.
  • R 30 is C 1-3 alkoxy, such as –OCH 3 .
  • R 31 is H.
  • R 31 is halogen. In some embodiments, R 31 is F. In some embodiments, R 3 is . In some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, . In some embodiments, R 3 is . In some embodiments, some embodiments, . In some embodiments, some embodiments, some embodiments, some embodiments, some embodiments, . In some embodiments, , . In some embodiments, some embodiments, some embodiments, some embodiments, . .
  • R 3 is C 5-8 bicycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1-3 alkyl and C 1-3 haloalkyl. In some embodiments, R 3 is bicyclo[1.1.1]pentyl optionally substituted with CF 3 or C 1 alkyl. In some embodiments, . In some embodiments, R 3 is C3-6 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl and C1-3 haloalkyl.
  • R 3 is of Formula XXV: Formula XXV wherein R 33 is H, halogen, C 1-3 alkyl and C 1-3 haloalkyl; R 34 is H, halogen, C1-3 alkyl and C1-3 haloalkyl; q is 1, 2 or 3; and p is 1, 2 or 3. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R 33 is H. In some embodiments, R 33 is halogen, such as F. In some embodiments, R 33 is C1-3 alkyl, such as –CH 3 .
  • R 33 is C 1-3 haloalkyl, such as –CF 3 or –CHF 2 .
  • R 34 is H.
  • R 34 is halogen, such as F.
  • R 34 is C 1-3 alkyl, such as –CH 3 .
  • R 34 is C 1-3 haloalkyl, such as –CF 3 or –CHF 2 .
  • R 3 is .
  • R 3 is .
  • R 3 is .
  • R 3 emb is .
  • R 3 is .
  • X D is C(R 14 ).
  • R 4 is of Formula IIA.
  • R 4 is of Formula IIB.
  • Formula IIA Formula IIB
  • X B is C(R 11 ).
  • R 4 is of Formula IIC.
  • R 4 is of Formula IID.
  • Formula IID Formula IIC
  • X B is C(R 11 ) and X D is C(R 14 ).
  • R 4 is of Formula IIE.
  • R 4 is of Formula IIF.
  • R 4 is of Formula IIG.
  • R 4 is of Formula IIH.
  • R 4 is a 6-membered ring.
  • X E is O, C(R 16 )(R 17 ) or NR 18 ; m is 1; and n is 1.
  • X B is N; X C is C(R 12 )(R 13 ); X D is C(R 14 ); X E is O; X F is C(R 19 )(R 20 ); X G is C(R 21 )(R 22 ); m is 1; and n is 1.
  • X B is C(R 11 ); X C is C(R 12 )(R 13 ); X D is C(R 14 ); X E is O; X F is C(R 19 )(R 20 ); X G is C(R 21 )(R 22 ); m is 1; and n is 1.
  • X B is N; X C is C(R 12 )(R 13 ); X D is C(R 14 ); X E is NR 18 ; X F is C(R 19 )(R 20 ); X G is C(R 21 )(R 22 ); m is 1; and n is 1.
  • X B is N; X C is C(R 12 )(R 13 ); X D is C(R 14 ); X E is C(R 16 )(R 17 ); X F is C(R 19 )(R 20 ); X G is C(R 21 )(R 22 ); m is 1; and n is 1.
  • X B is N.
  • X B is C(R 11 ).
  • R 11 is H.
  • R 11 is C1-3 alkyl.
  • X C is C(R 12 )(R 13 ).
  • R 12 is individually H.
  • R 12 is individually C1-3 alkyl.
  • R 12 is a bond and R 11 is C1-3 alkyl, and R 11 and R 12 are linked together to form a 3-5 membered ring.
  • R 13 is individually H. In some embodiments, R 13 is individually C1-3 alkyl.
  • X D is C(R 14 ). In some embodiments, X D is N. In some embodiments, R 14 is H. In some embodiments, R 14 is C1-3 alkyl. In some embodiments, when X B is N, then X D is C(R 14 ). In some embodiments, R 23 is a bond.
  • R 4 is of Formula XXVI: Formula XXVI wherein X B is N or C(H); R 15 is 5-membered heteroaryl or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, -CN, and C3-6 cycloalkyl; R 19 is H, halogen or C1-3 alkyl; and R 20 is H, halogen or C1-3 alkyl.
  • R 15 is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, and halogen.
  • R 15 is selected from the group consisting of Formula V, Formula VI, Formula VII, Formula VIII, Formula IX Formula X, Formula XI, and Formula XII: F ormula V Formula VI Formula VII Formula VIII Formula X Formula XI Formula XII wherein R 37 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, -O-C1-6 alkyl, H, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, and halogen.
  • R 15 is of Formula V.
  • R 15 is of Formula VI.
  • R 15 is of Formula VII. In some embodiments, R 15 is of Formula VIII. In some embodiments, R 15 is of Formula IX. In some embodiments, R 15 is of Formula X. In some embodiments, R 15 is of Formula XI. In some embodiments, R 15 is of Formula XII.
  • R 15 is selected from the group consisting of Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, and Formula XXIII: ormua Formula XIII Formula XXIII wherein R 37 and R 38 are independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, -O-C 1-6 alkyl, H, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, and halogen.
  • R 15 is Formula XIII. In some embodiments, R 15 is Formula XIV. In some embodiments, R 15 is Formula XV. In some embodiments, R 15 is Formula XVI. In some embodiments, R 15 is Formula XVII. In some embodiments, R 15 is Formula XVIII. In some embodiments, R 15 is Formula XIX. In some embodiments, R 15 is Formula XX. In some embodiments, R 15 is Formula XXI. In some embodiments, R 15 is Formula XXII. In some embodiments, R 15 is Formula XXIII. In some embodiments, R 37 is C 1-3 alkyl. In some embodiments, R 37 is CH 3 .
  • R 37 is C 3-6 cycloalkyl. In some embodiments, R 37 is C 3 cycloalkyl. In some embodiments, R 15 is . In some embodiments, R 15 is . In some embodiments, R 15 is . In some embodiments, R 15 is . In some embodiments, R 15 is . In some embodiments, R 15 is . In some embodiments, . In some embodiments, R 15 . In some embodiments, . In some embodiments, R 15 is . In some embodiments, R 15 . In some embodiments, . In some embodiments, R 15 is . In some embodiments, . In some embodiments, R 15 is . In some embodiments, . In some embodiments, . In some embodiments, R 15 is . In some embodiments, . In some embodiments, . In some embodiments, R 15 is . In some embodiments, . .
  • R 15 is a 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, -O-C 1-6 alkyl, H, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, and halogen.
  • R 15 is of Formula XXIV: Formula XXIV wherein X J is N or CH; X K is N or C(R 7 ); X L is N or C(R 8 ); R 7 is C 1-3 alkyl; R 8 is C 1-3 alkyl; and R 36 is H or C 1-3 alkyl.
  • X J is CH.
  • X K is N.
  • X K is C(R 7 ).
  • R 7 is –CH3.
  • X L is N.
  • X L is C(R 8 ).
  • R 8 is –CH3.
  • R 36 is H.
  • R 36 is C1-3 alkyl. In some embodiments, R 36 is –CH3. In some embodiments, at least one of X J , X K , and X L is N. In some embodiments, one of X J , X K , and X L is N. In some embodiments, two of X J , X K , and X L are N.
  • R 15 i is .
  • R 15 is In some embodiments, X E is C(R 16 )(R 17 ). In some embodiments, X E is O. In some embodiments, X E is NR 18 . In some embodiments, X E is a bond.
  • R 19 is H. In some embodiments, R 19 is halogen. In some embodiments, R 19 is F. In some embodiments, R 19 is C 1-3 alkyl. In some embodiments, R 19 is CH 3 .
  • R 20 is H. In some embodiments, R 20 is halogen. In some embodiments, R 20 is F. In some embodiments, R 20 is C1-3 alkyl.
  • R 20 is CH3. In some embodiments, R 19 and R 20 are C 19 1-3 alkyl, and R and R 20 are optionally linked together to form a 3-6 membered ring.
  • X G is C(R 21 )(R 22 ). In some embodiments, X G is C(O). In some embodiments, R 21 is H. In some embodiments, R 22 is H In some embodiments, m is 1. In some embodiments, m is 0. In some embodiments, m is 2. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, n is 2.
  • R 4 is embodiments, some embodiments, R 4 is some embodiments, some embodiments, R 4 is embodiments, some embodiments, R 4 . In some embodiments, some embodiments, R 4 is some embodiments, I . In some embodiments, R 4 is some embodiments, . embodiments, . In some embodiments, R 4 is embodiments, some embodiments, . In some embodiments, some embodiments, R 4 is e . In some embodiments, . In some embodiments, some embodiments, R 4 is . In some diments, embodiments, some embodiments, In some embodiments, In some embodiments, R 4 is . In some embodiments, R 4 is embodiments, some embodiments, In some embodiments, R 4 is .
