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WO2025017059A1 - Trem2 modulators - Google Patents

Trem2 modulators 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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French (fr)
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/en
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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

The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2"). 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.

Description

TREM2 modulators
Technical field
The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 (“TREM2”). 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.
Background
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))).
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)).
Signaling via TREM2 is well described through co-receptor DAP12. 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. After ligation of TREM2, ITAM (immunoreceptor tyrosine-based 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.
Proteolytic cleavage of the ectodomain of TREM2 by metalloproteinases, including ADAM 10 and ADAM 17 and possibly matrix metalloproteinases, leads to the shedding of soluble TREM2 (sTREM2), which can be detected in human cerebrospinal fluid (CSF). sTREM2 has been suggested as a potential biomarker for microglia activity in early-stage Alzheimer’s disease (Suarez-Calvet, M. et al. (2016)).
Deficiency of either TREM2 or DAP12 leads to a blunted microglial response to pathological agents. The impact of 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. (2017)), whereas 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). 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). Thus, there is a high and unmet medical need for TREM2 modulators to address these indications.
Summary
The present invention relates to compounds that modulates TREM2. P6647PC00 In one aspect, the present invention relates to a compound of Formula IA or Formula IB:
Figure imgf000004_0001
Formula IA wherein XA is N or C(R5); 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 R6; 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 R9; 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, 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-membered heteroaryl is 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; wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with –O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000005_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, - C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5- membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6- membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. In one aspect, 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. Definitions As used herein, 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%. The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. The terms “C1-3 alkyl”, “C1-5 alkyl” and “C1-6 alkyl” as used herein refer to a straight or branched hydrocarbon chains containing from 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. Representative examples of 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. The term “C2-4 alkenyl” as used herein 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. Representative examples of C2-4 alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl -2 -propenyl, and butenyl. The term “C3-6 cycloalkyl” as used herein 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. The terms “diC1-3 alkylamino” as used herein refer to -NR*R**, wherein R* and R** independently represent a C1-3 alkyl as defined herein. Representative examples of diC1-3 alkylamino include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, - N(CH3)(CH2CH3), -N(CH2 CH2CH3)2 and -N(CH(CH3)2)2. The term “C1-3 alkoxy” and “C1-6 alkoxy” as used herein refer to -OR#, wherein R# represents a C1-3 alkyl and C1-6 alkyl group, respectively, as defined herein. Representative examples of C1-3 alkoxy and C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. The term “halogen” as used herein refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl. The term “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. For example, the term “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). Further, the term “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. Representative examples of 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). The term “CN” is used herein to indicate a cyano group ( ). The term “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. Representative examples of a 6- membered heteroaryl include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl. The term “C3-6 heterocycloalkyl” as used herein 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. In some embodiments, a “C3-6 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. If the C3-6 heterocycloalkyl group is a C6 heterocycloalkyl, one or two carbon atoms are substituted with a heteroatom independently selected from N, O, and S. Representative examples of C3-6 heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. The term “spiro compound” as used herein refers to a compound having one atom (usually a quaternary carbon) as the only common member of two rings, The term “C5-8 spiroalkyl” as used herein 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. The term “C5-8 tricycloalkyl” as used herein 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[1.1.1.01,3]pentanyl, tricyclo[2.1.1.01,4]hexanyl, tricyclo [3.1.1.01,5]hexanyl and tricyclo[3.2.1.01,5]octanyl. The term “C5-8 bicycloalkyl” as used herein refers a bicyclic ring system, wherein both cycloalkyl rings share the same two ring atoms. The term “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. For example, the term “C5-8 bicycloalkyl” includes bicyclo[1.1.1]pentyl. For example, the term “C5-8 bicycloalkyl” includes
Figure imgf000009_0001
. The term “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. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “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. Also included within the scope of the term “aryl,” as it is used herein, 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. The terms “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. The term “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. The terms “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. A heteroaryl ring may include one or more oxo (=O) or thioxo (=S) substituent. 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. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, 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. In some embodiments, a chemical group is “a bond”, which may also be referred to as said chemical group is absent. For example, when Ra in CH3-Ra-OH is “a bond”, it refers to CH3OH. In some embodiments, 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). The term “stable,” as used herein, 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. As used herein, the term “pharmaceutically acceptable 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. Detailed description In one aspect, the present invention relates to a compound of Formula IA or Formula IB:
Figure imgf000012_0001
Formula IA wherein XA is N or C(R5); 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 R6; 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 R9; 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, 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-membered heteroaryl is 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, wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with –O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000013_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, - C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5- membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6- membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. In one aspect, the present invention relates to a compound of Formula IA or Formula IB:
Figure imgf000015_0001
Formula IA wherein XA is N or C(R5); 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 R6; 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 R9; 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, 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-membered heteroaryl is 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; wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with –O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000016_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, - C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5- membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6- membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. In one aspect, the present invention relates to a compound of Formula IA or Formula IB:
Figure imgf000018_0001
Formula IA wherein XA is N or C(R5); 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 R6; 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 R9; 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, 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-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, and CN; wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with –O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000019_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, - C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5- membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6- membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. In some embodiments, 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:
Figure imgf000021_0001
Formula IA wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl and H; R3 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; XA is N or C(H); R4 is of Formula XXVI:
Figure imgf000021_0002
Formula XXVI wherein XB is N or C(H); R15 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; R19 is H, halogen or C1-3 alkyl; and R20 is H, halogen or C1-3 alkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, XA is N. In some embodiments, XA is C(R5) and R5 is H. In some embodiments, the compound is of Formula IA and XA is N. In some embodiments, the compound is of Formula IA and XA is C(R5) and R5 is H. In some embodiments, the compound is of Formula IB and XA is C(R5) and R5 is H. In some embodiments, R1 is C1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R6. In some embodiments, R1 is C1-3 alkyl. In some embodiments, R1 is -CH3. In some embodiments, R1 is C1-6 alkyl substituted with 1 to 3 individually selected substituents R6. In some embodiments, R1 is C1-3 alkyl substituted with 1 to 3 individually selected substituents R6. In some embodiments, R6 is halogen. In some embodiments, R6 is F. In some embodiments, R1 is C1-6 haloalkyl. In some embodiments, R1 is C1-3 haloalkyl. In some embodiments, R1 is -CF3. In some embodiments, R2 is C1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R9. In some embodiments, R2 is C1-3 alkyl optionally substituted with 1 to 3 individually selected substituents R9. In some embodiments, R2 is -CH3. In some embodiments, R2 is halogen. In some embodiments, R2 is Cl. In some embodiments, R2 is F. In some embodiments, R3 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, R3 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. In some embodiments, R3 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. In some embodiments, R3 is of Formula III:
Figure imgf000023_0001
Formula III wherein XH is C(R31) or N; XI is C(R32) or N; R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; and R32 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN. In some embodiments, R3 is of Formula III, wherein XH is C(R31) or N; XI is C(R32) or N; R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; and R32 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN. In some embodiments, XH is C(R31). In some embodiments, XH is N. In some embodiments, XI is C(R32), or a pharmaceutically acceptable salt thereof. In some embodiments, XI is N. In some embodiments, XH is C(R31), and XI is C(R32), or a pharmaceutically acceptable salt thereof. In some embodiments, XH is N, and XI is C(R32). In some embodiments, XH is C(R31), and XI is N. In some embodiments, R31 is H. In some embodiments, R3 is of Formula IV:
Figure imgf000024_0001
Formula IV wherein R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; and R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN. In some embodiments, R3 is of Formula IV wherein R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; and R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN. In some embodiments, R28 is H. In some embodiments, R28 is halogen. In some embodiments, R28 is F or Cl. In some embodiments, R28 is C1-3 alkyl, such as –CH3. In some embodiments, R28 is CN. In some embodiments, R29 is H. In some embodiments, R29 is halogen. In some embodiments, R29 is F. In some embodiments, R30 is halogen. In some embodiments, R30 is F or Cl. In some embodiments, R30 is C1-3 alkyl, such as – CH3. In some embodiments, R30 is C1-3 haloalkyl, such as –CF3. In some embodiments, R30 is C1-3 haloalkyl, such as –CHF2. In some embodiments, R30 is CN. In some embodiments, R30 is C1-3 alkoxy, such as –OCH3.In some embodiments, R31 is H. In some embodiments, R31 is halogen. In some embodiments, R31 is F. In some embodiments, R3 is
Figure imgf000024_0002
. In some embodiments,
Figure imgf000024_0003
some embodiments,
Figure imgf000025_0002
some embodiments,
Figure imgf000025_0001
some embodiments,
Figure imgf000025_0003
some embodiments,
Figure imgf000025_0004
some embodiments,
Figure imgf000025_0005
some embodiments,
Figure imgf000025_0006
some embodiments,
Figure imgf000025_0007
. In some embodiments, R3 is
Figure imgf000025_0008
. In some embodiments,
Figure imgf000025_0009
some embodiments,
Figure imgf000025_0010
. In some embodiments,
Figure imgf000025_0011
In some embodiments,
Figure imgf000025_0012
some embodiments,
Figure imgf000025_0014
some embodiments,
Figure imgf000025_0013
. In some embodiments,
Figure imgf000025_0015
, . In some embodiments,
Figure imgf000026_0002
some embodiments,
Figure imgf000026_0001
some embodiments,
Figure imgf000026_0004
some embodiments,
Figure imgf000026_0003
. In some embodiments, R3 is C5-8 bicycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl and C1-3 haloalkyl. In some embodiments, R3 is bicyclo[1.1.1]pentyl optionally substituted with CF3 or C1 alkyl. In some embodiments,
Figure imgf000026_0005
. In some embodiments, R3 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. In some embodiments, R3 is of Formula XXV:
Figure imgf000026_0006
Formula XXV wherein R33 is H, halogen, C1-3 alkyl and C1-3 haloalkyl; R34 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, R33 is H. In some embodiments, R33 is halogen, such as F. In some embodiments, R33 is C1-3 alkyl, such as –CH3. In some embodiments, R33 is C1-3 haloalkyl, such as –CF3 or –CHF2. In some embodiments, R34 is H. In some embodiments, R34 is halogen, such as F. In some embodiments, R34 is C1-3 alkyl, such as –CH3. In some embodiments, R34 is C1-3
Figure imgf000027_0001
haloalkyl, such as –CF3 or –CHF2. In some embodiments, R3 is . In some embodiments, R3 is
Figure imgf000027_0002
. In some embodiments, R3 is
Figure imgf000027_0003
. In some odiments, R3
Figure imgf000027_0004
emb is . In some embodiments,
Figure imgf000027_0005
some embodiments,
Figure imgf000027_0006
some embodiments,
Figure imgf000027_0007
some embodiments,
Figure imgf000027_0009
some embodiments,
Figure imgf000027_0008
some embodiments,
Figure imgf000028_0001
some embodiments, R3 is
Figure imgf000028_0002
. In some embodiments,
Figure imgf000028_0003
. In some embodiments, XD is C(R14). In some embodiments, R4 is of Formula IIA. In some embodiments, R4 is of Formula IIB.
Figure imgf000028_0004
Formula IIA Formula IIB In some embodiments, XB is C(R11). In some embodiments, R4 is of Formula IIC. In some embodiments, R4 is of Formula IID.
Figure imgf000028_0005
Formula IID Formula IIC In some embodiments, XB is C(R11) and XD is C(R14). In some embodiments, R4 is of Formula IIE. In some embodiments, R4 is of Formula IIF. In some embodiments, R4 is of Formula IIG. In some embodiments, R4 is of Formula IIH.
Figure imgf000029_0001
Formula IIG Formula IIH In some embodiments, R4 is a 6-membered ring. In some embodiments, XE is O, C(R16)(R17) or NR18; m is 1; and n is 1. In some embodiments, XB is N; XC is C(R12)(R13); XD is C(R14); XE is O; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1. In some embodiments, XB is C(R11); XC is C(R12)(R13); XD is C(R14); XE is O; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1. In some embodiments, XB is N; XC is C(R12)(R13); XD is C(R14); XE is NR18; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1. In some embodiments, XB is N; XC is C(R12)(R13); XD is C(R14); XE is C(R16)(R17); XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1. In some embodiments, XB is N. In some embodiments, XB is C(R11). In some embodiments, R11 is H. In some embodiments, R11 is C1-3 alkyl. In some embodiments, XC is C(R12)(R13). In some embodiments, R12 is individually H. In some embodiments, R12 is individually C1-3 alkyl. In some embodiments, R12 is a bond and R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring. In some embodiments, R13 is individually H. In some embodiments, R13 is individually C1-3 alkyl. In some embodiments, XD is C(R14). In some embodiments, XD is N. In some embodiments, R14 is H. In some embodiments, R14 is C1-3 alkyl. In some embodiments, when XB is N, then XD is C(R14). In some embodiments, R23 is a bond. In some embodiments, R4 is of Formula XXVI:
Figure imgf000030_0001
Formula XXVI wherein XB is N or C(H); R15 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; R19 is H, halogen or C1-3 alkyl; and R20 is H, halogen or C1-3 alkyl. In some embodiments, R15 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. In some embodiments, R15 is selected from the group consisting of Formula V, Formula VI, Formula VII, Formula VIII, Formula IX Formula X, Formula XI, and Formula XII:
Figure imgf000030_0002
Formula V Formula VI Formula VII Formula VIII
Figure imgf000030_0003
Formula X Formula XI Formula XII wherein R37 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. In some embodiments, R15 is of Formula V. In some embodiments, R15 is of Formula VI. In some embodiments, R15 is of Formula VII. In some embodiments, R15 is of Formula VIII. In some embodiments, R15 is of Formula IX. In some embodiments, R15 is of Formula X. In some embodiments, R15 is of Formula XI. In some embodiments, R15 is of Formula XII. In some embodiments, R15 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:
Figure imgf000031_0001
ormua Formula XIII
Figure imgf000031_0002
Formula XXIII wherein R37 and R38 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. In some embodiments, R15 is Formula XIII. In some embodiments, R15 is Formula XIV. In some embodiments, R15 is Formula XV. In some embodiments, R15 is Formula XVI. In some embodiments, R15 is Formula XVII. In some embodiments, R15 is Formula XVIII. In some embodiments, R15 is Formula XIX. In some embodiments, R15 is Formula XX. In some embodiments, R15 is Formula XXI. In some embodiments, R15 is Formula XXII. In some embodiments, R15 is Formula XXIII. In some embodiments, R37 is C1-3 alkyl. In some embodiments, R37 is CH3. In some embodiments, R37 is C3-6 cycloalkyl. In some embodiments, R37 is C3 cycloalkyl. In some embodiments, R15 is
Figure imgf000032_0001
. In some embodiments, R15 is
Figure imgf000032_0002
. In some embodiments, R15 is
Figure imgf000032_0003
. In some embodiments,
Figure imgf000032_0004
In some embodiments, R15 is
Figure imgf000032_0006
. In some embodiments, R15 is
Figure imgf000032_0005
. In some embodiments,
Figure imgf000032_0007
. In some embodiments, R15
Figure imgf000032_0008
. In some embodiments,
Figure imgf000032_0009
. In some embodiments, R15 is
Figure imgf000032_0010
. In some embodiments, R15
Figure imgf000032_0012
. In some embodiments,
Figure imgf000032_0011
. In some embodiments, R15 is
Figure imgf000032_0013
. In some embodiments,
Figure imgf000032_0014
. In some embodiments,
Figure imgf000032_0016
. In some embodiments, R15 is
Figure imgf000032_0015
. In some embodiments,
Figure imgf000032_0018
. In some embodiments,
Figure imgf000032_0017
In some embodiments, R15 is a 6-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, H, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, and halogen. In some embodiments, R15 is of Formula XXIV:
Figure imgf000033_0001
Formula XXIV wherein XJ is N or CH; XK is N or C(R7); XL is N or C(R8); R7 is C1-3 alkyl; R8 is C1-3 alkyl; and R36 is H or C1-3 alkyl. In some embodiments, XJ is CH. In some embodiments, XK is N. In some embodiments, XK is C(R7). In some embodiments, R7 is –CH3. In some embodiments, XL is N. In some embodiments, XL is C(R8). In some embodiments, R8 is –CH3. In some embodiments, R36 is H. In some embodiments, R36 is C1-3 alkyl. In some embodiments, R36 is –CH3. In some embodiments, at least one of XJ , XK , and XL is N. In some embodiments, one of XJ , XK , and XL is N. In some embodiments, two of XJ , XK , and XL are N.