  • R 4 is embodiments, some embodiments, In some embodiments, . In some embodiments, R 4 is . embodiments, embodiments, R 4 is . In some embodiments, R 4 is embodiments, R 4 is In some embodiments, R 4 is . In some embodiments, In some embodiments, R 4 is . In some embodiments, R 4 is embodiments, some embodiments, In some embodiments, some embodiments, R 4 is . In some embodiments, R 4 is embodiments, some embodiments, In some embodiments, some embodiments, R 4 is embodiments, some embodiments, some embodiments, some embodiments, R 4 is
  • R 4 is embodiments, some embodiments, R 4 is embodiments, some embodiments, R 4 is embodiments, some embodiments, R 4 is e ome embodiments, R ome embodiments, R some embodiments, R ome 4 embodiments, R is s e embodiments, R 4 is In some embodiments, R 4 is , . In some embodiments, R 4 is . In some embodiments, . In some embodiments, R 4 is a 5-membered ring. In some embodiments, m is 1; X E is a bond; and n is 1.
  • X B is N; X C is CH 2 ; m is 1; X D is C(H); X E is a bond; X F is C(H 2 ); G X is C(H2); and n is 1.
  • R 4 is . In some embodiments, some embodiments, R 4 is , . In some embodiments, R 4 is a 4-membered ring. In some embodiments, m is 1; X E is a bond; and n is 0.
  • X B is N; X C is CH 2 ; m is 1; X D is C(H); X E is a bond; X F is C(H 2 ); and n is 0.
  • X B is N; X C is CH 2 ; m is 1; X D is C(H); X E is a bond; X F is C(H2); n is 0; and R 15 is .
  • R 4 is . In some embodiments, R 4 is . In some embodiments, R 4 is a 3-membered ring.
  • m is 0; X E is a bond; and n is 0.
  • X B X E is a bond; X F is C(H 2 ); and n is 0.
  • the compound is of Formula IA, wherein: R 1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and H; R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halogen and H; R 3 is phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl and CN, wherein one methylene group of the C1-3 alkyl is optionally replaced with -O-; X A is N or CH; X B is N or CH; X C is C(H) 2 ; X D is C(H); X E is O; X F is C(R 19 )(R 20 ), wherein each R 19 and R 20 are individually selected as H or CH 3 ; X G is C(H) 2 ; m is 1; n
  • the compound is of Formula IA, wherein: R 1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and H; R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, and H; R 3 is phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl; X A is CH; X B is N; X C is C(H)2; X D is C(H); X E is O; X F is C(H)2; X G is C(H)2; m is 1; n is 1; R 23 is a bond; and R 15 is 5-membered heteroaryl or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 al
  • the compound is of Formula IA and wherein: R 1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R 2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, and H; R 3 is phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, and C 1-3 haloalkyl; X A is N; X B is C(H); X C is C(H) 2 ; X D is C(H); X E is O; X F is C(H) 2 ; X G is C(H) 2 ; m is 1; n is 1; R 23 is a bond; and R 15 is 5-membered heteroaryl or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl;
  • the compound is 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2- (1-methyl-1 H-pyrazol-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is (R)- 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)- 4H-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)morpholino)-4H-pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(4- chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(4-chloro-2- fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(4-chloro-2-fluorophenyl)-2,3- dimethyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is (R)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1 H-pyrazol-4- yl)morpholino)-2,3-dimethyl-4H-pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is (S)-9-(4-chloro-2- fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1 H-pyrazol-4-yl)morpholino)-2,3-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)morpholino)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 6-(4- chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-4H- pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6- methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,6S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6- methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,6R)-2-(1 -cyclopropyl- 1 H-pyrazol-4-yl)-6- methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6- methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,6R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)-6- methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl- 4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-9-(2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-((2S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4- difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7- ((2R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-
  • the compound is 7-((2S,4R)-2-(1-cyclopropyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-3-fluoro-2-methyl-4H- pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-9-(2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-((2S,4S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7- ((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4- difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(2, 4-difluorophenyl)-2-methyl-7-(2-methyl-6-(1 -methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4- difluorophenyl)-2-methyl-7-(2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7- ((2S, 6R)-2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H- pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,6S)-2- methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1, 2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,6R)-2- methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1, 2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2S,4R,6S)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7- ((2R, 4R,6S)-2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H- pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7- ((2R,4R,6R)-2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H- pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2S,4S,6S)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2S,4S,6R)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4S,6S)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-(2-(2-methoxypyridin- 4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9- (2,4-difluorophenyl)-3-fluoro-7-((2S)-2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4- yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-7- ((2R)-2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-((2S,4R)-2-(2- methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-((2R,4R)-2-(2-methoxypyridin-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9- (2,4-difluorophenyl)-3-fluoro-7-((2S,4S)-2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran- 4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-7- ((2R,4S)-2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)- 3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)- 3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(7-((2S,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)- 3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)- 3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2S,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-(2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2R,4R)-2-(1-methyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2S,4S)-2-(1-methyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3- fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9- yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1 ,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3- chloro-7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl- 4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2S,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2- a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9- yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl- 7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H- pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2R,4R)-2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9- yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2S,4S)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1 ,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3- chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4- oxo-4H-pyrazino[1 ,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)- 7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H- pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4R)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2- fluorophenyl)-2-methyl-7-((2R,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7- ((2S,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7- ((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-7-(2-(1-cyclopropyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-chlorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4- chlorophenyl)-7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-7- ((2S,4S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H- pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-7-((2R,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-7-(2-(1-methyl- 1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-chlorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-2- methyl-7-((2R,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H- pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2S,4S)-2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-(2-(1-cyclopropyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(3,4- difluorophenyl)-2-methyl-7-((2R,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran- 4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7- ((2S,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2R,4S)-2- (1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4R)-2- (1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4R)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-(2-(1-methyl- 1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2R,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-2-methyl-7-((2S,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7- ((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-(2-(1-methyl- 1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H- pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2R,4R)-2-(1-methyl-1 H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2S,4S)-2-(1-methyl-1 H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1 H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4- (difluoromethyl)phenyl)-2-methyl-7-((2R,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4- (difluoromethyl)phenyl)-2-methyl-7-((2S,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-methyl-7-((2S,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-(2-(1-methyl- 1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9- (2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2S,4S)-2- (1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2R,4S)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)- 3-fluoro-2-methyl-7-(2-methyl-6-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7- ((2S,6S)-2-methyl-6-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H- pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2R,6S)-2- methyl-6-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2S,6R)-2- methyl-6-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2R,6R)-2- methyl-6-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2S,4R,6S)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2R,4R,6S)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2S,4R,6R)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2R,4R,6R)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2S,4S,6S)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2R,4S,6S)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2S,4S,6R)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(2,4-difluorophenyl)-3-fluoro-2-methyl-7-((2R,4S,6R)- 2-methyl-6-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-fluoro-4-(3-fluoro-2-methyl-7-(2-(1 -methyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9- yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-fluoro-4-(3-fluoro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1 ,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- fluoro-4-(3-fluoro-2-methyl-7-((2R, 4R)-2-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-fluoro-4-(3-fluoro-2- methyl-7-((2S, 4S)-2-(1 -methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H- pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-fluoro-4-(3-fluoro-2-methyl-7- ((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1 ,2- a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is (S)-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1- methyl-1 H-pyrazol-4-yl)morpholino)-4H-pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is (R)-
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-(2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-chlorophenyl)-7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-2-methyl-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-
  • the compound is 3-chloro-2-methyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-(2-(1-cyclopropyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4- (3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo- 4H-pyrazino[1 ,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-(2-(1-cyclopropyl- 1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1 ,2-a]pyrimidin- 9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-(2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-2-methyl-9-(2 ,4, 5-trifluorophenyl)-4H-pyrazi no[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-2-methyl-7-(2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-(2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9- yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-(2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1 ,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 9- (2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholin-4- yl]pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof
  • the compound is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-(2- methyl-4-pyridyl)tetrahydropyran-4-yl]pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7- [2,2-difluoro-6-(2-methyl-4-pyridyl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl- pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9- (2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholin-4- yl]pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2,2-difluoro-6-(2-methyl-4-pyridyl)morpholin-4-yl]-9-(2,4- difluorophenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2-methyl- pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2- (1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-3-methyl- pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-9-(2,4-difluorophenyl)-2-methyl-3-(trifluoromethyl)pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2- (1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2-methyl- pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-9-(2,4-difluorophenyl)-3-(trifluoromethyl)pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2- (1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- (trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1-cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-9-(2,4-difluorophenyl)pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- (trifluoromethyl)pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7-[2-(1-cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]-2,3-dimethyl-4-oxo-pyrido[1,2-a]pyrimidin-9-yl]-3-fluoro- benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2-(1 -cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4- difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7- [2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-4-oxo-pyrido[1,2- a]pyrimidin-9-yl]-3-fluoro-benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2,2-difluoro-6-(1-methylpyrazol-4- yl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 7-[2- (1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)pyrido[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin- 4-yl]-4-oxo-2-(trifluoromethyl)pyrido[1 ,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)- 2-methyl-pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2-methyl-4-oxo-pyrido[1 ,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7- [2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-4-oxo-3- (trifluoromethyl)pyrido[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7-[2-(1- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-oxo-2-(trifluoromethyl)pyrido[1,2- a]pyrimidin-9-yl]-3-fluoro-benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7-[2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-4-oxo-pyrido[1,2-a]pyrimidin-9-yl]-3-fluoro- benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-[7-[2-(1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-oxo-2- (trifluoromethyl)pyrazino[1 ,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(3- methoxycyclobutyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 9-(3-methoxycyclobutyl)-2,3-dimethyl- 7-[rac-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]pyrido[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7- ((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7- ((2S,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-7-((2R,4S)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-7-((2S,4R)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-9-(4-chlorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2R,4S)-2- (1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H- pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7- ((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7- ((2S,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1 ,2- a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2R,4S)-2- (1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1 ,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7- ((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo- 4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2S,4R)-2-(1- cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2- a]pyrimidin-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H- pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9- yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1 ,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 3- chloro-7-((2R,4S)-2-(1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl- 9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-7-((2S,4R)-2- (1-cyclopropyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2R,4S)-2- (1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H- pyrazino[1,2-a]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.
  • the compound is 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4- one, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-4-oxo-4H-pyrazino[1 ,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3- chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4- oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl- 7-((2R,4S)-2-(1-methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H- pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • the compound is 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1- methyl-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9- yl)benzonitrile, or a pharmaceutically acceptable salt thereof.
  • Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1 H-, 2H- and 4H- 1 ,2,4-triazole, 1 H- and 2H- isoindole, and 1 H- and 2H- pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Tautomeric forms can also include methyltropic tautomers, which result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a methyl group.
  • Compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. In some embodiments, the compounds of the invention include one or more isotopes of atoms in an amount greater than the natural abundance of the isotope. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, a compound of the invention includes at least one deuterium atom in an amount that is greater than the natural abundance of deuterium (e.g., the compound is enriched in deuterium).
  • the present invention is directed to an intermediate compound, or a pharmaceutically acceptable salt thereof, which can be used in the synthesis of the compounds of the present invention.
  • said intermediate compound is in some embodiments one of the intermediate compounds, or a pharmaceutically acceptable salt thereof, of any one of the working examples herein.
  • the compound of the present invention is selected from any of the intermediate compounds, or a pharmaceutically acceptable salt thereof of any one of the intermediates designated 1-1 to 1-13 herein.
  • the compounds of the present invention may contain, for example, one or more asymmetric carbon atoms, and therefore may exist as stereoisomers, enantiomers and diastereomers.
  • the scope of the instant invention is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form and stereoisomeric mixtures of any chemical structures disclosed herein, unless the stereochemistry is specifically identified. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated.
  • stereoisomer or “stereoisomerically pure” compound as used herein refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound.
  • a typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.
  • the compound as defined herein is stereoisomerically pure.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, for example as an active ingredient, a pharmaceutically effective amount of a compound as disclosed herein.
  • said pharmaceutical composition comprises a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
  • a compound as disclosed herein for use in therapy may be administered in the form of the raw chemical compound, it is often preferred to introduce the active ingredient, optionally in the form of a pharmaceutically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • the invention provides pharmaceutical compositions comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and/or prophylactic ingredients, known and used in the art.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Examples of excipients and their use may be found in Remington’s Pharmaceutical Sciences 20th Edition (Lippincott Williams & Wilkins, 2000).
  • a therapeutic amount or therapeutically effective amount or dose refers to that amount of active ingredient, i.e. the compounds or compositions as disclosed herein, which treats, alleviates, abates, or reduces the severity of symptoms of a disease in a subject, such as ameliorates one or more symptoms of the condition or the condition itself.
  • a therapeutic amount of a compound as described herein may improve patient survival, increase survival time or rate, diminish symptoms, make an injury, disease, or condition (e.g, a neurodegenerative disease) more tolerable, slow the rate of degeneration or decline, or improve a patient’s physical or mental well-being.
  • Therapeutic efficacy and toxicity may be determined by standard pharmacological procedures in cell cultures or experimental animals.
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by ratio between plasma levels resulting in therapeutic effects and plasma ratios resulting in toxic effects.
  • Pharmaceutical compositions exhibiting large therapeutic indexes are preferred.
  • the therapeutically effective dose of a compound as disclosed herein is in the range of about 0.01 mg/kg to about 100 mg/kg bodyweight/day.
  • the dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.
  • To administer refers to a method of delivering agents, compounds, or compositions to the desired site of biological action. These methods include, but are not limited to, enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.
  • the compound of the present invention is a TREM2 modulator, such as a TREM2 agonist.
  • the assay described in Example 32 may be used to assess and characterize a compound’s ability to act as an agonist of TREM2.
  • the compounds of the present invention are useful for the activation of TREM2.
  • the compounds of the present invention activates TREM2.
  • the compounds of the present invention enhances TREM2 activity.
  • a compound of the present invention induces phosphorylation of a kinase that interacts with the TREM2/DAP12 signalling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b.
  • the compounds of the present invention enhances or activates TREM2 signalling through DAP12.
  • the compounds of the present invention enhances or activates TREM2-induced phosphorylation levels of the Syk kinase.
  • a compound of the present invention induces or enhances phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more as compared to a control value; such as is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more as compared to a control value.
  • the potency of compounds of the present invention are in some embodiments expressed as ECso corresponding to the concentration of compound able to activate the phospho-Syk AlphaScreen signal to 50% of the maximal response.
  • the compounds of the present invention has an EC50 value of less than 1000 nM, such as an EC50 value between 100 nM and 1000 nM, such as an EC50 value between 10 nM and 100 nM, such as an an EC50 value between 1 nM and 10 nM, such as an EC50 value ⁇ 1 nM.
  • the compounds of the present invention are capable of increasing the expression of one or more TREM2 regulated genes. In some embodiments the compounds of the present invention increases the expression of one or more TREM2 regulated genes. In some embodiments the compounds of the present invention are capable or increasing one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119 (see Example 205). In some embodiments the compounds of the present invention increases expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119.
  • a compound of the present invention increases expression levels, such as brain expression levels, if the level expression of the gene in a sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more as compared to a control value; such as is increased by at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, or more as compared to a control value (e.g. untreated control/vehicle).
  • a control value e.g. untreated control/vehicle
  • the compounds of the present invention are of use in the treatment of diseases and disorders of a living body, including human.
  • treatment includes treatment, prevention, and/or alleviation or amelioration of one or more diseases and disorders or one or more symptoms of a disease or disorder.
  • the compound as described herein is for use as a medicament.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a condition associated with a loss of function of TREM2.
  • the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a condition associated with a mutation in TREM2.
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a neurodegenerative disease.
  • a compound as described herein is used in treating a neurodegenerative disease that is characterized by a loss of function of TREM2. In some embodiments, a compound as described herein is used in treating a neurodegenerative disease that is characterized by a mutation in TREM2.
  • the present invention relates to a method for enhancing or increasing TREM2 activity in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
  • the present invention relates to method for one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2/DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and/or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM1 19; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, as defined herein.
  • the neurodegenerative disease is a tauopathy.
  • Tautopathies depicts some neurodegenerative disorders characterized by tau deposits in the brain, with symptoms of dementia and parkinsonism.
  • the neurodegenerative disease is a tauopathy selected from the group consisting of Primary age related tauopathy (PART), globular glial tauopathy, Chronic traumatic encephalopathy (CTE), Progressive supranuclear palsy, Corticobasal degeneration, diffuse neurofibrillary tangles with calcification (DNTC), Frontotemporal dementia (FTD), and FTD with parkinsonism-17 (FTD with parkinsonism linked to chromosome 17; FTDP-17).
  • PART Primary age related tauopathy
  • CTE Chronic traumatic encephalopathy
  • DNTC diffuse neurofibrillary tangles with calcification
  • FTD Frontotemporal dementia
  • FTD with parkinsonism-17 FTD with parkinsonism linked to chromosome 17; FTDP-17).
  • the neurodegenerative disease is a neurodegenerative disorders associated with TDP-43 (TDP-43 proteinopathies or TDP-43-opathies). Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases.
  • the neurodegenerative disease is a TDP-43 proteinopathy selected from the group consisting of amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis (sALS), familial amyotrophic lateral sclerosis (fALS), frontotemporal lobar degeneration/disease (FTLD), Primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), FTLD-tau, FTLD-FUS (bvFTLD), FTLD-TDP-43 or FTLD-ll (types a, b and c), Facial onset sensory and motor neuronopathy (FOSMN), Limbic-predominant age-related TDP-43 encephalopathy (LATE), cerebral age-related TDP-43 with sclerosis (CARTS), Guam Parkinson-dementia complex (G-PDC) and ALS (G-ALS), Kii ALS/PDC, amyotrophic lateral sclerosis/parkinsonism-dement
  • ALS
  • the neurodegenerative disease is Multisystem proteinopathy (MSP).
  • MSP is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle, bone, and/or the central nervous system.
  • MSP can manifest clinically as classical amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or as a combination of these disorders (IBMPFD, IBMPFD/ALS).
  • ALS amyotrophic lateral sclerosis
  • FTD frontotemporal dementia
  • IBM inclusion body myopathy
  • PDB Paget's disease of bone
  • IBMPFD IBMPFD/ALS
  • the neurodegenerative disease is a synucleinopathy.
  • Synucleinopathies also called a-Synucleinopathies
  • a-Synucleinopathies are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.
  • the neurodegenerative disease is a synucleinopathy selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), neuroaxonal dystrophies, Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD/ALB).
  • PD Parkinson's disease
  • DLB dementia with Lewy bodies
  • MSA multiple system atrophy
  • AD/ALB Alzheimer's Disease with Amygdalar Restricted Lewy Bodies
  • the neurodegenerative disease is cognitive deficit and/or memory loss.