n some embodiments, R15
Figure imgf000034_0001
i is . In some embodiments, R15 is
Figure imgf000034_0002
In some embodiments, XE is C(R16)(R17). In some embodiments, XE is O. In some embodiments, XE is NR18. In some embodiments, XE is a bond. In some embodiments, R19 is H. In some embodiments, R19 is halogen. In some embodiments, R19 is F. In some embodiments, R19 is C1-3 alkyl. In some embodiments, R19 is CH3. In some embodiments, R20 is H. In some embodiments, R20 is halogen. In some embodiments, R20 is F. In some embodiments, R20 is C1-3 alkyl. In some embodiments, R20 is CH3. In some embodiments, R19 and R20 are C 19 1-3 alkyl, and R and R20 are optionally linked together to form a 3-6 membered ring. In some embodiments, XG is C(R21)(R22). In some embodiments, XG is C(O). In some embodiments, R21 is H. In some embodiments, R22 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.
Figure imgf000035_0001
some embodiments,
Figure imgf000035_0002
some embodiments, R4 is
Figure imgf000035_0003
embodiments,
Figure imgf000035_0004
some embodiments, R4 is
Figure imgf000035_0006
Figure imgf000035_0005
some embodiments,
Figure imgf000036_0001
some embodiments, R4 is
Figure imgf000036_0002
embodiments,
Figure imgf000036_0003
some embodiments, R4
Figure imgf000036_0004
. In some embodiments,
Figure imgf000037_0001
some embodiments, R4 is
Figure imgf000037_0002
some embodiments,
Figure imgf000037_0003
Figure imgf000037_0006
I
Figure imgf000037_0004
. In some embodiments, R4 is
Figure imgf000037_0007
Figure imgf000037_0005
some embodiments,
Figure imgf000038_0001
.
Figure imgf000038_0002
Figure imgf000038_0003
embodiments,
Figure imgf000038_0004
. In some embodiments, R4 is
Figure imgf000038_0005
embodiments,
Figure imgf000038_0006
some embodiments,
Figure imgf000038_0007
.
Figure imgf000039_0001
In some embodiments,
Figure imgf000039_0002
some embodiments, R4 is
Figure imgf000039_0003
Figure imgf000039_0004
e
Figure imgf000039_0005
Figure imgf000039_0006
. In some embodiments,
Figure imgf000040_0001
. In some embodiments,
Figure imgf000040_0002
some embodiments, R4 is
Figure imgf000040_0003
. In some
Figure imgf000040_0004
Figure imgf000040_0009
diments,
Figure imgf000040_0005
embodiments,
Figure imgf000040_0006
some embodiments,
Figure imgf000040_0007
In some embodiments,
Figure imgf000040_0008
Figure imgf000041_0001
In some embodiments, R4 is . In some embodiments, R4 is
Figure imgf000041_0002
embodiments,
Figure imgf000041_0004
some embodiments,
Figure imgf000041_0003
In some embodiments,
Figure imgf000041_0005
Figure imgf000041_0006
In some embodiments, R4 is . In some embodiments, R4 is
Figure imgf000041_0007
embodiments,
Figure imgf000041_0009
some embodiments,
Figure imgf000041_0008
In some embodiments,
Figure imgf000042_0001
. In some embodiments, R4 is .
Figure imgf000042_0004
embodiments,
Figure imgf000042_0002
Figure imgf000042_0003
embodiments, R4 is
Figure imgf000043_0001
. In some embodiments, R4 is
Figure imgf000043_0002
embodiments, R4 is
Figure imgf000043_0004
In some embodiments, R4 is
Figure imgf000043_0003
. In some embodiments,
Figure imgf000043_0005
In some embodiments, R4 is
Figure imgf000043_0006
. In some embodiments, R4 is
Figure imgf000043_0007
embodiments,
Figure imgf000043_0008
some embodiments,
Figure imgf000043_0009
In some embodiments,
Figure imgf000043_0010
some embodiments, R4 is
Figure imgf000044_0001
embodiments,
Figure imgf000044_0002
. In some embodiments, R4 is
Figure imgf000044_0003
embodiments,
Figure imgf000044_0004
some embodiments, R4 is
Figure imgf000044_0005
embodiments,
Figure imgf000044_0006
some embodiments, R4 is e
Figure imgf000045_0001
Figure imgf000045_0002
ome embodiments, R
Figure imgf000045_0004
ome embodiments, R
Figure imgf000045_0003
some embodiments, R ome 4
Figure imgf000045_0005
embodiments, R is s
Figure imgf000045_0006
e embodiments, R4 is
Figure imgf000045_0007
In some embodiments, R4 is
Figure imgf000046_0001
, . In some
Figure imgf000046_0002
Figure imgf000046_0004
embodiments, R4 is . In some embodiments,
Figure imgf000046_0003
. In some embodiments, R4 is a 5-membered ring. In some embodiments, m is 1; XE is a bond; and n is 1. In some embodiments, XB is N; XC is CH2; m is 1; XD is C(H); XE is a bond; XF is C(H2); G
Figure imgf000046_0005
X is C(H2); and n is 1. In some embodiments, R4 is . In some embodiments,
Figure imgf000046_0006
some embodiments, R4 is
Figure imgf000046_0007
, . In some embodiments, R4 is a 4-membered ring. In some embodiments, m is 1; XE is a bond; and n is 0. In some embodiments, XB is N; XC is CH2; m is 1; XD is C(H); XE is a bond; XF is C(H2); and n is 0. In some embodiments, XB is N; XC is CH2; m is 1; XD is C(H); XE is a bond;
Figure imgf000046_0008
XF is C(H2); n is 0; and R15 is . In some embodiments, R4 is
Figure imgf000047_0001
. In some embodiments, R4 is
Figure imgf000047_0002
. In some embodiments, R is . In some embodiments,
Figure imgf000047_0003
. In some embodiments, R4 is a 3-membered ring. In some embodiments, m is 0; XE is a bond; and n is 0. In some embodiments, XB XE is a bond; XF is C(H2); and n is 0. In some embodiments,
Figure imgf000047_0004
some
Figure imgf000047_0005
In some embodiments, the compound is of Formula IA, wherein: R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, halogen and H; R3 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-; XA is N or CH; XB is N or CH; XC is C(H)2; XD is C(H); XE is O; XF is C(R19)(R20), wherein each R19 and R20 are individually selected as H or CH3; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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 alkoxy, -CN, and C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula IA, wherein: R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, and H; R3 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; XA is CH; XB is N; XC is C(H)2; XD is C(H); XE is O; XF is C(H)2; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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 alkoxy, -CN, and C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula IA and wherein: R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, and H; R3 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; XA is N; XB is C(H); XC is C(H)2; XD is C(H); XE is O; XF is C(H)2; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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. In some embodiments, the compound is selected from the group consisting of: Cl
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
acceptable salt thereof.
In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the compound is 7- ((2R)-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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the compound is 9-(2,4-difluorophenyl)-
3-fluoro-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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the compound is (R)-
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.
In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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).
All compounds described herein, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates).
In one aspect, 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. For example, 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. In some embodiments 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. Accordingly, 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.
The term “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. For example, 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.
In some embodiments, the compound as defined herein is stereoisomerically pure.
Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents, for example as outlined in the example section. Pharmaceutical composition
The present invention also relates to a pharmaceutical composition comprising, for example as an active ingredient, a pharmaceutically effective amount of a compound as disclosed herein. In some embodiments, 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.
While 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.
In some embodiments, 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, e.g. ED50, 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. In some embodiments, 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.
Biological activity
As demonstrated in Example 32 compounds of the present invention are capable of modulating TREM2. Thus, in some embodiments, 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. In some embodiments the compounds of the present invention are useful for the activation of TREM2. In some embodiments the compounds of the present invention activates TREM2. In some embodiments the compounds of the present invention enhances TREM2 activity. In some embodiments, 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. In some embodiments the compounds of the present invention enhances or activates TREM2 signalling through DAP12. In some embodiments the compounds of the present invention enhances or activates TREM2-induced phosphorylation levels of the Syk kinase. In some embodiments, 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. In some embodiments 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.
In some embodiments 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.
In some embodiments, 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).
Medical use
Being modulators of TREM2, the compounds of the present invention are of use in the treatment of diseases and disorders of a living body, including human. As used herein, the term “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. In one aspect, the compound as described herein is for use as a medicament. In one aspect, 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. In one aspect, 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.
In one aspect, 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.
In some embodiments, 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.
In one aspect, 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.
In one aspect, 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.
In some embodiments, the neurodegenerative disease is a tauopathy. Tautopathies depicts some neurodegenerative disorders characterized by tau deposits in the brain, with symptoms of dementia and parkinsonism. In some embodiments, 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).
In some embodiments, 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.
In some embodiments, 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-dementia complex of Guam (ALS-PDC), Multisystem proteinopathy (MSP; also referred to as inclusion body myopathy, IBM, associated with early-onset Paget disease of the bone and FTLD dementia), Perry disease, and disorders with concomitant TDP-43 pathology, including Alzheimer’s disease (AD) and Chronic traumatic encephalopathy (CTE).
In some embodiments, 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).
In some embodiments, the neurodegenerative disease is a synucleinopathy. Synucleinopathies (also called a-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.
In some embodiments, 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).
In some embodiments, the neurodegenerative disease is cognitive deficit and/or memory loss. In some embodiments, the neurodegenerative disease is dementia. In some embodiments, 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.
Disorders of peripheral nerves (peripheral neuropathy) are the most common neurological complications of systemic amyloidosis. In some embodiments, the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).
In some embodiments, the neurodegenerative disease is a demyelinating disorder. In some embodiments, the neurodegenerative disease is a demyelinating disorder of the central nervous system, CNS. In some embodiments, 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. In some embodiments, 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.
In some embodiments, the neurodegenerative disease is a demyelinating disorder of the peripheral nervous system, PNS. In some embodiments, 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.
In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments 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).
In some embodiments the neurodegenerative disease is a Leukoencephalopathy. Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. In some embodiments 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. In some embodiments, the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia).
In some embodiments 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).
In some embodiments 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. In some embodiments 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).
In some embodiments, the neurodegenerative disease is a transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease, Gerstmann-Straussler- Scheinker disease (GSS), kuru, and fatal familial insomnia.
In one aspect, 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.
In one aspect, 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.
In some embodiments, the subject is a mammal, such as a human.
In one aspect, 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.
In one aspect, 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). In some embodiments the disease or disorder associated with dysfunction of CSF1R is a neurodegenerative disease associated with dysfunction of CSF1 R. In some embodiments 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. In some embodiments 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.
In some embodiments the neurodegenerative disease associated with dysfunction of CSF1R is a Leukoencephalopathy.
In some embodiments 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).
In some embodiments the neurodegenerative disease is a condition associated with dysfunction of ATP- binding cassette transporter 1 (ABCD1).
In one aspect, 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). Most lysosomal storage disorders cause progressive neurodegeneration leading to early death.
In some embodiments 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.
In some embodiments 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.
In some embodiments 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.
In some embodiments the LSD is selected from the group consisting of Batten disease, cyctinosis, Danon disease and Pompe disease.
In one aspect, 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. In some embodiments said disease or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia and dysosteoplasia.
In one aspect, 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.
In one aspect, 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. In some embodiments the TBI is chronic traumatic encephalopathy (CTE).
In one aspect, 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). In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of inflammation. In some embodiments 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).
A reduction in the functional levels of TREM2 results in dysregulation of lipid metabolism. In one aspect, 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. In certain embodiments, the dysregulated lipid metabolism comprises increased intracellular and/or extracellular accumulation of one or more lipids. In some embodiments said dysregulated lipid metabolism is atherosclerosis.
In one aspect, 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,
In one aspect, 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.
In some embodiments, 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. Examples of such animals include mammals such as humans, rodents, dogs, cats, zoo animals and farm animals. In some embodiments, the subject referred to herein is a mammal, such as a human.