  • the neurodegenerative disease is dementia.
  • the neurodegenerative disease is dementia selected from the group consisting of Alzheimer’s disease, Parkinson’s disease dementia, Huntingtons disease dementia, vascular dementia, HIV dementia, frontotemporal dementia, dementia with lewy bodies, prion disease dementia, argyrophilic grain dementia, dementia pugilistica, Guadeloupean parkinsonism with dementia, neurofibrillary tangle- predominant dementia, tangle only dementia, Down’s syndrome, semantic dementia, familial British dementia, familial Danish dementia, and other dementias caused by another medical condition such as brain tumors, subdural hematoma, endocrine disorders, nutritional deficiencies, infections, immune disorders, liver or kidney failure, metabolic disorders such as Kufs disease, some leukodystrophies, some neurological disorders such as epilepsy, and multiple sclerosis.
  • peripheral nerves are the most common neurological complications of systemic amyloidosis.
  • the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).
  • the neurodegenerative disease is a demyelinating disorder.
  • the neurodegenerative disease is a demyelinating disorder of the central nervous system, CNS.
  • the demyelinating disorder is a myelinoclastic or demyelinating disorder, such as selected from the group consisting of multiple sclerosis, neuromyelitis optica (Devic’s disease) and idiopathic inflammatorydemyelinating diseases.
  • the demyelinating disorder is a leukodystrophic or dysmyelinating disorder, such as selected from the group consisting of CNS neuropathies such as vitamin B12 deficiency, central pontine myelinolysis, myelopathies such as tabes dorsalis (syphilitic myelopathy), leukoencephalopathies and leukodystrophies.
  • CNS neuropathies such as vitamin B12 deficiency, central pontine myelinolysis, myelopathies such as tabes dorsalis (syphilitic myelopathy), leukoencephalopathies and leukodystrophies.
  • the neurodegenerative disease is a demyelinating disorder of the peripheral nervous system, PNS.
  • the demyelinating disorder is selected from the group consisting of Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy; Anti-MAG peripheral neuropathy; Charcot-Marie-Tooth disease and its counterpart Hereditary neuropathy with liability to pressure palsy; Copper deficiency-associated conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy); and Progressive inflammatory neuropathy.
  • the neurodegenerative disease is Alzheimer’s disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD) with the R47H mutation. In some embodiments, the neurodegenerative disease is early Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Frontotemporal lobar degeneration (FTLD). In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease (NHD). In some embodiments, the neurodegenerative disease is FTLD-like syndrome. In some embodiments, the neurodegenerative disease is Huntington disease.
  • the neurodegenerative disease is Amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is multiple sclerosis (MS). In some embodiments, the neurodegenerative disease is Guillain-Barre syndrome. In some embodiments, the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathies. In some embodiments, the neurodegenerative disease is progressive subcortical gliosis. In some embodiments, the neurodegenerative disease is Charcot-Marie-Tooth disease. In some embodiments, the neurodegenerative disease is prion disease, such as prion protein cerebral amyloid angiopathy. In some embodiments, the neurodegenerative disease is stroke.
  • ALS Amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • the neurodegenerative disease is Guillain-Barre syndrome.
  • the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathies.
  • the neurodegenerative disease is progressive subcortical gliosis.
  • the neurodegenerative disease is Char
  • the neurodegenerative disease is cerebral amyloid angiopathy (CAA). In some embodiments the neurodegenerative disease is fragile X-associated tremor ataxia syndrome (FXTAS). In some embodiments the neurodegenerative disease is herpes simplex virus (HSV) encephalitis. In some embodiments the neurodegenerative disease is HIV-associated neurocognitive disorders (HAND). In some embodiments the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments the neurodegenerative disease is corticobasal degeneration. In some embodiments the neurodegenerative disease is Hallevorden-Spatz disease. In some embodiments the neurodegenerative disease is pallido-ponto-nigral degeneration.
  • CAA cerebral amyloid angiopathy
  • FXTAS fragile X-associated tremor ataxia syndrome
  • HAND herpes simplex virus
  • HAND HIV-associated neurocognitive disorders
  • PSP progressive supranuclear palsy
  • the neurodegenerative disease is corticobasal
  • the neurodegenerative disease is postencephalitic parkinsonism. In some embodiments the neurodegenerative disease is subacute sclerosing panencephalitis (SSPE). In some embodiments the neurodegenerative disease is retinal degeneration (e.g., macular degeneration).
  • SSPE subacute sclerosing panencephalitis
  • the neurodegenerative disease is retinal degeneration (e.g., macular degeneration).
  • the neurodegenerative disease is a Leukoencephalopathy.
  • Leukoencephalopathy leukodystrophy-like diseases
  • the neurodegenerative disease is a Leukoencephalopathy selected from the group consisting of Progressive multifocal leukoencephalopathy, Toxic leukoencephalopathy, Leukoencephalopathy with vanishing white matter, Leukoencephalopathy with neuroaxonal spheroids, Reversible posterior leukoencephalopathy syndrome, Megalencephalic leukoencephalopathy with subcortical cysts, and Hypertensive leukoencephalopathy.
  • the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia).
  • the neurodegenerative disease is selected from the group consisting of cerebral autosomal dominant arteriopathy with subcortical infarcts or leukoencephalopathy; cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; and retinal vasculopathy with cerebral leukoencephalopathy (or cerebroretinal vasculopathy).
  • the neurodegenerative disease is a leukodystrophy. In some embodiments the neurodegenerative disease is vanishing white matter disease (VWM). Leukodystrophies are a group of rare, genetic disorders that affect the white matter of the brain. In some embodiments the neurodegenerative disease is a leukodystrophy selected from the group consisting of metachromatic leukodystrophy (MLD, also known as globoid cell leukodystrophy), Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, hypomyelinating leukodystrophy type 7 (4H syndrome), Pelizaeus-Merzbacher disease, cerebrotendineous xanthomatosis and leukoendephalopathy with vanishing white matter.
  • MLD metachromatic leukodystrophy
  • Krabbe disease also known as globoid cell leukodystrophy
  • Canavan disease X-linked adrenoleukodystrophy
  • the neurodegenerative disease is adult-onset autosomal dominant leukodystrophy (ADLD). In some embodiments the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD). In some embodiments the neurodegenerative disease is Nasu-Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL).
  • ADLD adult-onset autosomal dominant leukodystrophy
  • X-ALD X-linked adrenoleukodystrophy
  • PLOSL polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy
  • the neurodegenerative disease is a transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease, Gerstmann-Straussler- Scheinker disease (GSS), kuru, and fatal familial insomnia.
  • TSE transmissible spongiform encephalopathy
  • the present invention relates to a method for treatment of a neurodegenerative disease comprising administering a compound, or a pharmaceutically acceptable salt thereof, as described herein to a subject in need thereof.
  • the present invention relates to a method for treatment of a neurodegenerative disease comprising one or more steps of administering a therapeutically effective amoubt of a compound, or a pharmaceutically acceptable salt thereof, as defined herein to a subject in need thereof.
  • the subject is a mammal, such as a human.
  • the present invention relates to use of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the manufacture of a medicament for treatment of a neurodegenerative disease.
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder associated with dysfunction of Colony stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M- CSFR, or cluster of differentiation 115 / CD115).
  • CSF1R Colony stimulating factor 1 receptor
  • M- CSFR macrophage colony-stimulating factor receptor
  • CD115 cluster of differentiation 115 / CD115.
  • the disease or disorder associated with dysfunction of CSF1R is a neurodegenerative disease associated with dysfunction of CSF1 R.
  • the disease or disorder is caused by a heterozygous CSF1 R mutation, a homozygous CSF1 R mutation, a splice mutation in the csflr gene, a missense mutation in the csflr gene, a mutation in the catalytic kinase domain of CSF1R, a mutation in an immunoglobulin domain of CSF1R, a mutation in the ectodomain of CSF1R, a loss-of-function mutation in CSF1R.
  • the disease or disorder result from a change (e.g. increase, decrease or cessation) in the activity of CSF1 R and/or a decrease or cessation in the activity of CSF 1 R.
  • the neurodegenerative disease associated with dysfunction of CSF1R is a Leukoencephalopathy.
  • the neurodegenerative disease associated with dysfunction of CSF1R is selected from the group consisting of: adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), CSF1 R-related leukoencephalopathy, hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophy (POLD), pediatric-onset leukoencephalopathy, congenital absence of microglia, brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS), and Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
  • ALSP adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
  • HDLS hereditary diffuse leukoencephalopathy with axonal spheroids
  • POLD pigmentary orthochromatic leukodystrophy
  • BANDDOS brain abnormalities
  • the neurodegenerative disease is a condition associated with dysfunction of ATP- binding cassette transporter 1 (ABCD1).
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a lysosomal storage disorder (LSD).
  • LSD lysosomal storage disorder
  • the LSD is a lipidoses, such as a lipidoses selected from the group consisting of cholesteryl ester storage disease, fucosidosis, Schindler disease and Wolman disease.
  • the LSD is a sphingolipidoses, such as a sphingolipidoses selected from the group consisting of Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (Types A, B and C), Sandhoff disease, Farmer disease, multiple sulfatase deficiency and Tay-Sachs disease.