The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. Accordingly, the scope of the methods and uses herein is to be understood to encompass methods and uses employing all such forms.
Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of the present invention. As used herein, 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.” In some embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. In some embodiments, 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. In some embodiments, the method includes coadministering one or more additional therapeutic agent. Examples of 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. In some embodiments, 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). As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Methods of manufacturing
Generally, the compounds of Formula IA and Formula IB as described herein may be synthesised according to the following Schemes:
All starting materials are either commercially available or known in the art and may be synthesised by using known procedures. Starting materials may also be synthesised using the procedures disclosed herein. Reaction conditions such as reaction temperature, solvent and reagents for the Schemes in this section may be found in the experimental section herein.
As shown in Scheme 1, a suitably substituted pyridine or pyrazine can be functionalised in many ways to deliver the desired compounds. For example, the R3 group can be introduced first via a cross coupling reaction which is then followed by cyclisation (where Q = NH2) with a keto ester R1C(O)CHR2CO2R and then a further substitution or cross coupling reaction. Alternatively, R4 can be introduced first via nucleophilic substitution or cross coupling followed by cyclisation and then finally cross coupling to introduce R3. In a further alternative, cyclisation occurs first, then R3 is introduced via cross coupling and then finally R4 via a second cross coupling reaction or via a nucleophilic displacement.
Figure imgf000096_0001
Scheme 1. Examples of synthetic routes for compounds of Formula IA. Q is NH2 or NO2; X is halogen; Y is halogen; R is alkyl; and XA, R1, R2, R3 and R4 are as defined herein.
Other examples can be made as shown in Scheme 2. In some cases cyclisation is performed with R2 = H, which is then converted to a halogen using a suitable halogenating reagent such as NIS or Selectfluor.
Figure imgf000097_0001
Figure imgf000097_0004
Figure imgf000097_0002
E n motai-c^a;vscd coupling (e g. W = BfOHfe).
Ihcn if.'dutPior
Scheme 2. Examples of synthetic routes for compounds of Formula IA. Q is NH2; X is halogen; Y is halogen; R is alkyl; and XA, R1, R2, R3 and R4 are as defined herein. Further examples can be made as shown in Scheme 3. An amino-pyridone or pyrimidonone is cyclised with a keto ester R1C(O)CHR2CC>2R. Activation, for example using POCI3 is followed by introduction of R3 via a metal-catalysed cross coupling reaction and R4 is incorporated using a second cross coupling reaction or a nucleophilic displacement.
Figure imgf000097_0003
cooping coupling to n. W = B;OHk;. (e.g. W = B(OHy
E.g. nucleophilic siiMtiUtion
(e.g. W = NH)
Scheme 3. Examples of synthetic routes for compounds of Formula IB. X is halogen; Y is halogen; R is alkyl; and XA, R1, R2, R3 and R4 are as defined herein. In schemes 1 and 2, when W is NH in R4W, then said N atom is part of the R4 group, i.e. XB is N.
Items
1 . A compound of Formula IA or Formula IB:
Figure imgf000098_0001
Formula IA wherein
XA is N or C(R5);
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 R6;
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 withl to 3 individually selected substituents R9;
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, 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-membered heteroaryl is 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, wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with -O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000099_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, - O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6-membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. 2. A compound of Formula IA or Formula IB:
Figure imgf000101_0001
Formula IA wherein XA is N or C(R5); 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 R6; 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 R9; 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, 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-membered heteroaryl is 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, wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with –O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000102_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, - O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6-membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; 35 XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. 3. A compound of Formula IA or Formula IB:
Figure imgf000104_0001
Formula IB Formula IA wherein XA is N or C(R5); 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 R6; 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 R9; 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, 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-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl and CN; wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with –O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000105_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, - O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6-membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, 35 wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. 4. The compound according to item 1, wherein the compound is of Formula IA, or a pharmaceutically acceptable salt thereof. 5. The compound according to item 1, wherein the compound is of Formula IB, or a pharmaceutically acceptable salt thereof. 6. A compound of Formula IA:
Figure imgf000107_0001
Formula IA wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl and H; R3 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; XA is N or C(H); R4 is of Formula XXVI:
Figure imgf000108_0001
Formula XXVI wherein XB is N or C(H); R15 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; R19 is H, halogen or C1-3 alkyl; and R20 is H, halogen or C1-3 alkyl; or a pharmaceutically acceptable salt thereof. 7. The compound according to any one of the preceding items, wherein XA is N, or a pharmaceutically acceptable salt thereof. 8. The compound according to any one of the preceding items, wherein XA is C(R5) and R5 is H, or a pharmaceutically acceptable salt thereof. 9. The compound according to item 1, wherein the compound is of Formula IA and XA is N, or a pharmaceutically acceptable salt thereof. 10. The compound according to item 1, wherein the compound is of Formula IA and XA is C(R5) and R5 is H, or a pharmaceutically acceptable salt thereof. 11. The compound according to item 1, wherein the compound is of Formula IB and XA is C(R5) and R5 is H, or a pharmaceutically acceptable salt thereof. 12. The compound according to any one of the preceding items, wherein R1 is C1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R6, or a pharmaceutically acceptable salt thereof. 13. The compound according to any one of the preceding items, wherein R1 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 14. The compound according to any one of the preceding items, wherein R1 is - CH3, or a pharmaceutically acceptable salt thereof. 15. The compound according to any one of the preceding items, wherein R1 is C1-6 alkyl substituted with 1 to 3 individually selected substituents R6, or a pharmaceutically acceptable salt thereof. 16. The compound according to any one of the preceding items, wherein R1 is C1-3 alkyl substituted with 1 to 3 individually selected substituents R6, or a pharmaceutically acceptable salt thereof. 17. The compound according to any one of the preceding items, wherein R6 is halogen, or a pharmaceutically acceptable salt thereof. 18. The compound according to any one of the preceding items, wherein R6 is F, or a pharmaceutically acceptable salt thereof. 19. The compound according to any one of the preceding items, wherein R1 is C1-6 haloalkyl, or a pharmaceutically acceptable salt thereof. 20. The compound according to any one of the preceding items, wherein R1 is C1-3 haloalkyl, or a pharmaceutically acceptable salt thereof. 21. The compound according to any one of the preceding items, wherein R1 is - CF3, or a pharmaceutically acceptable salt thereof. 22. The compound according to any one of the preceding items, wherein R2 is C1-6 alkyl optionally substituted with 1 to 3 individually selected substituents R9, or a pharmaceutically acceptable salt thereof. 23. The compound according to any one of the preceding items, wherein R2 is C1-3 alkyl optionally substituted with 1 to 3 individually selected substituents R9, or a pharmaceutically acceptable salt thereof. 24. The compound according to any one of the preceding items, wherein R2 is - CH3, or a pharmaceutically acceptable salt thereof. 25. The compound according to any one of the preceding items, wherein R2 is halogen, or a pharmaceutically acceptable salt thereof. 26. The compound according to any one of the preceding items, wherein R2 is Cl, or a pharmaceutically acceptable salt thereof. 27. The compound according to any one of the preceding items, wherein R2 is F, or a pharmaceutically acceptable salt thereof. 28. The compound according to any one of the preceding items, wherein R3 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. 29. The compound according to any one of the preceding items, wherein R3 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. 30. The compound according to any one of the preceding items, wherein R3 is of Formula III:
Figure imgf000110_0001
Formula III wherein XH is C(R31) or N; XI is C(R32) or N; R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; and R32 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN, or a pharmaceutically acceptable salt thereof. 31. The compound according to any one of the preceding items, wherein R3 is of Formula III:
Figure imgf000110_0002
Formula III wherein XH is C(R31) or N; XI is C(R32) or N; R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; and R32 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN, or a pharmaceutically acceptable salt thereof. 32. The compound according to any one of items 30 to 31, wherein XH is C(R31), or a pharmaceutically acceptable salt thereof. 33. The compound according to any one of items 30 to 31, wherein XH is N, or a pharmaceutically acceptable salt thereof. 34. The compound according to any one of the preceding items, wherein XI is C(R32), or a pharmaceutically acceptable salt thereof. 35. The compound according to any one of the preceding items, wherein XI is N, or a pharmaceutically acceptable salt thereof. 36. The compound according to any one of the preceding items, wherein XH is C(R31), and XI is C(R32), or a pharmaceutically acceptable salt thereof. 37. The compound according to any one of the preceding items, wherein XH is N, and XI is C(R32), or a pharmaceutically acceptable salt thereof. 38. The compound according to any one of the preceding items, wherein XH is C(R31), and XI is N, or a pharmaceutically acceptable salt thereof. 39. The compound according to any one of the preceding items, wherein R31 is H, or a pharmaceutically acceptable salt thereof. 40. The compound according to any one of the preceding items, wherein R3 is of Formula IV:
Figure imgf000111_0001
Formula IV wherein R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; and R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN, or a pharmaceutically acceptable salt thereof. 41. The compound according to any one of the preceding items, wherein R3 is of Formula IV:
Figure imgf000112_0001
Formula IV wherein R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; and R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN, or a pharmaceutically acceptable salt thereof. 42. The compound according to any one of the preceding items, wherein R3 is of Formula IV:
Figure imgf000112_0002
Formula IV wherein R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkoxy; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN; and R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy or CN, or a pharmaceutically acceptable salt thereof. 43. The compound according to any one of the preceding items, wherein R28 is H, or a pharmaceutically acceptable salt thereof. 44. The compound according to any one of the preceding items, wherein R28 is halogen, or a pharmaceutically acceptable salt thereof. 45. The compound according to any one of the preceding items, wherein R28 is F or Cl, or a pharmaceutically acceptable salt thereof. 46. The compound according to any one of the preceding items, wherein R28 is F, or a pharmaceutically acceptable salt thereof. 47. The compound according to any one of the preceding items, wherein R28 is Cl, or a pharmaceutically acceptable salt thereof. 48. The compound according to any one of the preceding items, wherein R28 is C1-3 alkyl, such as –CH3, or a pharmaceutically acceptable salt thereof. 49. The compound according to any one of the preceding items, wherein R28 is CN, or a pharmaceutically acceptable salt thereof. 50. The compound according to any one of the preceding items, wherein R29 is H, or a pharmaceutically acceptable salt thereof. 51. The compound according to any one of the preceding items, wherein R29 is halogen, or a pharmaceutically acceptable salt thereof. 52. The compound according to any one of the preceding items, wherein R29 is F, or a pharmaceutically acceptable salt thereof. 53. The compound according to any one of the preceding items, wherein R30 is halogen, or a pharmaceutically acceptable salt thereof. 54. The compound according to any one of the preceding items, wherein R30 is F or Cl, or a pharmaceutically acceptable salt thereof. 55. The compound according to any one of the preceding items, wherein R30 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 R30 is C1-3 alkoxy, such as –OCH3, or a pharmaceutically acceptable salt thereof. 57. The compound according to any one of the preceding items, wherein R30 is C1-3 haloalkyl, such as –CF3, or a pharmaceutically acceptable salt thereof. 58. The compound according to any one of the preceding items, wherein R30 is C1-3 haloalkyl, such as –CHF2, or a pharmaceutically acceptable salt thereof. 59. The compound according to any one of the preceding items, wherein R30 is CN, or a pharmaceutically acceptable salt thereof. 60. The compound according to any one of the preceding items, wherein R31 is H, or a pharmaceutically acceptable salt thereof. 61. The compound according to any one of the preceding items, wherein R31 is halogen, or a pharmaceutically acceptable salt thereof. 62. The compound according to any one of the preceding items, wherein R31 is F, or a pharmaceutically acceptable salt thereof. 63. The compound according to any one of the preceding items, wherein R3 is selected from the group consisting of:
Figure imgf000114_0001
or a pharmaceutically acceptable salt thereof. 64. The compound according to any one of the preceding items, wherein R3 is selected from the group consisting of:
Figure imgf000114_0002
, or a pharmaceutically acceptable salt thereof. 65. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000114_0003
. 66. The compound according to any one of the preceding items, or a 10 pharmaceutically acceptable salt thereof, wherein
Figure imgf000114_0004
. 67. The compound according to any one of the preceding items, or a
Figure imgf000115_0001
pharmaceutically acceptable salt thereof, wherein R3 is . 68. The compound according to any one of the preceding items, or a
Figure imgf000115_0002
pharmaceutically acceptable salt thereof, wherein R3 is . 69. The compound according to any one of the preceding items, or a 3
Figure imgf000115_0003
pharmaceutically acceptable salt thereof, wherein R is . 70. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein
Figure imgf000115_0004
. 71. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of:
Figure imgf000115_0005
, , . 72. The compound according to any one of the preceding items, wherein R3 is C5-8 bicycloalkyl 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. 73. The compound according to any one of the preceding items, wherein R3 is bicyclo[1.1.1]pentyl optionally substituted with CF3 or C1 alkyl, or a pharmaceutically acceptable salt thereof. 74. The compound according to any one of the preceding items, wherein R3 is
Figure imgf000116_0001
pharmaceutically acceptable salt thereof. 75. The compound according to any one of the preceding items, wherein R3 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. The compound according to any one of the preceding items, wherein R3 is of Formula XXV:
Figure imgf000116_0002