  • Fabry disease Fabry disease
  • Gaucher disease Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (Types A, B and C), Sandhoff disease, Farmer disease, multiple sulfatase deficiency and Tay-Sachs disease.
  • the LSD is a mucopolysaccharidoses, such as a mucopolysaccharidoses selected from the group consinting of Hunter syndrome, Hurler syndomre, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome and Natowicz syndrome.
  • a mucopolysaccharidoses selected from the group consinting of Hunter syndrome, Hurler syndomre, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome and Natowicz syndrome.
  • the LSD is selected from the group consisting of Batten disease, cyctinosis, Danon disease and Pompe disease.
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder of the bones and/or joints.
  • said disease or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia and dysosteoplasia.
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of autism spectrum disorders, autism and Aspergers syndrome.
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of traumatic brain injuries (TBI) and spinal cord injuries.
  • Traumatic brain injuries (TBI) may also be known as intracranial injuries. Traumatic brain injuries occur when an external force traumatically injures the brain.
  • Spinal cord injuries (SCI) include any injury to the spinal cord that is caused by trauma instead of disease.
  • the TBI is chronic traumatic encephalopathy (CTE).
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of muscular dystrophy such as myotonic dystrophy (DM) including Type 1 DM (DM1) and Type 2 DM (DM2).
  • DM myotonic dystrophy
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of inflammation.
  • said inflammation is selected from the group consisting of inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, and certain bowel conditions including Inflammatory bowel disease (IBD).
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of dysregulated lipid metabolism.
  • the dysregulated lipid metabolism comprises increased intracellular and/or extracellular accumulation of one or more lipids.
  • said dysregulated lipid metabolism is atherosclerosis.
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of metabolic syndrome and conditions associated with metabolic syndrome, such as obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, and alcoholic and non-alcoholic steatohepatitis,
  • the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of Amyloidosis, including AL amyloidosis (immunoglobulin light chain amyloidosis), AA amyloidosis (secondary amyloidosis), familial amyloidosis, familial systemic amyloidosis, Wild-type amyloidosis (senile systemic amyloidosis) and Localized amyloidosis.
  • AL amyloidosis immunoglobulin light chain amyloidosis
  • AA amyloidosis secondary amyloidosis
  • familial amyloidosis familial amyloidosis
  • familial systemic amyloidosis familial systemic amyloidosis
  • Wild-type amyloidosis senile systemic amyloidosis
  • Localized amyloidosis Localized amyloidosis.
  • the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease. In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the method comprises administering to the subject a compound as described herein, or a pharmaceutical composition comprising a compound as described herein.
  • the compounds of the present invention may be used to treat an animal patient belonging to any classification.
  • animals include mammals such as humans, rodents, dogs, cats, zoo animals and farm animals.
  • the subject referred to herein is a mammal, such as a human.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of the present invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents.
  • the method includes coadministering one or more additional therapeutic agent.
  • therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu- Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.
  • the therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for a disease selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD).
  • a disease selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage
  • a suitably substituted pyridine or pyrazine can be functionalised in many ways to deliver the desired compounds.
  • R 4 can be introduced first via nucleophilic substitution or cross coupling followed by cyclisation and then finally cross coupling to introduce R 3 .
  • cyclisation occurs first, then R 3 is introduced via cross coupling and then finally R 4 via a second cross coupling reaction or via a nucleophilic displacement.
  • Scheme 3 Examples of synthetic routes for compounds of Formula IB.
  • X is halogen; Y is halogen; R is alkyl; and X A , R 1 , R 2 , R 3 and R 4 are as defined herein.
  • schemes 1 and 2 when W is NH in R 4 W, then said N atom is part of the R 4 group, i.e. X B is N.
  • X A is N or C(R 5 );
  • R 5 is H
  • R 1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R 6 ;
  • R 2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, halogen and H, wherein the C1-6 alkyl or C3-6 cycloalkyl is optionally substituted withl to 3 individually selected substituents R 9 ;
  • R 3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, C5-8 bicycloalkyl cyclopent- 1-en-1-yl, cyclohex- 1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heterorayl, azetidine-1-yl, pyrrolidine-1 -yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidine-1-yl, and -OCH2-(C3-6 cycloalkyl), wherein the C1-6 alkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 bicycloalkyl, C5-8 tricycloalkyl, cyclopent- 1-en-1-yl, cyclohex- 1-en-1-yl, phenyl, 6-membered heteroaryl or 5-member
  • a compound of Formula IA or Formula IB Formula IA wherein XA is N or C(R 5 ); R5 is H; R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, and H, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R 6 ; R2 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, halogen and H, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with1 to 3 individually selected substituents R 9 ; R3 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-8 spiroalkyl, C 5-8 tricycloalkyl, C 5-8 bicycloalkyl cyclopent-1-en-1-y
  • a compound of Formula IA or Formula IB Formula IB Formula IA wherein XA is N or C(R 5 ); R5 is H; R1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and H, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R 6 ; R2 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, and H, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is optionally substituted with1 to 3 individually selected substituents R 9 ; R3 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 5-8 spiroalkyl, C 5-8 tricycloalkyl, C 5-8 bicycloalkyl cyclopent-1-en
  • a compound of Formula IA Formula IA wherein R 1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and H; R 2 is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl and H; R 3 is phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, and C 1-3 haloalkyl; X A is N or C(H); R 4 is of Formula XXVI: Formula XXVI wherein X B is N or C(H); R 15 is 5-membered heteroaryl or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C
  • R 1 is C1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R 6 , or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-3 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is - CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-6 alkyl substituted with 1 to 3 individually selected substituents R 6 , or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-3 alkyl substituted with 1 to 3 individually selected substituents R 6 , or a pharmaceutically acceptable salt thereof. 17.
  • R 6 is halogen, or a pharmaceutically acceptable salt thereof.
  • R 6 is F, or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-6 haloalkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is C 1-3 haloalkyl, or a pharmaceutically acceptable salt thereof. 21.
  • R 1 is - CF 3 , or a pharmaceutically acceptable salt thereof.
  • R 2 is C 1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R 9 , or a pharmaceutically acceptable salt thereof.
  • R 2 is C1-3 alkyl optionally substituted with 1 to 3 individually selected substituents R 9 , or a pharmaceutically acceptable salt thereof.
  • R 2 is - CH3, or a pharmaceutically acceptable salt thereof. 25.
  • R 2 is halogen, or a pharmaceutically acceptable salt thereof.
  • R 2 is Cl, or a pharmaceutically acceptable salt thereof.
  • R 2 is F, or a pharmaceutically acceptable salt thereof.
  • R 3 is phenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl and CN, or a pharmaceutically acceptable salt thereof.
  • R 3 is 6- membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl and CN, or a pharmaceutically acceptable salt thereof.
  • R 3 is of Formula III: Formula III wherein X H is C(R 31 ) or N; X I is C(R 32 ) or N; R 28 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 29 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 30 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 31 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; and R 32 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN, or a pharmaceutically acceptable salt thereof.
  • R 3 is of Formula III: Formula III wherein X H is C(R 31 ) or N; X I is C(R 32 ) or N; R 28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R 29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R 30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R 31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; and R 32 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN, or a pharmaceutically acceptable salt thereof.
  • R 3 is of Formula IV: Formula IV wherein R 28 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 29 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; R 30 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN; and R 31 is H, halogen, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy or CN, or a pharmaceutically acceptable salt thereof. 41.
  • R 3 is of Formula IV: Formula IV wherein R 28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R 29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R 30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; and R 31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN, or a pharmaceutically acceptable salt thereof. 42.
  • R 3 is of Formula IV: Formula IV wherein R 28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkoxy; R 29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R 30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; and R 31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN, or a pharmaceutically acceptable salt thereof. 43.
  • R 28 is H, or a pharmaceutically acceptable salt thereof. 44. The compound according to any one of the preceding items, wherein R 28 is halogen, or a pharmaceutically acceptable salt thereof. 45. The compound according to any one of the preceding items, wherein R 28 is F or Cl, or a pharmaceutically acceptable salt thereof. 46. The compound according to any one of the preceding items, wherein R 28 is F, or a pharmaceutically acceptable salt thereof. 47. The compound according to any one of the preceding items, wherein R 28 is Cl, or a pharmaceutically acceptable salt thereof. 48.
  • R 28 is C 1-3 alkyl, such as –CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 28 is C 1-3 alkyl, such as –CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 28 is CN, or a pharmaceutically acceptable salt thereof.
  • R 29 is H, or a pharmaceutically acceptable salt thereof.
  • 51. The compound according to any one of the preceding items, wherein R 29 is halogen, or a pharmaceutically acceptable salt thereof.
  • R 29 is F, or a pharmaceutically acceptable salt thereof. 53.
  • R 30 is halogen, or a pharmaceutically acceptable salt thereof.
  • R 30 is F or Cl, or a pharmaceutically acceptable salt thereof.
  • 55 The compound according to any one of the preceding items, wherein R 30 is C1-3 alkyl, such as –CH3, or a pharmaceutically acceptable salt thereof.
  • 56. The compound according to any one of the preceding items, wherein R 30 is C1-3 alkoxy, such as –OCH3, or a pharmaceutically acceptable salt thereof.
  • R 30 is C1-3 haloalkyl, such as –CF3, or a pharmaceutically acceptable salt thereof.
  • R 30 is C1-3 haloalkyl, such as –CHF2, or a pharmaceutically acceptable salt thereof.