Formula XXV wherein R33 is H, halogen, C1-3 alkyl and C1-3 haloalkyl; R34 is H, halogen, C1-3 alkyl and C1-3 haloalkyl; q is 1, 2 or 3; and p is 1, 2 or 3, or a pharmaceutically acceptable salt thereof. 77. The compound according to any one of the preceding items, wherein q is 1, or a pharmaceutically acceptable salt thereof. 78. The compound according to any one of the preceding items, wherein q is 2, or a pharmaceutically acceptable salt thereof. 79. The compound according to any one of the preceding items, wherein p is 1, or a pharmaceutically acceptable salt thereof. 80. The compound according to any one of the preceding items, wherein p is 2, or a pharmaceutically acceptable salt thereof. 81. The compound according to any one of the preceding items, wherein R33 is H, or a pharmaceutically acceptable salt thereof. 82. The compound according to any one of the preceding items, wherein R33 is halogen, such as F, or a pharmaceutically acceptable salt thereof. 83. The compound according to any one of the preceding items, wherein R33 is C1-3 alkyl, such as –CH3, or a pharmaceutically acceptable salt thereof. 84. The compound according to any one of the preceding items, wherein R33 is C1-3 haloalkyl, such as –CF3 or –CHF2, or a pharmaceutically acceptable salt thereof. 85. The compound according to any one of the preceding items, wherein R34 is H, or a pharmaceutically acceptable salt thereof. 86. The compound according to any one of the preceding items, wherein R34 is halogen, such as F, or a pharmaceutically acceptable salt thereof. 87. The compound according to any one of the preceding items, wherein R34 is C1-3 alkyl, such as –CH3, or a pharmaceutically acceptable salt thereof. 88. The compound according to any one of the preceding items, wherein R34 is C1-3 haloalkyl, such as –CF3 or –CHF2, or a pharmaceutically acceptable salt thereof. 89. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of:
Figure imgf000117_0001
90. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R3 is
Figure imgf000117_0002
. 91. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R3 is
Figure imgf000117_0003
. 92. The compound according to any one of the preceding items, wherein R4 is of Formula XXVI:
Figure imgf000118_0001
Formula XXVI wherein XB is N or C(H); R15 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; R19 is H, halogen or C1-3 alkyl; and R20 is H, halogen or C1-3 alkyl; or a pharmaceutically acceptable salt thereof. 93. The compound according to any one of the preceding items, wherein XD is C(R14), or a pharmaceutically acceptable salt thereof. 94. The compound according to any one of the preceding items, wherein R4 is of Formula IIA,
Figure imgf000118_0002
, Formula IIA or a pharmaceutically acceptable salt thereof. 95. The compound according to any one of the preceding items, wherein R4 is of Formula IIB,
Figure imgf000118_0003
, Formula IIB or a pharmaceutically acceptable salt thereof. 96. The compound according to any one of the preceding items, wherein XB is C(R11), or a pharmaceutically acceptable salt thereof. 97. The compound according to any one of the preceding items, wherein R4 is of Formula IIC,
Figure imgf000119_0001
, Formula IIC or a pharmaceutically acceptable salt thereof. 98. The compound according to any one of the preceding items, wherein R4 is of Formula IID,
Figure imgf000119_0002
, Formula IID or a pharmaceutically acceptable salt thereof. 99. The compound according to any one of the preceding items, wherein XB is C(R11) and XD is C(R14), or a pharmaceutically acceptable salt thereof. 100. The compound according to any one of the preceding items, wherein R4 is of Formula IIE,
Figure imgf000119_0003
, Formula IIE or a pharmaceutically acceptable salt thereof. 101. The compound according to any one of the preceding items, wherein R4 is of Formula IIF,
Figure imgf000120_0001
, Formula IIF or a pharmaceutically acceptable salt thereof. 102. The compound according to any one of the preceding items, wherein R4 is of Formula IIG,
Figure imgf000120_0002
, Formula IIG or a pharmaceutically acceptable salt thereof. 103. The compound according to any one of the preceding items, wherein R4 is of Formula IIH,
Figure imgf000120_0003
, Formula IIH or a pharmaceutically acceptable salt thereof. 104. The compound according to any one of the preceding items, wherein R4 is a 6-membered ring, or a pharmaceutically acceptable salt thereof. 105. The compound according to any one of the preceding items, wherein XE is O, C(R16)(R17) or NR18; m is 1; and n is 1, or a pharmaceutically acceptable salt thereof. 106. The compound according to any one of the preceding items, wherein XB is N; XC is C(R12)(R13); XD is C(R14); XE is O; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1, or a pharmaceutically acceptable salt thereof. 107. The compound according to any one of the preceding items, wherein XB is C(R11); XC is C(R12)(R13); XD is C(R14); XE is O; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1, or a pharmaceutically acceptable salt thereof. 108. The compound according to any one of the preceding items, wherein XB is N; XC is C(R12)(R13); XD is C(R14); XE is NR18; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1, or a pharmaceutically acceptable salt thereof. 109. The compound according to any one of the preceding items, wherein XB is N; XC is C(R12)(R13); XD is C(R14); XE is C(R16)(R17); XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1, or a pharmaceutically acceptable salt thereof. 110. The compound according to any one of the preceding items, wherein XB is N, or a pharmaceutically acceptable salt thereof. 111. The compound according to any one of the preceding items, wherein XB is C(R11), or a pharmaceutically acceptable salt thereof. 112. The compound according to any one of the preceding items, wherein R11 is H, or a pharmaceutically acceptable salt thereof. 113. The compound according to any one of the preceding items, wherein R11 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 114. The compound according to any one of the preceding items, wherein XC is C(R12)(R13), or a pharmaceutically acceptable salt thereof. 115. The compound according to any one of the preceding items, wherein R12 is individually H, or a pharmaceutically acceptable salt thereof. 116. The compound according to any one of the preceding items, wherein R12 is individually C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 117. The compound according to any one of the preceding items, wherein R12 is a bond and R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring, or a pharmaceutically acceptable salt thereof. 118. The compound according to any one of the preceding items, wherein R13 is individually H, or a pharmaceutically acceptable salt thereof. 119. The compound according to any one of the preceding items, wherein R13 is individually C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 120. The compound according to any one of the preceding items, wherein XD is C(R14), or a pharmaceutically acceptable salt thereof. 121. The compound according to any one of the preceding items, wherein XD is N, or a pharmaceutically acceptable salt thereof. 122. The compound according to any one of the preceding items, wherein R14 is H, or a pharmaceutically acceptable salt thereof. 123. The compound according to any one of the preceding items, wherein R14 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 124. The compound according to any one of the preceding items, wherein when XB is N, then XD is C(R14), or a pharmaceutically acceptable salt thereof. 125. The compound according to any one of the preceding items, wherein R23 is a bond, or a pharmaceutically acceptable salt thereof. 126. The compound according to any one of the preceding items, wherein R15 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, or a pharmaceutically acceptable salt thereof. 127. The compound according to any one of the preceding items, wherein R15 is selected from the group consisting of Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, and Formula XII:
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0003
Formula X Formula XII wherein R37 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. The compound according to any one of the preceding items, wherein R15 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:
Figure imgf000122_0004
Formula XIV Formula XVII Formula XIII
Figure imgf000123_0001
Formula XXIII wherein R37 and R38 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. 129. The compound according to any one of the preceding items, wherein R37 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 130. The compound according to any one of the preceding items, wherein R37 is CH3, or a pharmaceutically acceptable salt thereof. 131. The compound according to any one of the preceding items, wherein R37 is C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof. 132. The compound according to any one of the preceding items, wherein R37 is C3 cycloalkyl, or a pharmaceutically acceptable salt thereof. 133. The compound according to any one of the preceding items, wherein R15 is selected from the group consisting of:
Figure imgf000123_0002
and
Figure imgf000124_0001
, or a pharmaceutically acceptable salt thereof. 134. The compound according to any one of the preceding items, wherein R15 is
Figure imgf000124_0002
, or a pharmaceutically acceptable salt thereof. 135. The compound according to any one of the preceding items, wherein R15 is
Figure imgf000124_0003
, or a pharmaceutically acceptable salt thereof. 136. The compound according to any one of the preceding items, wherein R15 is a 6-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, 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. 137. The compound according to any one of the preceding items, wherein R15 is of Formula XXIV:
Figure imgf000124_0004
Formula XXIV wherein XJ is N or CH; XK is N or C(R7); XL is N or C(R8); R7 is C1-3 alkyl; R8 is C1-3 alkyl; and R36 is H or C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 138. The compound according to any one of the preceding items, wherein XJ is CH, or a pharmaceutically acceptable salt thereof. 139. The compound according to any one of the preceding items, wherein XK is N, or a pharmaceutically acceptable salt thereof. 140. The compound according to any one of the preceding items, wherein XK is C(R7), or a pharmaceutically acceptable salt thereof. 141. The compound according to any one of the preceding items, wherein R7 is –CH3, or a pharmaceutically acceptable salt thereof. 142. The compound according to any one of the preceding items, wherein XL is N, or a pharmaceutically acceptable salt thereof. 143. The compound according to any one of the preceding items, wherein XL is C(R8), or a pharmaceutically acceptable salt thereof. 144. The compound according to any one of the preceding items, wherein R8 is –CH3, or a pharmaceutically acceptable salt thereof. 145. The compound according to any one of the preceding items, wherein R36 is H, or a pharmaceutically acceptable salt thereof. 146. The compound according to any one of the preceding items, wherein R36 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 147. The compound according to any one of the preceding items, wherein R36 is –CH3, or a pharmaceutically acceptable salt thereof. 148. The compound according to any one of the preceding items, wherein at least one of XJ , XK , and XL is N, or a pharmaceutically acceptable salt thereof. 149. The compound according to any one of the preceding items, wherein one of XJ , XK , and XL is N, or a pharmaceutically acceptable salt thereof. 150. The compound according to any one of the preceding items, wherein two of XJ , XK , and XL are N, or a pharmaceutically acceptable salt thereof. 151. The compound according to any one of the preceding items, wherein R15 is selected from the group consisting of
Figure imgf000125_0001
Figure imgf000125_0002
, or a pharmaceutically acceptable salt thereof. 152. The compound according to any one of the preceding items, wherein R15
Figure imgf000126_0001
, or a pharmaceutically acceptable salt thereof. 153. The compound according to any one of the preceding items, wherein XE is C(R16)(R17), or a pharmaceutically acceptable salt thereof. 154. The compound according to any one of the preceding items, wherein XE is O, or a pharmaceutically acceptable salt thereof. 155. The compound according to any one of the preceding items, wherein XE is NR18, or a pharmaceutically acceptable salt thereof. 156. The compound according to any one of the preceding items, wherein XE is a bond, or a pharmaceutically acceptable salt thereof. 157. The compound according to any one of the preceding items, wherein R19 is H, or a pharmaceutically acceptable salt thereof. 158. The compound according to any one of the preceding items, wherein R19 is halogen, or a pharmaceutically acceptable salt thereof. 159. The compound according to any one of the preceding items, wherein R19 is F, or a pharmaceutically acceptable salt thereof. 160. The compound according to any one of the preceding items, wherein R19 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 161. The compound according to any one of the preceding items, wherein R19 is CH3, or a pharmaceutically acceptable salt thereof. 162. The compound according to any one of the preceding items, wherein R20 is H, or a pharmaceutically acceptable salt thereof. 163. The compound according to any one of the preceding items, wherein R20 is halogen, or a pharmaceutically acceptable salt thereof. 164. The compound according to any one of the preceding items, wherein R20 is F, or a pharmaceutically acceptable salt thereof. 165. The compound according to any one of the preceding items, wherein R20 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 166. The compound according to any one of the preceding items, wherein R20 is CH3, or a pharmaceutically acceptable salt thereof. 167. The compound according to any one of the preceding items, wherein R19 and R20 are C1-3 alkyl, and R19 and R20 are optionally linked together to form a 3- 6 membered ring, or a pharmaceutically acceptable salt thereof. 168. The compound according to any one of the preceding items, wherein XG is C(R21)(R22), or a pharmaceutically acceptable salt thereof. 169. The compound according to any one of the preceding items, wherein XG is C(O), or a pharmaceutically acceptable salt thereof. 170. The compound according to any one of the preceding items, wherein R21 is H, or a pharmaceutically acceptable salt thereof. 171. The compound according to any one of the preceding items, wherein R22 is H, or a pharmaceutically acceptable salt thereof. 172. The compound according to any one of the preceding items, wherein m is 1, or a pharmaceutically acceptable salt thereof. 173. The compound according to any one of the preceding items, wherein m is 0, or a pharmaceutically acceptable salt thereof. 174. The compound according to any one of the preceding items, wherein m is 2, or a pharmaceutically acceptable salt thereof. 175. The compound according to any one of the preceding items, wherein n is 1, or a pharmaceutically acceptable salt thereof. 176. The compound according to any one of the preceding items, wherein n is 0, or a pharmaceutically acceptable salt thereof. 177. The compound according to any one of the preceding items, wherein n is 2, or a pharmaceutically acceptable salt thereof. 178. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of:
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
, or a pharmaceutically acceptable salt thereof. 179. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: ,
Figure imgf000129_0002
, ,
Figure imgf000130_0001
,
Figure imgf000131_0001
, and or a pharmaceutically acceptable salt thereof. 180. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: ,
Figure imgf000131_0002
or a pharmaceutically acceptable salt thereof. 181. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: ,
Figure imgf000131_0003
or a pharmaceutically acceptable salt thereof. 182. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: , ,
Figure imgf000132_0001
, or a pharmaceutically acceptable salt thereof. 183. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of:
Figure imgf000132_0002
Figure imgf000133_0001
, or a pharmaceutically acceptable salt thereof. 184. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of:
Figure imgf000133_0002
,
Figure imgf000134_0001
, , or a pharmaceutically acceptable salt thereof. 185. The compound according to any one of the preceding items, wherein R4 is a 5-membered ring, or a pharmaceutically acceptable salt thereof. 186. The compound according to any one of the preceding items, wherein m is 1; XE is a bond; and n is 1, or a pharmaceutically acceptable salt thereof. 187. The compound according to any one of the preceding items, wherein XB is N; XC is CH2; m is 1; XD is C(H); XE is a bond; XF is C(H2); XG is C(H2); and n is 1, or a pharmaceutically acceptable salt thereof. 188. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of:
Figure imgf000135_0001
, or a pharmaceutically acceptable salt thereof. 189. The compound according to any one of the preceding items, wherein R4 is a 4-membered ring, or a pharmaceutically acceptable salt thereof. 190. The compound according to any one of the preceding items, wherein m is 1; XE is a bond; and n is 0, or a pharmaceutically acceptable salt thereof. 191. The compound according to any one of the preceding items, wherein XB is N; XC is CH2; m is 1; XD is C(H); XE is a bond; XF is C(H2); and n is 0, or a pharmaceutically acceptable salt thereof. 192. The compound according to any one of the preceding items, wherein XB is N; XC is CH2; m is 1; XD is C(H); XE is a bond; XF is C(H2); n is 0; and R15 is