  • R 30 is C1-3 haloalkyl, such as –CHF2, or a pharmaceutically acceptable salt thereof.
  • R 30 is CN, or a pharmaceutically acceptable salt thereof.
  • R 31 is H, or a pharmaceutically acceptable salt thereof.
  • R 31 is halogen, or a pharmaceutically acceptable salt thereof.
  • R 31 is F, or a pharmaceutically acceptable salt thereof.
  • R 3 is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  • 64 The compound according to any one of the preceding items, wherein R 3 is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.
  • 65 The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein . 66.
  • R 3 is . 68.
  • R 3 is .
  • R 3 is bicyclo[1.1.1]pentyl optionally substituted with CF 3 or C 1 alkyl, or a pharmaceutically acceptable salt thereof. 74. The compound according to any one of the preceding items, wherein R 3 is pharmaceutically acceptable salt thereof. 75. The compound according to any one of the preceding items, wherein R 3 is C3-6 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl and C1-3 haloalkyl, or a pharmaceutically acceptable salt thereof. 76.
  • R 3 is of Formula XXV: Formula XXV wherein R 33 is H, halogen, C 1-3 alkyl and C 1-3 haloalkyl; R 34 is H, halogen, C 1-3 alkyl and C 1-3 haloalkyl; q is 1, 2 or 3; and p is 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
  • R 33 is H, halogen, C 1-3 alkyl and C 1-3 haloalkyl
  • R 34 is H, halogen, C 1-3 alkyl and C 1-3 haloalkyl
  • q is 1, 2 or 3
  • p is 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
  • R 33 is C 1-3 haloalkyl, such as –CF 3 or –CHF 2 , or a pharmaceutically acceptable salt thereof.
  • R 34 is H, or a pharmaceutically acceptable salt thereof.
  • R 34 is halogen, such as F, or a pharmaceutically acceptable salt thereof.
  • R 34 is C 1-3 alkyl, such as –CH 3 , or a pharmaceutically acceptable salt thereof.
  • R 34 is C 1-3 haloalkyl, such as –CF 3 or –CHF 2 , or a pharmaceutically acceptable salt thereof.
  • R 3 is selected from the group consisting of: 90.
  • R 91 The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R 3 is . 92.
  • R 4 is of Formula XXVI: Formula XXVI wherein X B is N or C(H); R 15 is 5-membered heteroaryl or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, -CN, and C3-6 cycloalkyl; R 19 is H, halogen or C1-3 alkyl; and R 20 is H, halogen or C1-3 alkyl; or a pharmaceutically acceptable salt thereof.
  • X D is C(R 14 ), or a pharmaceutically acceptable salt thereof.
  • R 4 is of Formula IIH, , Formula IIH or a pharmaceutically acceptable salt thereof.
  • R 4 is a 6-membered ring, or a pharmaceutically acceptable salt thereof.
  • X E is O, C(R 16 )(R 17 ) or NR 18 ; m is 1; and n is 1, or a pharmaceutically acceptable salt thereof.
  • X B is C(R 11 ); X C is C(R 12 )(R 13 ); X D is C(R 14 ); X E is O; X F is C(R 19 )(R 20 ); X G is C(R 21 )(R 22 ); m is 1; and n is 1, or a pharmaceutically acceptable salt thereof.
  • R 12 is a bond and R 11 is C1-3 alkyl, and R 11 and R 12 are linked together to form a 3-5 membered ring, or a pharmaceutically acceptable salt thereof.
  • R 13 is individually H, or a pharmaceutically acceptable salt thereof.
  • X D is C(R 14 ), or a pharmaceutically acceptable salt thereof.
  • R 15 is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, - O-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, and halogen, or a pharmaceutically acceptable salt thereof.
  • substituents independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, - O-C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, and halogen, or a pharmaceutically acceptable salt thereof.
  • R 15 is selected from the group consisting of Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, and Formula XII: Formula X Formula XII wherein R 37 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, - O-C1-6 alkyl, H, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, and halogen, or a pharmaceutically acceptable salt thereof. 128.
  • R 15 is selected from the group consisting of Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, and Formula XXIII: Formula XIV Formula XVII Formula XIII
  • R 37 and R 38 are independently selected from the group consisting of C1- 6 alkyl, C3-6 cycloalkyl, -O-C1-6 alkyl, H, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, and halogen, or a pharmaceutically acceptable salt thereof.
  • R 37 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 37 is CH3, or a pharmaceutically acceptable salt thereof.
  • R 15 is a 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, - O-C 1-6 alkyl, H, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 1-3 alkyl)O(C 1-3 alkyl), -CN, and halogen, or a pharmaceutically acceptable salt thereof. 137.
  • R 15 is of Formula XXIV: Formula XXIV wherein X J is N or CH; X K is N or C(R 7 ); X L is N or C(R 8 ); R 7 is C1-3 alkyl; R 8 is C1-3 alkyl; and R 36 is H or C1-3 alkyl, or a pharmaceutically acceptable salt thereof.
  • X J is CH, or a pharmaceutically acceptable salt thereof.
  • X K is N, or a pharmaceutically acceptable salt thereof.
  • R 19 is C 1-3 alkyl, or a pharmaceutically acceptable salt thereof. 161.
  • the compound according to any one of the preceding items, wherein R 19 is CH 3 , or a pharmaceutically acceptable salt thereof. 162.
  • the compound according to any one of the preceding items, wherein R 20 is H, or a pharmaceutically acceptable salt thereof. 163.
  • the compound according to any one of the preceding items, wherein R 20 is halogen, or a pharmaceutically acceptable salt thereof.
  • R 20 is F, or a pharmaceutically acceptable salt thereof. 165.
  • R 20 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.
  • R 20 is CH3, or a pharmaceutically acceptable salt thereof.
  • R 19 and R 20 are C1-3 alkyl, and R 19 and R 20 are optionally linked together to form a 3- 6 membered ring, or a pharmaceutically acceptable salt thereof.
  • X G is C(R 21 )(R 22 ), or a pharmaceutically acceptable salt thereof.
  • n 1, or a pharmaceutically acceptable salt thereof.
  • n is 0, or a pharmaceutically acceptable salt thereof.
  • n is 2, or a pharmaceutically acceptable salt thereof.
  • R 4 is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.
  • R 4 is selected from the group consisting of: , , , , , and or a pharmaceutically acceptable salt thereof.
  • R 4 is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof. 181.
  • the compound according to any one of the preceding items, wherein R 4 is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof. 184.
  • R 4 is selected from the group consisting of: , or a pharmaceutically acceptable salt thereof.
  • R 4 is a 4-membered ring, or a pharmaceutically acceptable salt thereof.
  • m is 1; X E is a bond; and n is 0, or a pharmaceutically acceptable salt thereof.
  • X B is N; X C is CH2; m is 1; X D is C(H); X E is a bond; X F is C(H2); and n is 0, or a pharmaceutically acceptable salt thereof.
  • R 1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H
  • R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, halogen and H
  • R 3 is phenyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl and CN, wherein one methylene group of the C 1-3 alkyl is optionally replaced with -O-
  • X A is N or CH
  • X B is N or CH
  • X C is C(H) 2
  • X D is C(H);
  • X E is O
  • X F is C(R 19 )(R 20 ), wherein each R 19 and R 20 are individually selected as H or CH3
  • X G is C(H)2; m is 1;
  • the compound enhances or activates TREM2 signaling through DAP12; and/or wherein the compound induces phosphorylation of a kinase that interacts with the TREM2/DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b; and/or wherein the compound enhances TREM2-induced phosphorylation levels of the Syk kinase.
  • a pharmaceutical composition comprising a compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and/or diluents.
  • a condition associated with a loss of function of TREM2 such as for use in the treatment of a condition associated with a mutation of TREM2.
  • a tauopathy a TDP-43 proteinopathy
  • a synucleinopathy dementia
  • amyloidosis dementia
  • demyelinating disorder of the CNS a demyelinating disorder of the PNS
  • a Leukoencephalopathy a leukodystrophy
  • TSE transmissible spongiform encephalopathy
  • LSD lysosomal storage disorder
  • a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demye
  • a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease
  • a method for treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 205, to a subject in need thereof.
  • a compound according to any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 205 for the manufacture of a medicament for the treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease.
  • a method of enhancing or increasing TREM2 activity such as a method of one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2/DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and/or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, according to any one
  • Reverse Phase Prep-Purification method Unless stated otherwise, preparative HPLC was done on Waters auto purification instrument operating at ambient temperature and flow rate of 16 mL/min Prep-A Column name: YMC-Actus C18 (250 x 20 mm, 5 ⁇ ).
  • Prep-D Column name: CHROMCORE 120 C18,5 ⁇ m (21.2 ⁇ 250mm).
  • SFC condition -1 Chiral separation of was done by running sample in Waters Thar SFC-80 instrument equipped with UV Detector 40D by using CHIRALPAK-IG (30.0 mm x 250mm), 5 ⁇ Column operating at 35 oC temperature, maintaining flow rate of 70 ml/min, using 60% CO2 in super critical state & 40% of (100% MeOH) as Mobile phase, run this isocratic mixture upto 10.0 minutes and also maintained the isobaric condition of 110 bar at 220 nm wavelength.