Figure imgf000135_0002
, or a pharmaceutically acceptable salt thereof. 193. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: ,
Figure imgf000135_0003
or a pharmaceutically acceptable salt thereof. 194. The compound according to any one of the preceding items, wherein R4 is a 3-membered ring, or a pharmaceutically acceptable salt thereof. 195. The compound according to any one of the preceding items, wherein m is 0; XE is a bond; and n is 0, or a pharmaceutically acceptable salt thereof. 196. The compound according to any one of the preceding items, wherein XB is C(H); m is 0; XD is C(H); XE is a bond; XF is C(H2); and n is 0, or a pharmaceutically acceptable salt thereof. 197. The compound according to any one of the preceding items, wherein R4
Figure imgf000136_0001
, or a pharmaceutically acceptable salt thereof. 198. The compound according to any one of the preceding items, wherein the compound is of Formula IA and wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, halogen and H; R3 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-; XA is N or CH; XB is N or CH; XC is C(H)2; XD is C(H); XE is O; XF is C(R19)(R20), wherein each R19 and R20 are individually selected as H or CH3; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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 alkoxy, -CN, and C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof. 199. The compound according to any one of the preceding items, wherein the compound is of Formula IA and wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, and H; R3 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; XA is CH; XB is N; XC is C(H)2; XD is C(H); XE is O; XF is C(H)2; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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. 200. The compound according to any one of the preceding items, wherein the compound is of Formula IA and wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, and H; R3 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; XA is N; XB is C(H); XC is C(H)2; XD is C(H); XE is O; XF is C(H)2; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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. 201. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting 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; (R)-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; (S)-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; 9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; 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; (R)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4- yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; (S)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4- yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; (S)-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; 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; 3-chloro-9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4- (trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4- difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4- oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4- oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo- 4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo- 4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 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; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[1,2-a]pyrimidin-4-one; 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; 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; 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; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- methyl-pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-3- methyl-pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- methyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-3- (trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- (trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4- difluorophenyl)pyrazino[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- (trifluoromethyl)pyrazino[1,2-a]pyrimidin-4-one; 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; 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; 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; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4- difluorophenyl)pyrido[1,2-a]pyrimidin-4-one; 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; 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; 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; 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; 4-[7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-oxo-2- (trifluoromethyl)pyrido[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-4-oxo-pyrido[1,2- a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-oxo-2- (trifluoromethyl)pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 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; 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; 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4- difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4- difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; and 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-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. 202. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, such as a TREM2 activator, such as a TREM2 agonist. 203. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein 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. 204. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound increases the expression of one or more TREM2 regulated genes, such as wherein the compound increases the expression of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119. 205. 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. 206. The 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 use as a medicament. 207. The 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 use in the treatment of 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. 208. The 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 use in the treatment of a neurodegenerative disease. 209. The compound or composition for use according to item 208, wherein said neurodegenerative disease is 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). 210. The 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 use in the treatment of 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 demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke. 211. The 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 use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, autism spectrum disorders, autism and Aspergers syndrome, traumatic brain injuries (TBI), spinal cord injuries, muscular dystrophy, myotonic dystrophy, inclusion- body myositis, systemic lupus erythematosus (SLE), RA, gout, bowel conditions, Inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, Amyloidosis. 212. The compound or composition for use according to any one of items 206 to 211, wherein said compound is administered in an amount of about 0.01 mg/kg to about 100 mg/kg bodyweight/day. 213. The compound or composition for use according to any one of items 206 to 211, wherein said compound is administered via enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery. 214. A method for treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease, said method 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. 215. Use 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, 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. 216. 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 of items 1 to 204. Abbreviations DCM Dichloromethane PIDA Phenyliodine(III) diacetate HPLC High performance liquid chromatography MeCN Acetonitrile MeOH Methanol EtOH Ethanol THF Tetrahydrofuran DMF Dimethyl formamide TFA Trifluoroacetic Acid DIPEA Diisopropylethylamine EtOAc Ethyl acetate NBS N-bromo succinimide NCS N-chloro succinimide Pd/C Palladium on carbon NaOAc Sodium acetate AcOH Acetic acid NaHCO3 Sodium bicarbonate NH4OAc Ammonium acetate NiCl2·6H2O Nickel chloride; hexahydrate DMAP 4-Dimethylaminopyridine Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd(tBu3P)2 Bis(tri-tert-butylphosphine)palladium(0) PdCl2(dppf) [1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) RuPhos 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl Xanthphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Me2NH2,HCl Methylamine hydrochloride HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate NH4OAc Ammonium acetate RuPhos- Pd-G3 (2-Dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate rt Room temperature Rt Retention time SFC Supercritical fluid chromatography Prep HPLC Preparative high performance liquid chromatography NP Normal phase mL millilitre mg milligram g gram mmol millimole mol mole LCMS conditions: Condition A LCMS Column- Acquity BEH C18 (50 x 2.1 mm, 1.7u), Initially (90% [0.05% HCOOH in water] and 10% [0.05% HCOOH in CH3CN: water (90:10)] is held up to 0.75 min, then to 50% [0.05% HCOOH in water] and 50% [0.05% HCOOH in CH3CN: water (90:10)] in 1.00 min, then to 2% [0.05% HCOOH in water] and 98% [0.05% HCOOH in CH3CN: water (90:10)] in 2.00 min held this mobile phase composition up to 2.25 min and finally back to initial condition in 2.60 min and held up to 3.00 min). Flow: 0.60 ml/min. Condition B Column -Xbridge C18 (4.6 x 50 mm, 5 u) mobile phase: 90 % [10 mM Ammonium Acetate in Water] and 10 % [CH3CN] to 70% [10 mM Ammonium Acetate in Water] and 30% [CH3CN] in 1.5 min, further to 10% [10 mM Ammonium Acetate in Water] and 90% [CH3CN] in 3.00 min, held this mobile phase composition up to 4.00 min and finally back to initial condition in 5.00 min. Flow =1.20 ml/min Condition C LCMS Column- Acquity BEH C8 (50 x 2.1 mm, 1.7u), Initially (95% [0.05% HCOOH in water] and 5% [0.05% HCOOH in CH3CN: water (90:10)] is held up to 0.75 min, then to 75% [0.05% HCOOH in water] and 25% [0.05% HCOOH in CH3CN: water (90:10)] in 1.50 min, then to 5% [0.05% HCOOH in water] and 95% [0.05% HCOOH in CH3CN: water (90:10)] in 3.00 min held this mobile phase composition up to 4.00 min and finally back to initial condition in 4.50 min and held up to 5.10 min). Flow: 0.80 ml/min. Condition D Column- Xbridge C18 column (3.5 µm, 50 x 3 mm),(initially 95% [5 mM NH4OAc in water] and 5% [5 mM NH4OAc in ACN: Water (90:10)] held for 0.75 min, then to 70% [5 mM NH4OAc in water] and 30% [5 mM NH4OAc in ACN: Water (90:10) ] in 1.00 min, and finally 2% [5 mM NH4OAc in water] and 98% [5 mM NH4OAc in ACN: Water (90:10) ] in 2.00 min, held this mobile phase composition up to 2.50 min and finally back to initial condition in 2.75 min and held this composition up to 3.0 min). Flow: 1.20 ml/min. Condition E Column- YMC Triart C18 (33 x 2.1 mm, 3u), (initially 98% [0.05% HCOOH in water] and 2% [0.05% HCOOH in ACN: Water (90:10)] held for 0.75 min, then to 90% [0.05% HCOOH in water] and 10% [0.05% HCOOH in ACN: Water (90:10) ] in 1.0 min, further to 2% [0.05% HCOOH in water] and 98% [0.05% HCOOH in ACN: Water (90:10) ] in 2.00 min, held this mobile phase composition up to 2.50 min and finally back to initial condition in 4.90 min and held this composition up to 3.0 min). Flow: 1.0 ml/min. 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, 5µ). Mobile phase: A = 20Mm Ammonium bicarbonate in water, B = Acetonitrile; Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 40% A and 60% B in 3 min, then to 20% A and 80% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min Prep-B Column name: Chromcore C18 (250 x 21.2 mm, 5µ). Mobile phase: A = 20mM Ammonium Bicarbonate in water, B=Acetonitrile:Methanol(50:50); Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 35% A and 65% B in 3 min, then to 5% A and 95% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min. Prep-C Column name: Hydrosphere C18 (250 x 20 mm, 5µ). Mobile phase: A = 10mM Ammonium Acetate in water, B=Acetonitrile; Gradient Profile: Mobile phase initial composition of 60% A and 40% B, then 45% A and 55% B in 3 min, then to 30% A and 70% B in 20 min., then to 5% A and 95% B in 21 min., held this composition up to 22 min. for column washing, then returned to initial composition in 23 min. and held till 25 min. Prep-D Column name: CHROMCORE 120 C18,5 µm (21.2 × 250mm). Mobile phase: A=Acetonitrile, B = 20mM Ammonium Bicarbonate in water; Gradient Profile: Mobile phase initial composition of 30% A and 70% B, then 50% A and 50% B in 3 min, then to 61.6% A and 38.4% B in 14 min., then to 100% A and 0% B in 14.1 min., held this composition up to 18 min. for column washing, then returned to initial composition in 18.1 min. and held till 21 min. SFC methods: 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), 5µ 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 ), 5µ 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. Column name: CHIRALPAK IG (250 X 4.6 mm) 5u. 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) 5µ. Operating at ambient temperature and flow rate is 21.0 mL/min. Mobile phase was mixture of 60% Hexane, 20% Dichloromethane and 20% Ethyl alcohol , held this isocratic mixture run upto 25 min with wavelength of 260 nm. NP Chiral Method 3: Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 X 21 mm) 5µ. 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. Operating at ambient temperature and flow rate is 18.0 mL/min. Mobile phase was mixture of 50% Hexane, 25% Dichloromethane and 25% Ethyl alcohol, held this isocratic mixture run up-to 25 min with wavelength of 328 nm. Synthesis of intermediates: Synthesis of 2-(1-methyl-1H-pyrazol-4-yl)morpholine (Intermediate I-1) Step-1 - Preparation of 2-chloro-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one:
Figure imgf000150_0001
In an oven-dried two neck round-bottom flask 4-bromo-1-methyl-1H-pyrazole (10 g, 62.2 mmol) was dissolved in dry THF (100 mL) and cooled to -78 °C. 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. A solution of 2-chloro-N-methoxy-N-methylacetamide (13 g, 93.2 mmol) in THF (40 mL) was then slowly added to it and reaction was prolonged for another one hour at 78 °C. After completion, the reaction mixture was quenched with saturated aqueous ammonium chloride solution and followed by extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated into vacuo. The crude was purified by column chromatography on silica gel (100-200 mesh size) using 20-50% ethyl acetate in hexane to afford 2-chloro-1-(1-methyl-1H-pyrazol-4- yl)ethan-1-one (3.5 g, 35.5% yield) as off-white solid. 1H NMR (400 MHz, DMSO D6) δ 8.46 (s, 1H), 7.99 (s, 1H), 4.81 (s, 2H), 3.88 (s, 3H). LCMS Condition A: Rt = 1.48 min. m/z 159.02 [M+H] +. Step-2 - Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazol-4- yl)ethan-1-one:
Figure imgf000150_0002
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 oC for 16 h. After completion excess solvent was removed under reduced pressure and the residue was with cold water and followed by extracted with ethyl acetate. Combined organic layer was dried over sodium sulphate and concentrated into vacuo to obtain the crude. The crude was purified by column chromatography on silica gel (100-200 mesh size) using 40-60% ethyl acetate in hexane to afford 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl- 1H-pyrazol-4-yl)ethan-1-one (6 g, 69.5% yield) as yellow oil. 1H NMR (400 MHz, DMSO D6) δ 8.38 (s, 1H), 7.92 (s, 1H), 7.56-7.27 (m, 5H), 4.44 (t, J= 5.04 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.51-3.48 (m, 2H), 2.61 (t, J= 6.32 Hz, 2H), LCMS Condition A: Rt = 0.46 min. m/z 274.3 [M+H] +. Step-3 - Preparation of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazol-4- yl)ethan-1-ol:
Figure imgf000151_0001
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. The 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. 1H NMR (400 MHz, DMSO D6) δ 7.47 (s, 1H), 7.35-7.29 (m, 5H), 7.26 (s, 1H).4.76 (d, J= 3.52 Hz, 1H), 4.62-4.58 (M, 1H), 4.38 (t, J= 5.36 Hz, 1H), 3.75 (s, 3H), 3.69 (d, J= 9.08 Hz, 2H), 3.48-3.4 (m, 2H), 2.63-2.54 (m, 3H). LCMS Condition A: Rt = 0.39 min. m/z 276.3 [M+H] +. Step-4 - Preparation of 4-benzyl-2-(1-methyl-1H-pyrazol-4-yl)morpholine (as HCl salt):
Figure imgf000152_0001
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. This material was forwarded for the next step without further purification. 1H NMR (400 MHz, DMSO D6) δ 12.05 (bs, 1H), 7.76 (s, 1H), 7.68-7.63 (m, 2H), 7.46- 7.43 (m, 3H), 7.41 (s, 1H), 4.95 (d, J= 10.0 Hz, 1H), 4.34 (s, 2H), 4.08-4.0 (m, 2H), 3.78 (s, 3H), 3.32 (d, J= 11.8 Hz, 1H), 3.21 (d, J= 12.12 Hz, 1H), 3.15-3.07 (m, 2H). LCMS Condition A: Rt = 0.40 min. m/z 258.3 [M+H] +. Step-5 - Preparation of 2-(1-methyl-1H-pyrazol-4-yl)morpholine, HCl salt (Intermediate-I-1):
Figure imgf000152_0002
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. Evaporation of the solvent under reduced pressure afforded 2-(1-methyl- 1H-pyrazol-4-yl)morpholine, HCl salt (1.2 g, 92.2% yield) as sticky solid. 1H NMR (400 MHz, DMSO D6) δ 9.82 (bs, 1H), 9.64 (bs, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 4.75 (d, J= 9.68 Hz, 1H), 3.98-3.86 (m, 2H), 3.78 (s, 3H), 3.31 (d, J= 11.32 Hz, 1H), 3.31 (d, J= 11.32 Hz, 1H), 3.183.31 (d, J= 11.36 Hz, 1H), 3.15-2.85 (m, 2H). LCMS Condition A: Rt = 0.70 min. m/z 168.1 [M+H] +. The intermediates I-2 & I-14 were synthesized using similar procedures described for Intermediate I-1 in 1-5 steps.
Figure imgf000152_0003
Figure imgf000153_0002
Synthesis of (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine, HCl salt (Intermediate I- 3) Step-1 - Chiral separation of (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine, HCl salt (Intermediate I-3) and (R)-2-(1-methyl-1H-pyrazol-4-yl)morpholine:
Figure imgf000153_0001
Chiral separation of 2-(1-methyl-1H-pyrazol-4-yl)morpholine (3 g, 0.086 mmol) was done by SFC (SFC condition-1) to afford (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (730.2 mg, 24.3% yield; eluted first, assigned as Intermediate I-3 (Peak-1) as light yellow gum and (R)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (762.3 mg, 25.4% yield eluted later, assigned as Peak-2 as light yellow gum. Stereochemistry of both peaks were assigned based on the report in WO 2021226135. Intermediate I-3 (Peak1): 1H NMR (400 MHz, DMSO-d6) δ 9.82 (brs, 1H), 9.64 (brs, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 4.75 (d, J= 9.68 Hz, 1H), 3.98-3.86 (m, 2H), 3.78 (s, 3H), 3.31 (d, J= 11.32 Hz, 1H), 3.31 (d, J= 11.32 Hz, 1H), 3.183.31 (d, J= 11.36 Hz, 1H), 3.15- 2.85 (m, 2H). LCMS Condition A: Rt = 0.70 min. m/z 168.1 [M+H]+. Peak-2: 1H NMR (400 MHz, DMSO-d6) δ 9.82 (brs, 1H), 9.64 (brs, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 4.75 (d, J= 9.68 Hz, 1H), 3.98-3.86 (m, 2H), 3.78 (s, 3H), 3.31 (d, J= 11.32 Hz, 1H), 3.31 (d, J= 11.32 Hz, 1H), 3.183.31 (d, J= 11.36 Hz, 1H), 3.15-2.85 (m, 2H). LCMS Condition A: Rt = 0.70 min. m/z 168.1 [M+H]+. Analytical chiral HPLC: CHIRALPAK AD-H (4.6 x 250 mm), 5μ Mobile Phase: 0.5%DEA in EtOH Flow Rate: 4.0 ml/min. Solubility: MeOH, Rt = 2.4 min for Peak1 and Rt = 3.02 min for Peak2. Synthesis of 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6- dihydro-2H-pyran-2-yl)-1H-pyrazole (Intermediate I-4) Step-1 - Preparation of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde:
Figure imgf000154_0001
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. Copper acetate (10.4 g, 57.3 mmol) was added to the reaction mixture. Resulting mixture was heated to 70 °C for 16 h. Reaction mixture was filtered through a short pad of celite, washed with methanol and concentrated under reduced pressure. Crude residue was extracted with ethyl acetate, washed with brine, dried over sodium sulphate, and concentrated under reduced pressure. Crude product was purified by combi-flash chromatography (10% ethyl acetate-hexane) to afford 1-cyclopropyl-1H-pyrazole-4- carbaldehyde (6 g, 84.1% yield) as colourless liquid. LCMS Condition A: Rt = 0.93 min. m/z 137.2 [M+H]+. Step-2 - Preparation of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4- yl trifluoromethanesulfonate:
Figure imgf000154_0002
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. Reaction mixture was quenched with saturated aqueous sodium bicarbonate solution, extracted with DCM, and concentrated under reduced pressure. Crude material was purified by column chromatography (20-40% ethyl acetate in hexane) to afford 6-(1-cyclopropyl-1H- pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (3 g, 34.2% yield) as brown gum. 1H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.36 (s, 1H), 6.20 (s, 1H), 5.32 (s, 1H), 3.91-3.64 (m, 3H), 2.49-2.42 (m, 2H), 1.11-0.88 (m, 4H). LCMS Condition B: Rt = 3.35 min. m/z 339 [M+H]+ Step-3 - Preparation of 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (Intermediate I-4) :
Figure imgf000155_0001
To a stirred solution of 6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1 g, 2.96 mmol) and Bis(pinacolato)diboron (1.2 g, 4.4 mmol) in 1,4-dioxane (15 mL) were added potassium acetate (1.2 g, 11.8 mmol) and degassed with argon. PdCl2(dppf). DCM (0.2 g, 0.3 mmol) was added under inert atmosphere. Resulting mixture was heated at 80 °C for 2 h. Reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite and washed with ethyl acetate. Combined organic layer was concentrated under reduced pressure and crude product was purified by column chromatography (30% ethyl acetate in hexane) to afford 1-cyclopropyl-4-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (0.5 g, 53% yield) as solid. LCMS Condition B : Rt = 3.19 min. m/z 317 [M+H] +. Following intermediates I-5 and I-6 were synthesized using similar procedures described for Intermediate I-4 two steps (step-2 & 3) using corresponding commercial aldehyde and alkyne.
Figure imgf000155_0002
The following table describes analytical data analysis and yield information of intermediates I-5 & I-6.
Figure imgf000155_0003
Figure imgf000156_0003
Synthesis of 7-bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one (Intermediate I-7): Step-1- Preparation of 5-bromo-3-(2,4-difluorophenyl)pyrazin-2-amine:
Figure imgf000156_0001
To a stirred suspension of 3,5-dibromopyrazin-2-amine (10 g, 39.5 mmol) and (2,4- difluorophenyl)boronic acid (6.2 g, 39.5 mmol) in toluene (225 mL), ethanol (50 mL) and water (40 mL) was added K3PO4 (16.8 g,17.1 mmol) and purged with argon. Pd(PPh3)4 (2.1 g, 1.9 mmol) was added under inert atmosphere. Resulting mixture was heated at 100 °C for 16 h. Reaction mixture was then passed through a short pad of celite and washed with ethyl acetate. Organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure. Crude product was purified by combi flash chromatography (5-15% ethyl acetate-hexane) to afford 5-bromo-3-(2,4- difluorophenyl)pyrazin-2-amine (8 g, 70.7% yield) as yellow solid. LCMS Condition A: Rt = 2.04 min. m/z 286.01 [M+H] + Step-2 - Preparation of 7-bromo-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one:
Figure imgf000156_0002
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. The reaction mixture was diluted with DCM (30 mL), and it was quenched with cold saturated sodium bicarbonate solution (25 mL). Reaction mass was filtered over celite pad, and the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous Na2SO4, and then evaporated under reduced pressure to get the crude. Crude product was purified by combi flash (2- 10% ethyl acetate in hexane) to get 7-bromo-9-(2,4-difluorophenyl)-2-methyl-4H- pyrazino[1,2-a]pyrimidin-4-one (300 mg, 24.3% yield) as off-white solid. LCMS Condition A: Rt = 2.32 min. m/z 352.3 [M+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):
Figure imgf000157_0001
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. Reaction mixture was poured into cold water and extracted with ethyl acetate. Combined organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure. Crude product was purified by combi flash chromatography (5% ethyl acetate- hexane) to afford 7-bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2- a]pyrimidin-4-one (450 mg, 58.6% yield) as yellow solid. LCMS Condition A: Rt = 2.33 min. m/z 386.04 [M+H] + Following intermediates I-8 to I-12 were synthesized by using similar procedures described for Intermediate I-7
Figure imgf000157_0002
Figure imgf000158_0002
The following table describes analytical data analysis and yield information of intermediates I-8 to I-12.
Figure imgf000158_0003
Synthesis of 4-((2R,6R)-4-iodo-6-methyltetrahydro-2H-pyran-2-yl)-1-methyl-1H- pyrazole (Intermediate I-13): Step-1 – Preparation of 4-((2R,6R)-4-iodo-6-methyltetrahydro-2H-pyran-2-yl)-1- methyl-1H-pyrazole (Intermediate I-13):
Figure imgf000158_0001
To a stirred solution of 1-methyl-1H-pyrazole-4-carbaldehyde (1 g, 9.1 mmol), (2R)-pent- 4-en-2-ol (0.93 g, 10.8 mmol) and tetrabutylammonium iodide (2.1 g, 10.9 mmol) in DCM (20 mL) was added trimethylsilyl trifluoromethanesulfonate (2 mL, 10.8 mmol) dropwise at rt and stirred for 16 h. After completion, reaction mixture was concentrated under reduced pressure, diluted with saturated Na2S2O3 solution, and extracted with EtOAc. Combined organic part was washed with water, brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Crude product was purified by combi flash column chromatography eluted at (50% EA in Hexane) to afford 4-((2R,6R)-4-iodo-6- methyltetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (0.7 g, 25% yield) as light-yellow liquid. LCMS Condition A: Rt = 2.01 min. m/z 307.13 [M+H]+. Synthesis of Examples Examples 1 to 8 Example 1: 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one Step-1 - Preparation of 3-chloro-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro- 2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one:
Figure imgf000159_0001
To a stirred solution of 7-bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H- pyrazino[1,2-a]pyrimidin-4-one [I-7] (500 mg, 1.3 mmol) and 1-cyclopropyl-4-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole [I-4] (817.9 mg, 2.6 mmol) in 1,4-dioxane (10 mL), and water (2.5 mL) was added K3PO4 (822.6 mg, 3.9 mmol) and purged with argon. Pd-118 (42.1 mg, 0.06 mmol) was added under inert atmosphere. Resulting mixture was heated at 90 °C for 0.5 h. Reaction mixture was then passed through a short pad of celite and washed with ethyl acetate. Organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure. Crude product was purified by combi flash chromatography (40-60% ethyl acetate-hexane) to afford 3-chloro-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H- pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one (300 mg, 46.7% yield) as light yellow solid. LCMS Condition A: Rt = 3.33 min. m/z 496.13 [M+H] + Step-2 - Preparation of 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one:
Figure imgf000160_0001
To a degassed solution 3-chloro-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H- pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one (200 mg, 0.4 mmol) in THF (20 mL) NaOAc (66 mg, 0.8 mmol) and acetic acid (0.05 mL, 0.8 mmol) were added and stirred for 10 min under inert atmosphere. Pd(OH)2 on carbon (20%, 84.7 mg) was added and degassed again. The resulting mixture was stirred under hydrogen balloon pressure at rt for 3 h. Reaction mixture was filtered through a short pad of celite and washed with ethyl acetate. Combined filtrate was concentrated under reduced pressure and crude product was purified by prep-HPLC (Prep-B) to afford 3- chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4- difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one (104 mg, 51.2% yield) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.75-7.72 (m, 2H), 7.43 (t, J=10.0 Hz, 1H), 7.37 (s, 1H), 7.27 (t, J= 8.4 Hz, 1H), 4.45 (d, J=11.2 Hz, 1H), 4.09 - 4.06 (m, 1H), 3.69 - 3.63 (m, 2H), 3.28-3.27 (m, 1H), 2.45 (s, 3H), 2.11 (d, J= 11.6 Hz, 1H), 1.87 - 1.77 (m, 3H), 1.00 - 0.98 (m, 2H), 0.91 - 0.89 (m, 2H). LCMS Condition C: Rt = 3.02 min. m/z 498.39 [M+H]+ Examples 2-8 were synthesized by using similar procedures described for Example 1.
Figure imgf000160_0002
Figure imgf000161_0001
The following table describes analytical data analysis and yield information of examples 2-8.
Figure imgf000162_0001
Figure imgf000163_0003
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
Figure imgf000163_0001
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 BiCl3 (76 mg, 0.2 mmol) were mixed. The resulting mixture was heated at 130 °C for 16 h. Reaction mixture was then diluted with DCM, washed with NaHCO3 solution, brine, dried over sodium sulphate, filtered, and concentrated under reduced pressure. Crude product was purified by combi flash chromatography (5% methanol-DCM) to get 7-bromo-9-chloro-2,3-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one (1.4 g, yield 57.7 %) as orange solid.. LCMS Condition A: Rt = 1.96 min. m/z 288.98 [M+H] + Step-2 - Preparation of 9-chloro-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
Figure imgf000163_0002
To a suspension of 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (650 mg, 2.3 mmol) and 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole [I-4] (2.1 gm, 6.8 mmol) in 1,4-dioxane (30 mL) and water (8 mL) was added K3PO4 (958.5 mg, 4.5 mmol) and purged the reaction mixture with argon for 5 min. Pd118 (73.7 mg, 0.11 mmol) was then added to it under inert atmosphere. Resulting mixture was heated at 90 °C for 4 h. Reaction mixture was then passed through a short bed of celite and washed with ethyl acetate. dried over sodium sulphate, filtered and concentrated under reduced pressure. Crude product was purified by combi flash chromatography (50-95% ethyl acetate-hexane) to get 9-chloro- 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 (700 mg, 78.1% yield) as yellowish solid. LCMS Condition A: Rt = 1.87 min. m/z 397.28 [M+H] +. 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
Figure imgf000164_0001
To a stirred solution of 9-chloro-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 (400 mg, 1 mmol) and (4- chloro-2-fluorophenyl)boronic acid (263 mg, 1.5 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was added K3PO4 (428 mg, 2 mmol) and purged the reaction mixture with argon for 5 min. Pd118 (32.9 mg, 0.05 mmol) was then added to it under inert atmosphere. Resulting mixture was heated at 90 °C for 2 h. Reaction mixture was then passed through a short bed of celite and washed with ethyl acetate. dried over sodium sulphate, filtered, and concentrated under reduced pressure. Crude product was purified by combi flash chromatography (50-95% ethyl acetate-hexane) to get grey solid 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 (250 mg, 50.4% yield) as grey solid. LCMS Condition A: Rt = 2.01 min. m/z 491.4 [M+H] +. 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) To a degassed solution 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) was dissolved in 1,4-Dioxane (20 mL) was added sodium acetate (60 mg) and acetic acid (0.05 mL) stirred for 10 min under inert atmosphere. Pd(OH)2 on carbon (20%, 40 mg) was added and degassed again. Resulting mixture was stirred under hydrogen balloon pressure at rt for 3 h. The reaction mixture was filtered through a short pad of celite and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The crude material was purified by reverse phase prep HPLC to afford 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 (55 mg, 54.7% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.72 (s, 1H), 7.57-7.55 (m, 2H) , 7.41- 7.39 (m, 2H), 4.45-4.42 (m, 1H), 4.08-4.05 (m, 1H), 3.67-3.64 (m, 2H), 3.19-3.11 (m, 1H), 2.28 (s, 3H), 2.13-2.09 (m, 4H), 1.87-1.74 (m, 3H), 0.97-0.91 (m, 4H). LCMS Condition A: Rt = 2.20 min. m/z 493.23[M+H] +. The following table describes information regarding separation of enantiomers Example 1A/1B to 9A/9B
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Following table describes analytical data analysis and yield information of examples 1A/1B to examples 9A/9B.