  • SFC condition -2 SFC PREP PURIFICATION of CR635-22308-31-P (T.N-86) is running on PIC SOLUTIONS-175 instrument equipped with Knauer 40D Detector by using I CELLULOSE J(30.0 mm x 250mm ), 5 ⁇ Column operating at 35 oC temperature, maintaining flow rate of 80 ml/min ,using 60% CO2 in super critical state & 40%[ 100% MeOH ] as Mobile phase, Run this isocratic mixture up to 14.0 minutes and also maintained the isobaric condition of 100 bar at 275nm wavelength Normal Phase Chiral Prep Methods: NP Chiral Method 1: Chiral separation was done on Agilent 1200 series instrument.
  • CHIRALPAK IG 250 X 4.6 mm
  • Operating at ambient temperature and flow rate is 1.0 mL/min.
  • Mobile phase was mixture of 50% Hexane ,25% Ethyl alcohol and 25% Dichloromethane ,IP amine 0.1%, held this isocratic mixture run upto 25 min with wavelength of 296 nm.
  • NP Chiral Method 2 Chiral separation was done on Agilent 1200 series instrument.
  • Column name: CHIRALPAK IG 250 X 21 mm
  • Operating at ambient temperature and flow rate is 21.0 mL/min.
  • NP Chiral Method 3 Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 X 21 mm) 5 ⁇ . Operating at ambient temperature and flow rate is 21.0 mL/min. Mobile phase was a mixture of 70% Hexane, 15% DCM and 15% EtOH, held this isocratic mixture run up to 20min with wavelength of 308nm.
  • NP Chiral Method 4 Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IC (250 X 20 mm) 5u.
  • n-BuLi (40 mL, 93.2 mmol; 2.3 M in hexane) was slowly added to it under argon atmosphere and reaction was continued for at -78 ° C for 1 h.
  • Step-2 Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazol-4- yl)ethan-1-one: To a suspension of 2-chloro-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (5 g, 31.6 mmol) in acetonitrile (50 mL) was added 2-(benzylamino)ethen-1-ol (5.7 g, 38.3 mmol) and potassium carbonate (8.8 g, 63.2 mmol) and heated the reaction mixture at 60 o C for 16 h.
  • Step-3 Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazol-4- yl)ethan-1-ol: To a stirred solution of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazol-4- yl)ethan-1-one (5 g, 18.3 mmol) was in dry Methanol and cooled the reaction mixture at 0 ° C. NaBH4 (1.4 g, 3.7 mmol) was added to it portion-wise for 10 min and reaction was kept stirring for 15 min at 0 ° C. Reaction was then warm to room temperature for 2 h.
  • reaction mixture was quenched with cold water and followed by extracted with dichloromethane. Combined organic layer was dried over sodium sulphate and concentrated into vacuo and purified by column chromatography on silica gel (100-200 mesh size) using 5% methanol in dichloromethane to afford 2-(benzyl(2- hydroxyethyl)amino)-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-ol (3.0 g, 59.5% yield) as yellow sticky oil.
  • Step-4 Preparation of 4-benzyl-2-(1-methyl-1H-pyrazol-4-yl)morpholine (as HCl salt): A mixture of afford 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazol-4-yl)ethan- 1-ol (2 g, 7.27 mmol) and aqueous HCl (6N, 20.0 mL) was heated to reflux for 2 h. The reaction mixture was evaporated under reduced pressure and the residue was washed with ether and dried under vacuum to afford 4-benzyl-2-(1-methyl-1H-pyrazol-4- yl)morpholine, HCl salt (1.7 g, 90.8% yield) as yellow sticky solid.
  • Step-5 Preparation of 2-(1-methyl-1H-pyrazol-4-yl)morpholine, HCl salt (Intermediate-I-1): An ethanolic (50 mL) solution of 4-benzyl-2-(1-methyl-1H-pyrazol-4-yl)morpholine (2 g, 7.8 mmol) was taken in a par-autoclave vessel (100 mL) and purged it with argon. Pd(OH)2 (0.5 g; 10% w/w) was added to it and reaction mixture was hydrogenated (30 psi) for 18 h at rt. The reaction mixture was filtered through a pad of celite and washed with ethanol.
  • Step-1 Preparation of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde: To a stirred solution of 1H-pyrazole-4-carbaldehyde (5 g, 52.1 mmol) in DCE (200 mL) were added cyclopropyl boronic acid (8.9 g, 104.2 mmol), 2,2- bipyridyl (8.9 g, 57.3 mmol) and sodium carbonate (15.8 g, 114.6 mmol) under oxygen atmosphere.
  • Step-2 Preparation of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4- yl trifluoromethanesulfonate: To a stirred solution of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde (3.5 g, 25.7 mmol) in DCM (80 mL) at 0 °C was added but-3-yn-1-ol (3.2 ml, 38.6 mmol) followed by addition of triflic acid (5.7 mL, 64.3 mmol). Resulting mixture was stirred at rt for 3 h.
  • Step-2 Preparation of 7-bromo-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one: To a stirred solution of 5-bromo-3-(2,4-difluorophenyl)pyrazin-2-amine (1.0 g ,3.5 mmol) and methyl 3-oxobutanoate (2.0 g, 17.5 mmol) in diphenyl ether (6 mL) was added BiCl3 (662 mg, 2.1 mmol) in portion at RT under nitrogen atmosphere. The reaction mixture was stirred at 150 °C for 4 h.
  • Step-3 Preparation of 7-bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H- pyrazino[1,2-a]pyrimidin-4-one (Intermediate I-7): To a stirred solution of 7-bromo-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one (700 mg, 2 mmol ) in DMF ( 10 mL ) was added NCS ( 398.2 mg, 3 mmol ) at room temperature. Resulting mixture was heated at 90 °C for 16 h.
  • Example 9 9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one: Step-1 - Preparation of 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin- 4-one In a sealed tube, 5-bromo-3-chloropyridin-2-amine (1 gm, 4.8 mmol), methyl 2-methyl-3- oxobutanoate (0.6 ml, 4.8 mmol) and BiCl 3 (76 mg, 0.2 mmol) were mixed.
  • Step-3 Preparation of 9-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazol- 4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
  • Step-4 Preparation of 9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (Example 9)
  • 9-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)- 3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one 100 mg, 0.2 mmol
  • 1,4-Dioxane 20 mL
  • sodium acetate 60 mg
  • acetic acid 0.05 mL
  • Example 10A and Example 10B Synthesis of 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4R,6R)-2-methyl-6-(1- methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4- one and 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4S,6R)-2-methyl-6-(1- methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4- one: Step-1 - Preparation of 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4R,6R)-2- methyl-6-(1-methyl-1H-pyrazol-4-yl)
  • reaction mass was degassed with argon for over 10 minutes.
  • Nickel (II) chloride ethylene glycol dimethyl ether complex (102 mg, 0.47 mmol), 4,4'-Di-tert-butyl-2,2'-bipyridyl (187 mg, 0.7 mmol) were then added to the reaction mixture.
  • Resulting mixture was heated at 100 °C for 16 h.
  • Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic part was washed with water, brine, dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure.
  • Example 11 Examples 11A and 11B were synthesized by using similar procedure described for Example 10A & 10B in one step and stereochemistry of both peaks were assigned in a similar fashion to Example 10A & 10B The following table describes analytical data analysis and yield information of examples 11A and 11B.
  • Example 12 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)-4H-pyrido[1,2-a]pyrimidin-4-one
  • Step-1 Preparation of 3-bromo-5-fluoro-2-nitropyridine: Potassium persulfate (10.2 g, 37.7 mmol) was added to sulfuric acid (10.7 mL) and the resulting mixture was stirred at rt for 10 min. It was cooled to 0 °C and 3-bromo-5- fluoropyridin-2-amine (1.8 g, 9.4 mmol) was added.
  • Reaction mixture continued to stir at 0 °C for 1.5 h. Reaction mixture was poured slowly into crushed ice, neutralized with aq. NH3, extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and evaporated under reduced pressure. Crude product was purified by combi flash chromatography (30-40% ethyl acetate-hexane) to get 3-bromo-5-fluoro- 2-nitropyridine (1 g, 48.1% yield) as brown solid.
  • Step-2 Preparation of 4-(5-bromo-6-nitropyridin-3-yl)-2-(1-methyl-1H-pyrazol-4- yl)morpholine: To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)morpholine [I-1](HCl salt, 113.4 mg, 0.7 mmol) in DMSO (2 mL) was added DIPEA (0.3 mL, 1.8 mmol) at RT and stirred for 15 min. To it was added 3-bromo-5-fluoro-2-nitropyridine (100 mg, 0.5 mmol) at RT.
  • Step-3 Preparation of 3-bromo-5-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)pyridin-2-amine: To a stirred solution of 4-(5-bromo-6-nitropyridin-3-yl)-2-(1-methyl-1H-pyrazol-4- yl)morpholine (166 mg, 0.5 mmol) in ethanol (2 mL) was added SnCl 2 .2H 2 O (1 g, 4.5 mmol) at RT. Resulting mixture was heated at 80 °C for 2 h. Reaction mixture was quenched with water, extracted with DCM.