Figure imgf000167_0002
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
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)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2- a]pyrimidin-4-one (example 10A) 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 (example 10B)
Figure imgf000172_0001
To a stirred solution of 7-bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H- pyrazino[1,2-a]pyrimidin-4-one [I-7] (180 mg, 0.47 mmol), 4-((2R,6R)-4-iodo-6- methyltetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole [I-13] (239.4 mg, 0.8 mmol) in DMA (6 mL) were added TBAI (257 mg ,0.7 mmol), Zinc (60 mg, 0.9 mmol). The 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. The crude material was purified by combi flash chromatography (40% ethyl acetate in hexane) followed by diastereomer separation by reverse phase prep HPLC (Prep-A method) to afford 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 [example 10A] (4.2 mg, 2% yield) 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 [example 10B] (13.2 mg, 6% yield) both as off white solid. Stereochemistry of both peaks were assigned arbitrarily. Example 10A: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.80-7.74 (m, 1H), 7.58 (s, 1H), 7.47-7.42 (m, 1H), 7.31-7.26 (m, 2H), 4.65 (d, J=10.8 Hz, 1H), 3.93-3.89 (m, 1H), 3.77 (s.3H), 3.59-3.58 (m, 1H), 2.47 (s, 3H), 2.37-2.32 (m, 1H), 2.23-2.20 (m, 1H), 2.07- 2.06 (m, 1H), 1.78-1.72 (m, 1H), 1.12-1.11 (m, 3H). Condition C: Rt = 2.97 min. m/z 486.33 [M+H]+ Example 10B: 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.74-7.73 (m, 1H), 7.64 (s, 1H), 7.39-7.43 (m, 1H), 7.37 (s, 1H), 7.31-7.26 (m, 1H), 4.52 (d, J=10.0 Hz, 1H), 3.77 (s. 3H), 3.76-3.75 (m, 1H), 3.35-3.34 (m, 1H), 2.47 (s, 3H), 2.07-2.06 (m, 1H), 1.98-1.97 (m, 1H), 1.77-1.75 (m, 1H), 1.50-1.49 (m, 1H), 1.23-1.22 (m, 3H). Condition C: Rt = 2.99 min. m/z 486.33 [M+H]+ 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
Figure imgf000173_0001
The following table describes analytical data analysis and yield information of examples 11A and 11B.
Figure imgf000173_0002
Figure imgf000174_0003
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:
Figure imgf000174_0001
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. 1H NMR (400 MHz, DMSO D6) δ 8.72 (m, 2 H) Step-2 - Preparation of 4-(5-bromo-6-nitropyridin-3-yl)-2-(1-methyl-1H-pyrazol-4- yl)morpholine:
Figure imgf000174_0002
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. Resulting mixture was stirred at RT for 3h. Reaction mixture was poured slowly into ice cold water, extracted with ethyl acetate. Combined organic layer was washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. Crude product was purified by combi flash chromatography (80-90% ethyl acetate-hexane) to get 4-(5-bromo-6-nitropyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (140 mg, 84.1% yield) as yellow solid. LCMS Condition B: Rt = 1.86 min. m/z 368.3 [M+H] +. Step-3 - Preparation of 3-bromo-5-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)pyridin-2-amine:
Figure imgf000175_0001
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 SnCl2.2H2O (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. Combined organic layer was washed with brine, dried over sodium sulphate, filtered and evaporated under reduced pressure. Crude product was purified by combi flash chromatography (5% methanol-DCM) to get 3-bromo-5-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyridin-2-amine (100 mg, 65.4% yield) as brown solid. LCMS Condition A: Rt = 1.56 min. m/z 338.3 [M+H] +. 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:
Figure imgf000175_0002
In a sealed tube, 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) and BiCl3 (6.5 mg, 0.02 mmol) were mixed. The resulting mixture was heated at 130 °C for 16 h. Reaction mixture was then diluted with DCM, washed with NaHCO3 solution, brine, dried over sodium sulphate, filtered, and evaporated under reduced pressure. Crude product was purified by combi flash chromatography (5% methanol-DCM) to get 9-bromo-2,3- dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidin-4-one (40 mg, 46.2% yield) as yellow solid.. LCMS Condition A: Rt = 1.89 min. m/z 418.3 [M+H] +. 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]:
Figure imgf000176_0001
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. PdCl2(dppf) (27.9 mg, 0.04 mmol) was added under inert atmosphere. The resulting mixture was heated at 60 °C for 3 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. Crude mass was purified by reverse phase prep HPLC (prep-A method) to afford 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 (38 mg, 21.3% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.72 (s, 1H), 7.57 – 7.53 (m, 2H), 7.45 (s, 1H), 7.42 – 7.39 (m, 1H), 4.63– 4.61 (m, 1H), 4.05– 4.03 (m, 1H), 3.85 – 3.79 (m, 5H), 3.59 – 3.56 (m, 1H), 2.89 – 2.84 (m, 1H), 2.79 – 2.67 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H). LCMS Condition C: Rt = 2.84 min. m/z 468.2 [M+H] +. Examples 13 and 14 Examples 13 and 14 were synthesized using similar procedure described for Example 12.
Figure imgf000176_0002
Figure imgf000177_0001
The following table describes analytical data analysis and yield information of examples 13 and 14.
Figure imgf000177_0002
Chiral separation details of Example 12A-12B to 13A-13B are captured in following table:
Figure imgf000178_0001
Following table describes analytical data analysis and yield information of examples 12A/12B and 13A/13B
Figure imgf000178_0002
Figure imgf000179_0001
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:
Figure imgf000180_0001
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. PdCl2(dppf)(350.7 mg, 0.5 mmol) was added under inert atmosphere. The resulting mixture was heated at 60 °C for 3 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. Crude mass was purified by combi flash chromatography (45% ethyl acetate in hexane) to afford 5-chloro-3-(4-chloro-2- fluorophenyl)pyrazin-2-amine (691 mg, 56.2% yield) as yellow solid. LCMS Condition A: Rt = 2.07 min. m/z 302.3 [M+H] +. Step-2 - Preparation of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H- pyrazino[1,2-a]pyrimidin-4-one
Figure imgf000180_0002
To a stirred mixture of 3-bromo-5-chloropyrazin-2-amine (247.9 mg, 0.9 mmol) and methyl 2-methyl-3-oxobutanoate (250 mg, 1.9 mmol) was added BiCl3 (30.2 mg, 1.9 mmol). Resulting mixture was heated at 170 °C for 6 h. The reaction mixture was quenched with ice cold sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated. Crude mass was purified by combi flash chromatography using 10% - 20% ethyl acetate in hexane on silica gel to afford 7-chloro- 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidin-4-one (70 mg, 20.7% yield) as brown solid. LCMS Condition C: Rt = 2.44 min. m/z 338.3 [M+H] +. 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]:
Figure imgf000181_0001
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. To it was added 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H- pyrazino[1,2-a]pyrimidin-4-one (150 mg, 0.4 mmol) at rt. Resulting mixture was heated at 110 °C for 16 h. Reaction mixture was concentrated under reduced pressure. Crude mass was purified by reverse phase preparative HPLC (Prep-A method) to afford 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one (10 mg, 4.9% yield) as yellow solid. 1H NMR (400 MHz, DMSO D6) δ 8.01 (s, 1H), 7.75 (s, 1H), 7.73-7.69 (m, 1H), 7.63-7.61 (m, 1H), 7.46-7.44 (m, 2H), 4.63-4.61 (m, 1H), 4.06-4.03 (m, 2H), 3.81-3.74 (m, 4H), 2.99-2.89 (m, 3H), 2.32 (s, 3H), 2.17 (s, 3H). LCMS Condition C: Rt = 2.91 min. m/z 469.3 [M+H] +. Example 16 (S)-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 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin- 4-one:
Figure imgf000181_0002
To a stirred mixture of 3-bromo-5-chloropyrazin-2-amine (500 mg, 2.39 mmol) and methyl 2-methyl-3-oxobutanoate (624 mg, 4.8 mmol) was added BiCl3 (75 mg, 0.24 mmol). Resulting mixture was heated at 130 °C for 16 h. The reaction mixture was quenched with ice cold sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulphate and concentrated. Crude mass was purified by combi flash chromatography using 30% - 40% ethyl acetate in hexane on silica gel to afford 7-bromo- 9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (250 mg, 36.2% yield) as yellow gummy mass. LCMS Condition C: Rt = 1.98 min. m/z 288.1 [M+H]+. Step-2 - Preparation of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one:
Figure imgf000182_0001
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). The resulting mixture was degassed with argon and Pd(dppf)Cl2 (25 mg, 0.04 mmol) was added. The resulting mixture was heated at 60 °C for 2 h. After completion, reaction mixture was passed through a pad of celite and washed with ethyl acetate and concentrated. Crude product was purified by combi flash chromatography using 10% - 20% ethyl acetate in hexane on silica gel to afford 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3- dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (50 mg, 37.2% yield) as yellow gummy mass. LCMS Condition C: Rt = 2.29 min. m/z 382.0 [M+H]+. Step-3 - Preparation of (S)-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-16)
Figure imgf000182_0002
To a stirred solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one ( 100 mg 0.3 mmol) in toluene ( 10 mL) were added (S)-2-(1-methyl- 1H-pyrazol-4-yl)morpholine [I-3](35 mg, 0.21 mmol), sodium tert-butoxide (75 mg 0.8 mmol) and Ru-Phos ( 6 mg, 0.01 mmol). The resulting mixture was degassed with argon and Ru-Phos-Pd-G3 (11 mg, 0.06 mmol) was added. The resulting mixture was heated at 80 °C for 1 h. After completion, reaction mixture was passed through celite bed and washed with DCM and concentrated. Crude product was purified by reverse phase preparative HPLC (Prep-B method) to afford (S)-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 (17 mg, 14.2% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.75 (s, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.62- 7.59 ( dd, J=9.6 Hz, J= 1.6 Hz, 1H), 7.46 (s, 1H), 7.44 (d, J=2.0 Hz, 1H), 4.63-4.60 ( dd, J=10.4 Hz, J= 2.4 Hz, 1H), 4.03 (d, J=12.0 Hz, 2H), 3.86 (d, J=12.0 Hz, 1H), 3.80 (s, 3H), 3.76-3.74 (m, 1H), 3.01-2.89 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H). LCMS Condition K: Rt = 2.90 min. m/z 469.3 [M+H]+. Example 17 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 Step-1 - Preparation of 6-amino-4-bromopyridin-2(1H)-one:
Figure imgf000183_0001
To a stirred solution of 4-bromopyridine-2,6-diamine (2 g, 10.6 mmol) in 50 % aqueous sulphuric acid (20 mL) was heated at 100 °C for 5 h. Reaction mixture was quenched with crushed ice and neutralized with sodium bicarbonate. The solid was precipitated out, filtered, washed with water, and dried to have 6-amino-4-bromopyridin-2(1H)-one (1.7 g, 84.1% yield) as brown solid. LCMS Condition C: Rt = 0.78 min. m/z 189.1 [M+H]+. Step-2 - Preparation of 8-bromo-6-hydroxy-2,3-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one:
Figure imgf000183_0002
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. Crude mass was purified by combi flash chromatography using 30% - 50% DCM in ethyl acetate on silica gel to afford 8-bromo- 6-hydroxy-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one (250 mg, 70% yield) as yellow gummy mass. LCMS Condition C: Rt = 1.55 min. m/z 269.1[M+H]+. Step-3 - Preparation of 6,8-dichloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one:
Figure imgf000184_0001
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. Crude reaction mixture was evaporated to dryness and purified by combi flash chromatography using 10% - 30% ethyl acetate in hexane on silica gel to afford 6,8-dichloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4- one (200 mg, 63.2% yield) as brown solid. LCMS Condition C: Rt = 2.00 min. m/z 243.2 [M+H]+. Step-4 - Preparation of 8-chloro-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H- pyrido[1,2-a]pyrimidin-4-one:
Figure imgf000184_0002
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), Na2CO3 (87 mg, 0.82 mmol). The resulting mixture was degassed with argon and Pd(dppf)Cl2 (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. The crude reaction mixture was extracted with ethyl acetate, dried over sodium sulphate, concentrated and purified bycombi flash chromatography using 20% - 30% ethyl acetate in hexane on silica gel to afford 8-chloro-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2- a]pyrimidin-4-one (40 mg, 28.7% yield) as brown solid. [structure was confirmed by 2D NMR]. LCMS Condition C: Rt = 2.35 min. m/z 337.2 [M+H]+. 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):
Figure imgf000184_0003
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 ). The resulting mixture was degassed with argon and Ru-Phos-Pd-G3 (10 mg, 0.01 mmol) was added. The resulting mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was passed through celite bed and washed with DCM and concentrated. Crude product was purified by reverse phase preparative HPLC to afford 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 (8 mg, 7% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (s, 1H), 7.50-7.46 (m, 2H), 7.37-7.30 (m, 2H), 7.02 (s, 1H), 6.70 (d, J= 1.6 Hz, 1H), 4.51 (d, J=10.0 Hz, 1H), 4.14 (brs, 1H), 3.99-3.91 (m, 2H), 3.80 (s, 3H), 3.69 (t, J= 11.6 Hz, 1H), 3.08 (m, 1H), 2.99-2.94 (m, 1H), 2.26 (s, 3H), 1.87 (s, 3H). LCMS Condition K: Rt = 2.38 min. m/z 468.3 [M+H]+. Examples 18 to 31 Examples 18-31were synthesized by using similar procedures described for Example 1 in two steps.
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
The following table describes analytical data analysis and yield information of examples 18-29.
Figure imgf000187_0002
Figure imgf000188_0001
Figure imgf000189_0001
The following table describes information regarding separation of enantiomers Example 18A/18B to 29A/29B
Figure imgf000189_0002
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Following table describes analytical data analysis and yield information of examples 18A/18B to examples 29A/29B:
Figure imgf000195_0002
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
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. 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. All the stock solutions were prepared at 20 mM in 100% DMSO. For compounds testing, the starting concentration was 100 pM, dilution steps 1 :6. A different concentration’s range was adapted for compound’s activity based on the preliminary results. Finally, a 384MPT reformatted for all compounds at 8 concentrations, quadruplicates, was used as “mother to child” process with a CyBi®-Well dispenser in which 1 pL of each compound was moved into a destination plate pre-filled with 65.6 pL of EMEM cell culture medium (BIOWHITTAKER_cat.BE12-125F), thus obtaining 3x concentrated compounds working solution. In columns 1-2 and 23-24 the control wells were added. In particular, 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. Cells were then diluted in HEK293 Culture Medium without antibiotics, counted and seeded into 384- well poly-D-Lysine coated microplates black/clear bottom (GREINER 781946) at a density of 10,000 cells/well in 25 pL/well by the use of a MATRIX WellMate dispenser. Plates were placed into a humidified cell culture incubator at 37°C with 5% CO2 until the experimental day. 20-24 hours after seeding mature medium was removed and replaced with 10 pL/well of EMEM cell medium supplemented with 0.1% Pluronic F-68 non-ionic surfactant (Thermofisher, 24040032), referred to as “Assay Buffer”, using the CyBi®-Well instrument. Then 5 pL/well of Assay Buffer containing 3X concentrated test compounds or the reference control agonist (in 0.5 % final DMSO concentration) were added to the cells with the CyBi®-Well instrument. Cell plates were incubated for 30 min into a humidified cell culture incubator at 37°C with 5% CO2., then the medium was removed by manually discard. 20 pL/well of lysis buffer were dispensed using the CyBi®-Well instrument and plates were incubated for 10 min at room temperature on a plate shaker (350rpm). Then, 10 pL/well of lysate were transferred to the Alpha plates. 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. At the end of the incubation 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.
Data analysis was performed with Genedata Screener® software and reported compounds activity as % effect in relation to the normalization standards. The AlphaScreen Signal was normalized versus Neutral Controls (Assay buffer plus 0.5% DMSO final cone.) and Stimulator Controls (ECwoof the reference control agonist in Assay buffer plus 0.5% DMSO final cone.) in order to obtain the Activity[%] for each well. The normalization places the compound activity values on an equivalent scale and makes them comparable across plates or different compound batches. Therefore, the compound activity values were scaled (based on the two references) to a common range (two-point normalization). The following equation was used by the software to normalize the signal values to the desired signal range:
N(x) = CR + [((x - < cr >)/ (< sr > - < cr >)) ■ (SR - CR)] where: 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) and SR is the desired median normalized value for the Scale Reference (100).
The final equation to calculate the Activity% can be simplified as follow: % Activity = 100 ■ (x - <NeutralControls>) I (<StimulatorControls> - <NeutralControls>) where full activation corresponds to % Activity = 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.
Y = So + ((Sinf -So) / (1 + (10L°9AC5° 1 10x)n)) where X is Log10 of compound concentration.
The equation has four parameters:
• Zero Activity (SO) - Activity level at zero concentration of test compound;
• Infinite Activity (Sinf) - Activity level at infinite concentration of test compound;
• ACso - Concentration at which activity reaches 50% of maximum level. This term corresponds to ECso in this assay;
• Hill coefficient (n) - Measure of the slope at ACso.
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:
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
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. Regarding Emax values, “+” denotes < 75% , “++” denotes 75-110% and “+++” denotes >110% maximal response relative to the maximal response of the reference agonist (8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6- [(2S)-2-(1-methyl-1 H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-[1,3]diazino[5,4-d]pyrimidin-4- one).
Examples 33 to 71
The following additional examples were made using similar methods to those described for previous examples, and were assessed in the biological assay described in Example 32.
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
References Colonna, M. et al. (2016) Nat Rev Neurosci 17, 201-207
Deczkowska, A. et al. (2020) Perspective, 181, 6, 1207-1217
Hammond, T. R. (2019) Immunity, 50, 4 5955-974
Suarez-Calvet, M. et al. (2016) EMBO Mol Med, 8, 466-476
Yamazaki, K. et al. (2015) Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 13(3), 324-326 Paloneva BM, J. et al. (2001) Neurology, 56 (11) 1552-1558;
Ulrich J. D. et al. (2017) Neuron., 19;94(2):237-248)
Atagi, Y. et al. (2015) J Biol Chem., 290(43), 26043-50
Kleinberger, G. et al (2014) Sci Transl Med., 2, 6 (243):243

Claims

Claims 1. A compound of Formula IA or Formula IB:
Figure imgf000220_0001
Formula IA wherein XA is N or C(R5); 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 R6; 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 R9; 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, 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-membered heteroaryl is 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, wherein one methylene group of the C3-6 cycloalkyl is optionally replaced with –O- or -N(R10)-; R10 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; and wherein the azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexan- 3-yl, piperidine-1-yl, or -OCH2-(C3-6 cycloalkyl) is 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 C1-3 haloalkoxy; R6 is individually selected from the group consisting of –O-C1-6 alkyl, C3-6 cycloalkyl and halogen; R9 is selected from the group consisting of –O-C1-6 alkyl,C3-6 cycloalkyl, C1-6 haloalkyl and phenyl, wherein the phenyl is optionally substituted with 1 to 5 substituents individually selected from –O-C1-6 alkyl; R4 is of Formula II:
Figure imgf000221_0001
Formula II wherein XB is N or C(R11); R11 is selected from the group consisting of H, C1-3 alkyl, -OH, -O- C1-3 alkyl and halogen; XC is C(R12)(R13); R12 is individually H, C1-3 alkyl or a bond; wherein when R12 is a bond then R11 is C1-3 alkyl, and R11 and R12 are linked together to form a 3-5 membered ring; R13 is individually H or C1-3 alkyl; XD is C(R14) or N; R14 is H or C1-3 alkyl; R23 is a bond, -O- or C1-6 hydrocarbon chain wherein one methylene group is optionally replaced with –O-; R15 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, - O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl and -O-(6-membered heteroaryl), wherein (a) the C3-6 cycloalkyl or C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy and halogen; (b) the phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl or -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or C1-6 haloalkyl of subsection (b) are optionally substituted with –OH, and wherein the C3-6 heterocycloalkyl of subsection (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl and –C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from –N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl and –N(R25)(R26); R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen; R25 is H or C1-3 alkyl; R26 is H or C1-3 alkyl; XE is C(R16)(R17), O, NR18 or a bond; R16 is H or F; R17 is H or F; R18 is H, C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl or C1-6 haloalkyl, wherein the C1-6 alkyl, -C(O)-C1-6 alkyl or -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy; XF is C(R19)(R20); R19 is H, halogen or C1-3 alkyl; R20 is H, halogen or C1-3 alkyl; wherein when R19 and R20 are C1-3 alkyl, then R19 and R20 are optionally linked together to form a 3-6 membered ring; and/or wherein when R19 and R20 are C1-3 alkyl, then one methylene group is optionally replaced with –O- or -N(R27)-, wherein R27 is selected from the group consisting of H, C1-3 alkyl and –C(O)C1-3 alkyl; XG is individually C(R21)(R22) or C(O); R21 is individually H, C1-3 alkyl or a bond; wherein when R21 is a bond then R19 is C1-3 alkyl, n is 1, and R21 and R19 are linked together to form a 3-5 membered ring; R22 is individually H or C1-3 alkyl; m is 0, 1 or 2; and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R3 is of Formula IV:
Figure imgf000223_0001
Formula IV wherein R28 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R29 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; R30 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN; and R31 is H, halogen, C1-3 alkyl, C1-3 haloalkyl or CN, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1, wherein R3 is C3-6 cycloalkyl 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.
4. The compound according to claim 3, wherein
Figure imgf000223_0002
, or a pharmaceutically acceptable salt thereof.
5. The compound according to any one of the preceding claims, wherein XB is C(R11); XC is C(R12)(R13); XD is C(R14); XE is O; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1, or a pharmaceutically acceptable salt thereof.
6. The compound according to any one of claims 1 to 4, wherein XB is N; XC is C(R12)(R13); XD is C(R14); XE is O; XF is C(R19)(R20); XG is C(R21)(R22); m is 1; and n is 1, or a pharmaceutically acceptable salt thereof.
7. The compound according to any one of the preceding claims, wherein R15 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, or a pharmaceutically acceptable salt thereof.
8. The compound according to any one of the preceding claims, wherein R15 is selected from the group consisting of Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, and Formula XII:
Figure imgf000224_0001
wherein R37 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.
9. The compound according to any one of the preceding claims, wherein R15 is of Formula XIII:
Figure imgf000224_0002
Formula XIII wherein R37 and 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.
10. The compound according to claim 9, wherein R37 is C1-3 alkyl, such as CH3, or C3-6 cycloalkyl, such as C3 cycloalkyl, or a pharmaceutically acceptable salt thereof.
11. The compound according to any one of the claims 1 to 6, wherein R15 is
Figure imgf000225_0001
, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, wherein the compound is of Formula IA:
Figure imgf000225_0002
Formula IA wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl and H; R3 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; XA is N or C(H); R4 is of Formula XXVI:
Figure imgf000225_0003
Formula XXVI wherein XB is N or C(H); R15 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; R19 is H, halogen or C1-3 alkyl; and R20 is H, halogen or C1-3 alkyl; or a pharmaceutically acceptable salt thereof.
13. The compound according to any one of the preceding claims, wherein XA is N, or a pharmaceutically acceptable salt thereof.
14. The compound according to any one of the preceding claims, wherein XA is C(H), or a pharmaceutically acceptable salt thereof.
15. The compound according to any one of claims 1 to 4 or 7 to 14, wherein XB is N, or a pharmaceutically acceptable salt thereof.
16. The compound according to any one of claims 1 to 4 or 7 to 14, wherein XB is C(H), or a pharmaceutically acceptable salt thereof.
17. The compound according to any one of the preceding claims, wherein R1 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.
18. The compound according to any one of the preceding claims, wherein R2 is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.
19. The compound according to any one of claims 1 to 17, wherein R2 is halogen, such as Cl, or a pharmaceutically acceptable salt thereof.
20. The compound according to any one of claims 1, 2, to 5 to 19, wherein R3 is ,
Figure imgf000226_0001
pharmaceutically acceptable salt thereof.
21. The compound according to any one of claims 1 to 4, 12 to 14, or 17 to 20, wherein R4 is selected from the group consisting of:
Figure imgf000226_0002
Figure imgf000227_0001
22. The compound according to any one of claims 1 to 4, 12 to 14, or 17 to 20, wherein R4 is selected from the group consisting of: ,
Figure imgf000227_0002
Figure imgf000228_0001
pharmaceutically acceptable salt thereof. 23. The compound according to claim 1, wherein the compound is of Formula IA and wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R3 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; XA is CH; XB is N; XC is C(H)2; XD is C(H); XE is O; XF is C(H)2; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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, or a pharmaceutically acceptable salt thereof. 24. The compound according to claim 1, wherein the compound is of Formula IA and wherein R1 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R2 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl and H; R3 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; XA is N; XB is C(H); XC is C(H)2; XD is C(H); XE is O; XF is C(H)2; XG is C(H)2; m is 1; n is 1; R23 is a bond; and R15 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, or a pharmaceutically acceptable salt thereof. 25. The compound according to claim 1, wherein the compound is selected from the group consisting 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; (R)-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; (S)-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; 9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; 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; (R)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4- yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; (S)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4- yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one; (S)-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; 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; 3-chloro-9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4- (trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4- difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4- oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4- oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5- trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo- 4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo- 4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 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; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[1,2-a]pyrimidin-4-one; 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; 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; 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; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3- dimethyl-pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- methyl-pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-3- methyl-pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- methyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-3- (trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- (trifluoromethyl)pyrido[1,2-a]pyrimidin-4-one; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4- difluorophenyl)pyrazino[1,2-a]pyrimidin-4-one; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4-difluorophenyl)-2- (trifluoromethyl)pyrazino[1,2-a]pyrimidin-4-one; 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; 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; 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; 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; 7-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-9-(2,4- difluorophenyl)pyrido[1,2-a]pyrimidin-4-one; 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; 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; 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; 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; 4-[7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-oxo-2- (trifluoromethyl)pyrido[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-4-oxo-pyrido[1,2- a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 4-[7-[2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-oxo-2- (trifluoromethyl)pyrazino[1,2-a]pyrimidin-9-yl]-3-fluoro-benzonitrile; 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; 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; 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4- difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4- difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2- methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9- (2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidin-4-one; 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)-3-fluorobenzonitrile; 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 4-oxo-4H-pyrazino[1,2-a]pyrimidin-9-yl)benzonitrile; and 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-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. 26. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, such as a TREM2 activator, such as a TREM2 agonist. 27. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and/or diluents. 28. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, for use as a medicament. 29. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, for use in the treatment of 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. 30. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, for use in the treatment of a neurodegenerative disease. 31. The compound or composition for use according to claim 30, wherein said neurodegenerative disease is 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). 32. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, for use in the treatment of 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 demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke. 33. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, autism spectrum disorders, autism and Aspergers syndrome, traumatic brain injuries (TBI), spinal cord injuries, muscular dystrophy, myotonic dystrophy, inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, bowel conditions, Inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, Amyloidosis. 34. A method for treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease, said method comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, to a subject in need thereof. 35. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 27, 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. 36. 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 of claims 1 to 26.
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