  • Step-4 Preparation of 9-bromo-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)-4H-pyrido[1,2-a]pyrimidin-4-one:
  • 3-bromo-5-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyridin-2-amine 70 mg, 0.2 mmol
  • methyl 2-methyl-3-oxobutanoate 53.9 mg, 0.4 mmol
  • BiCl3 6.5 mg, 0.02 mmol
  • Step-5 Preparation of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H- pyrazol-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidin-4-one
  • Example 12 To a stirred solution of 9-bromo-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)-4H-pyrido[1,2-a]pyrimidin-4-one (160 mg, 0.4 mmol) and (4-chloro-2- fluorophenyl)boronic acid (80.1 mg, 0.5 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was added sodium carbonate (81.1 mg, 0.8 mmol) and degassed with argon.
  • Example 12A-12B to 13A-13B are captured in following table:
  • Example 15 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)-4H-pyrazino[1,2-a]pyrimidin-4-one: Step-1 - Preparation of 5-chloro-3-(4-chloro-2-fluorophenyl)pyrazin-2-amine: To a stirred solution of 3-bromo-5-chloropyrazin-2-amine (1 g, 4.8 mmol) and (4-chloro- 2-fluorophenyl)boronic acid (752.8 mg, 4.3 mmol) in 1,4-dioxane (100 mL) and water (20 mL) was added sodium carbonate (762.6 mg, 7.2 mmol) and degassed with argon.
  • Step-2 Preparation of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H- pyrazino[1,2-a]pyrimidin-4-one
  • 3-bromo-5-chloropyrazin-2-amine 247.9 mg, 0.9 mmol
  • methyl 2-methyl-3-oxobutanoate 250 mg, 1.9 mmol
  • BiCl3 30.2 mg, 1.9 mmol
  • Step-3 Preparation of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H- pyrazol-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidin-4-one
  • Example 15 To a stirred solution of 2-(1-methyl-1H-pyrazol-4-yl)morpholine [I-1] (HCl salt, 148.3 mg, 0.9 mmol) in DMSO (3 mL) was added DIPEA (0.6 mL, 3.5 mmol) at rt and stirred for 15 min.
  • Step-2 Preparation of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.3 mmol) in 1,4-dioxane-water (10 mL, 9:1) were added (4-chloro-2- fluorophenyl)boronic acid ( 54 mg, 0.3 mmol), Na2CO3 (55 mg, 0.5 mmol).
  • Step-2 Preparation of 8-bromo-6-hydroxy-2,3-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one: To a stirred mixture of 6-amino-4-bromopyridin-2(1H)-one (250 mg, 1.32 mmol) and methyl 2-methyl-3-oxobutanoate (343 mg, 2.6 mmol) was added BiCl3 (41 mg, 0.13 mmol). Resulting mixture was heated at 130 °C for 16 h. The reaction mixture was quenched with ice cold sodium bicarbonate solution, extracted with DCM, dried over sodium sulphate and concentrated.
  • Step-3 Preparation of 6,8-dichloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 8-bromo-6-hydroxy-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (350 mg, 1.3 mmol) in POCl3 (12 mL) was added DIPEA (1.2 mL, 6.5 mmol) at 0 °C. Resulting mixture was stirred at 100 °C for 16 h.
  • Step-4 Preparation of 8-chloro-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one: To a stirred solution of 6,8-dichloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (100 mg, 0.41 mmol) in 1,4-dioxane-water (10 mL, 9:1) were added (4-chloro-2- fluorophenyl)boronic acid (64 mg, 0.4 mmol), Na 2 CO 3 (87 mg, 0.82 mmol).
  • the resulting mixture was degassed with argon and Pd(dppf)Cl 2 (30 mg, 0.04 mmol) was added. The resulting mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was passed through a pad of celite and washed with ethyl acetate.
  • Step-5 Preparation of 6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H- pyrazol-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidin-4-one
  • Example-72 To a stirred solution of 8-chloro-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one ( 80 mg 0.24 mmol) in toluene ( 10 mL) were added 2-(1-methyl-1H- pyrazol-4-yl)morpholine [I-1] (40 mg, 0.24 mmol), sodium tert-butoxide ( 75 mg 0.8 mmol) and Ruphos( 6 mg, 0.01 mmol ).
  • Example 32 Biological assay Human TREM2, in vitro Measurement of Triggering Receptor Expressed on Myeloid Cells 2 activity using cellular phosphorylation of Spleen Tyrosine Kinase (“Syk”) Assay Cell line: HEK-293 cells were co-transfected with separate plasmids encoding TREM2 and DAP12 to generate a stable cell line. After antibiotic selection, functional clone pool analysis and two successive limiting dilutions, the final clone “HEK293/DAP12+TREM2” underwent a qPCR analysis and a pharmacological validation.
  • Spleen Tyrosine Kinase Spleen Tyrosine Kinase
  • Assay TREM2 signaling through DAP12 was monitored in the HEK293/DAP12+TREM2 stable cell line by measuring the phosphorylation levels of the Syk kinase using the commercially available AlphaLISA SureFire Ultra p-SYK (Tyr525/526) Assay Kit (PerkinElmer #ALSU-PSYK), based on the Perkin Elmer AlphaScreen/AlphaLISA technology.
  • Compounds are transferred to the test plate and tested in full dose response, 8 concentrations in quadruplicate data points.
  • Compound serial dilutions were performed at Cybi-Felix instrument in 100% DMSO and the dose response curves were assembled in automated fashion in 384MPT at Hamilton STARIet instrument.
  • dose response curves of a reference control agonist were included in column 1 and 24 as reference control agonist (Reference control agonists used include Human TREM2 polyclonal Antibody AF1828: R&D Systems; Human TREM2 monoclonal Antibody MAB1828: R&D Systems).
  • the dose response curves were tested starting at 30 pM, dilution step 1:6. Both “source” compound plate and “destination” compound plate were barcoded and a relationship between the two plates was thus generated.
  • HEK293/DAP12+TREM2 cells were cultured in EMEM medium supplemented with IX Penicillin/Streptomycin (BIOWHITTAKER_cat.DE17-602E), ULTRAGLUTAMINE I 200mM, 10% Fetal Bovine Serum plus antibiotics referred to as “HEK293 Culture Medium”. The day before the experiment, cells were detached by gentle wash with DPBS, followed by 5 min incubation at 37°C with Trypsin solution.
  • the CyBi®-Well instrument was used to dispense 5 pL/well of AlphaLISA Acceptor Bead Solution in IX Immunoassay buffer (Perkin Elmer AL000F). Then the plates were sealed with Heat sealing foil, shaked for 2 minutes (350 rpm) and incubated for 1 hour at room temperature. Following the incubation with the AlphaLISA Acceptor Bead Solution, the CyBi®-Well instrument was used to dispense 5 pL/well of AlphaLISA Donor Bead Solution in IX Immunoassay buffer. The plates were sealed with Heat sealing foil, shaked for 2 minutes (350 rpm) and then incubated for 1 hour at room temperature.
  • an AlphaLISA signal was acquired from the donor and acceptor beads using the Pherastar FSX instrument, a high throughput multi-modal microplate reader calibrated to the plate type with the AlphaLISA mirror and filter-set in 384-well mode, 680-615 nanometer excitation wavelength.
  • the total integration time was 0,60 seconds with a 0,30 second excitation time and a gain of 3600.
  • N(x) CR + [((x - ⁇ cr >)/ ( ⁇ sr > - ⁇ cr >)) ⁇ (SR - CR)]
  • x is the signal value of a well
  • ⁇ cr > is the median of the signal values for the Central Reference wells of a plate (median of Neutral Controls)
  • ⁇ sr > is the median of the signal values for the Scale Reference wells of a plate (median of Stimulator Controls)
  • CR is the desired median normalized value for the Central Reference (0)
  • SR is the desired median normalized value for the Scale Reference (100).
  • the fitting of the dose-response curve of each test compound is performed in the Analyzer module of the Screener software on the normalized values and applying the “smart fit” strategy.
  • This strategy allowed an automatic selection between the “Constant Fit” and the “Hill Fit” model calculating which fit model best matched the experimental data.
  • the Constant Fit was applied when no change of activity was detected across the measured concentrations, and the corresponding compounds were further classified as “inactive”.
  • the Hill Fit was applied when the observed activity significantly changed with the compound concentration. In case of Hill Fit, Hill equation was used to determine the concentration at which activity reaches 50% of maximum level, i.e., ACso.
  • the equation has four parameters:
  • the potency of the test compounds was expressed as ECso corresponding to the test compound concentration able to activate the phospho-Syk AlphaScreen signal to 50% of the maximal response.
  • the ECso values measured in this assay for the exemplified compounds is set out in the table below: wherein “A “denotes an ECso value ⁇ 10 nM, “B” denotes an ECso value between 10 nM and 100 nM, “C” denotes an ECso value between 100 and 1000 nM, “D” denotes an ECso value greater than 1000 nM.

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Abstract

La présente invention concerne des composés utiles pour moduler le récepteur de déclenchement de type-2 exprimé sur les cellules myéloïdes (TREM2). L'invention concerne également les composés destinés à être utilisés dans le traitement d'états pathologiques liés à la perte de fonction de TREM2, tels que des maladies neurodégénératives, et des compositions pharmaceutiques comprenant les composés.
PCT/EP2024/070237 2023-07-17 2024-07-17 Modulateurs de trem2 Pending WO2025017059A1 (fr)

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WO2021226629A1 (fr) * 2020-05-04 2021-11-11 Amgen Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
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